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Entry
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- *607139 - FANCA GENE; FANCA
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*607139</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/607139">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000187741;t=ENST00000389301" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=2175" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607139" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000187741;t=ENST00000389301" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000135,NM_001018112,NM_001286167,NM_001351830" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000135" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607139" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=06186&isoform_id=06186_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/FANCA" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/1657312,2230888,3372554,3392904,3392906,3395416,3493167,3493328,5304881,5304883,5304885,14290430,30583571,40555780,46488016,66879666,66880553,111309146,111309382,118341692,119587089,119587090,146327552,146327807,147744560,194387772,221043486,444737803,555290155,1199277041" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/O15360" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=2175" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000187741;t=ENST00000389301" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=FANCA" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=FANCA" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+2175" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/FANCA" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:2175" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2175" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr16&hgg_gene=ENST00000389301.8&hgg_start=89737549&hgg_end=89816647&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3582" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3582" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/fanca" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607139[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607139[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/FANCA/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000187741" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=FANCA" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=FANCA" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=FANCA" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.rockefeller.edu/fanconi/mutate/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FANCA&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA27995" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:3582" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1341823" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/FANCA#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:1341823" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2175/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2175" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-060508-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
|
<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:607139" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
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</a>
|
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</span>
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</span>
|
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2175" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=FANCA&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
607139
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
|
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FANCA GENE; FANCA
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</span>
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</h3>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
FACA; FAA
|
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</span>
|
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</h4>
|
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</div>
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</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FANCA" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FANCA</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/16/754?start=-3&limit=10&highlight=754">16q24.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:89737549-89816647&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">16:89,737,549-89,816,647</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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|
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|
|
|
</span>
|
|
</p>
|
|
</div>
|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/16/754?start=-3&limit=10&highlight=754">
|
|
16q24.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Fanconi anemia, complementation group A
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/227650"> 227650 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
</tr>
|
|
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|
</tbody>
|
|
</table>
|
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</div>
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</div>
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<div>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p><a href="#34" class="mim-tip-reference" title="Soulier, J., Leblanc, T., Larghero, J., Dastot, H., Shimamura, A., Guardiola, P., Esperou, H., Ferry, C., Jubert, C., Feugeas, J.-P., Henri, A., Toubert, A., Socie, G., Baruchel, A., Sigaux, F., D'Andrea, A. D., Gluckman, E. <strong>Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway.</strong> Blood 105: 1329-1336, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15383454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15383454</a>] [<a href="https://doi.org/10.1182/blood-2004-05-1852" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15383454">Soulier et al. (2005)</a> noted that the FANCA, -C (<a href="/entry/613899">613899</a>), -E (<a href="/entry/613976">613976</a>), -F (<a href="/entry/613897">613897</a>), -G (<a href="/entry/602956">602956</a>), and -L (<a href="/entry/608111">608111</a>) proteins are part of a nuclear multiprotein core complex which triggers activating monoubiquitination of the FANCD2 (<a href="/entry/613984">613984</a>) protein during S phase of the growth cycle and after exposure to DNA crosslinking agents. The FA/BRCA pathway is involved in the repair of DNA damage. FANCM (<a href="/entry/609644">609644</a>) is also part of the FA core complex (<a href="#25" class="mim-tip-reference" title="Meetei, A. R., Medhurst, A. L., Ling, C., Xue, Y., Singh, T. R., Bier, P., Steltenpool, J., Stone, S., Dokal, I., Mathew, C. G., Hoatlin, M., Joenje, H., de Winter, J. P., Wang, W. <strong>A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.</strong> Nature Genet. 37: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16116422[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng1626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116422">Meetei et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15383454+16116422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#23" class="mim-tip-reference" title="Lo Ten Foe, J. R., Rooimans, M. A., Bosnoyan-Collins, L., Alon, N., Wijker, M., Parker, L., Lightfoot, J., Carreau, M., Callen, D. F., Savoia, A., Cheng, N. C., van Berkel, C. G. M., Strunk. M. H. P., Gille, J. J. P., Pals, G., Kruyt, F. A. E., Pronk, J. C., Arwert, F., Buchwald, M., Joenje, H. <strong>Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA.</strong> Nature Genet. 14: 320-323, 1996. Note: Erratum: Nature Genet. 14: 488 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896563</a>] [<a href="https://doi.org/10.1038/ng1196-320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896563">Lo Ten Foe et al. (1996)</a> used a cDNA expression library to complement the mitomycin C-sensitive phenotype of Fanconi anemia (see <a href="/entry/227650">227650</a>) lymphoblastoid cells. By this method they identified a cDNA clone that corrected the cross-linker hypersensitivity of FANCA cells but not of FANCC (<a href="/entry/227645">227645</a>) cells. The cDNA clone for the gene (called FAA by them) has an open reading frame of 4,368 bp and encodes a 1,455-amino acid polypeptide predicted to contain 2 overlapping bipartite nuclear localization signals and a partial leucine zipper consensus sequence, suggesting that the protein is localized in the nucleus. Northern blot analysis detected a 5.5-kb transcript in controls and in FA patients from complementation groups other than FAA. In an FAA cell line, the 5.5-kb band was virtually undetectable, suggesting reduced transcription or reduced stability of the FAA mRNA transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8896563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Through exon trapping and cDNA selection the <a href="#5" class="mim-tip-reference" title="Fanconi Anaemia/Breast Cancer Consortium. <strong>Positional cloning of the Fanconi anaemia group A gene.</strong> Nature Genet. 14: 324-328, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896564</a>] [<a href="https://doi.org/10.1038/ng1196-324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896564">Fanconi Anaemia/Breast Cancer Consortium (1996)</a> identified a candidate cDNA clone for FAA and through searches in the dbEST database they identified additional overlapping cDNA clones. Sequencing of these clones revealed a full-length FAA candidate gene that encodes a polypeptide of 1,455 amino acids. Sequence analysis revealed that the full-length cDNA isolated by positional cloning was identical to the cDNA clone isolated by complementation and reported by <a href="#23" class="mim-tip-reference" title="Lo Ten Foe, J. R., Rooimans, M. A., Bosnoyan-Collins, L., Alon, N., Wijker, M., Parker, L., Lightfoot, J., Carreau, M., Callen, D. F., Savoia, A., Cheng, N. C., van Berkel, C. G. M., Strunk. M. H. P., Gille, J. J. P., Pals, G., Kruyt, F. A. E., Pronk, J. C., Arwert, F., Buchwald, M., Joenje, H. <strong>Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA.</strong> Nature Genet. 14: 320-323, 1996. Note: Erratum: Nature Genet. 14: 488 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896563</a>] [<a href="https://doi.org/10.1038/ng1196-320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896563">Lo Ten Foe et al. (1996)</a>, except that the clone isolated by positional cloning had an additional 13 bp of 5-prime untranslated sequence and 2 amino acid substitutions (S501G and I717M). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8896564+8896563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Wong, J. C. Y., Alon, N., Norga, K., Kruyt, F. A. E., Youssoufian, H., Buchwald, M. <strong>Cloning and analysis of the mouse Fanconi anemia group A cDNA and an overlapping penta zinc finger cDNA.</strong> Genomics 67: 273-283, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10936049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10936049</a>] [<a href="https://doi.org/10.1006/geno.2000.6252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10936049">Wong et al. (2000)</a> cloned mouse Fanca. The deduced 1,439-amino acid protein shares 65% identity with human FANCA. The C-terminal partial leucine zipper and most of the N-terminal bipartite nuclear localization signal of human FANCA are conserved in mouse Fanca. Northern blot analysis detected several Fanca transcripts expressed in all adult mouse tissues examined and during all stages of embryonic development. The most abundant transcript was 1.6 kb and showed highest expression in intestine, liver, lung, and spleen. A 3.8-kb transcript was unique to brain, while a 4.5-kb transcript was expressed in all tissues except brain. In vitro transcription and translation of mouse Fanca cDNA yielded a protein with an apparent molecular mass of 161 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10936049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By genomic sequence analysis, <a href="#14" class="mim-tip-reference" title="Ianzano, L., D'Apolito, M., Centra, M., Savino, M., Levran, O., Auerbach, A. D., Cleton-Jansen, A.-M., Doggett, N. A., Pronk, J. C., Tipping, A. J., Gibson, R. A., Mathew, C. G., Whitmore, S. A., Apostolou, S., Callen, D. F., Zelante, L., Savoia, A. <strong>The genomic organization of the Fanconi anemia group A (FAA) gene.</strong> Genomics 41: 309-314, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9169126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9169126</a>] [<a href="https://doi.org/10.1006/geno.1997.4675" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9169126">Ianzano et al. (1997)</a> determined that the FANCA gene contains 43 exons and spans approximately 80 kb. The exon sizes range from 34 to 188 bp. The authors also described 3 alternative splicing events resulting in the loss of exon 37, a 23-bp deletion at the 5-prime end of exon 41, and a GCAG insertion at the 3-prime portion of exon 41. <a href="#14" class="mim-tip-reference" title="Ianzano, L., D'Apolito, M., Centra, M., Savino, M., Levran, O., Auerbach, A. D., Cleton-Jansen, A.-M., Doggett, N. A., Pronk, J. C., Tipping, A. J., Gibson, R. A., Mathew, C. G., Whitmore, S. A., Apostolou, S., Callen, D. F., Zelante, L., Savoia, A. <strong>The genomic organization of the Fanconi anemia group A (FAA) gene.</strong> Genomics 41: 309-314, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9169126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9169126</a>] [<a href="https://doi.org/10.1006/geno.1997.4675" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9169126">Ianzano et al. (1997)</a> noted that instead of TATA or CAAT boxes, the 5-prime region upstream of the putative transcription start site of FANCA has a GC-rich region, which is typical of housekeeping genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9169126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Although some studies suggested that the FA locus was on chromosome 20q (<a href="#24" class="mim-tip-reference" title="Mann, W. R., Venkatraj, V. S., Allen, R. G., Liu, Q., Olsen, D. A., Adler-Brecher, B., Mao, J.-I., Weiffenbach, B., Sherman, S. L., Auerbach, A. D. <strong>Fanconi anemia: evidence for linkage heterogeneity on chromosome 20q.</strong> Genomics 9: 329-337, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2004784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2004784</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90261-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2004784">Mann et al., 1991</a>; <a href="#35" class="mim-tip-reference" title="Steinlein, O., Fischer, C., Keil, R., Smigrodzki, R., Vogel, F. <strong>D20S19, linked to low voltage EEG, benign neonatal convulsions, and Fanconi anaemia, maps to a region of enhanced recombination and is localized between CpG islands.</strong> Hum. Molec. Genet. 1: 325-329, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303209</a>] [<a href="https://doi.org/10.1093/hmg/1.5.325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1303209">Steinlein et al., 1992</a>), <a href="#30" class="mim-tip-reference" title="Pronk, J. C., Gibson, R. A., Savoia, A., Wijker, M., Morgan, N. V., Melchionda, S., Ford, D., Temtamy, S., Ortega, J. J., Jansen, S., Havenga, C., Cohn, R. J., de Ravel, T. J., Roberts, I., Westerveld, A., Easton, D. F., Joenje, H., Mathew, C. G., Arwert, F. <strong>Localisation of the Fanconi anaemia complementation group A gene to chromosome 16q24.3.</strong> Nature Genet. 11: 338-340, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581462</a>] [<a href="https://doi.org/10.1038/ng1195-338" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7581462">Pronk et al. (1995)</a> determined that the FA1 gene (which they called FAA) is linked to microsatellite markers on 16q24.3. <a href="#30" class="mim-tip-reference" title="Pronk, J. C., Gibson, R. A., Savoia, A., Wijker, M., Morgan, N. V., Melchionda, S., Ford, D., Temtamy, S., Ortega, J. J., Jansen, S., Havenga, C., Cohn, R. J., de Ravel, T. J., Roberts, I., Westerveld, A., Easton, D. F., Joenje, H., Mathew, C. G., Arwert, F. <strong>Localisation of the Fanconi anaemia complementation group A gene to chromosome 16q24.3.</strong> Nature Genet. 11: 338-340, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581462</a>] [<a href="https://doi.org/10.1038/ng1195-338" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7581462">Pronk et al. (1995)</a> established a panel of families classified as Fanconi anemia type A by complementation analysis, and used them to search for the FAA gene by linkage analysis. <a href="#30" class="mim-tip-reference" title="Pronk, J. C., Gibson, R. A., Savoia, A., Wijker, M., Morgan, N. V., Melchionda, S., Ford, D., Temtamy, S., Ortega, J. J., Jansen, S., Havenga, C., Cohn, R. J., de Ravel, T. J., Roberts, I., Westerveld, A., Easton, D. F., Joenje, H., Mathew, C. G., Arwert, F. <strong>Localisation of the Fanconi anaemia complementation group A gene to chromosome 16q24.3.</strong> Nature Genet. 11: 338-340, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581462</a>] [<a href="https://doi.org/10.1038/ng1195-338" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7581462">Pronk et al. (1995)</a> found strong evidence of allelic association between the disease and the marker D16S303 in the Afrikaner population of South Africa, indicating founder effect, which had previously been suggested by <a href="#31" class="mim-tip-reference" title="Rosendorff, J., Bernstein, R., Macdougall, L., Jenkins, T. <strong>Fanconi anemia: another disease of unusually high prevalence in the Afrikaans population of South Africa.</strong> Am. J. Med. Genet. 27: 793-797, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3425596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3425596</a>] [<a href="https://doi.org/10.1002/ajmg.1320270408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3425596">Rosendorff et al. (1987)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1303209+7581462+2004784+3425596" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Gschwend, M., Levran, O., Kruglyak, L., Ranade, K., Verlander, P. C., Shen, S., Faure, S., Weissenbach, J., Altay, C., Lander, E. S., Auerbach, A. D., Botstein, D. <strong>A locus for Fanconi anemia on 16q determined by homozygosity mapping.</strong> Am. J. Hum. Genet. 59: 377-384, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755924</a>]" pmid="8755924">Gschwend et al. (1996)</a> used homozygosity mapping in the study of 23 inbred families with Fanconi anemia and identified linkage to a locus near marker D16S520 at 16q24.3. Although approximately 65% of the families displayed clear linkage to D16S250, the authors found strong evidence of genetic heterogeneity. Family ascertainment was biased against the previously identified FAC gene on chromosome 9, and no linkage was observed to that locus. Simultaneous search analysis suggested to <a href="#13" class="mim-tip-reference" title="Gschwend, M., Levran, O., Kruglyak, L., Ranade, K., Verlander, P. C., Shen, S., Faure, S., Weissenbach, J., Altay, C., Lander, E. S., Auerbach, A. D., Botstein, D. <strong>A locus for Fanconi anemia on 16q determined by homozygosity mapping.</strong> Am. J. Hum. Genet. 59: 377-384, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755924</a>]" pmid="8755924">Gschwend et al. (1996)</a> several additional chromosomal regions that could account for a small fraction of Fanconi anemia in the families studied, but the sample size was insufficient to provide statistical significance. They also demonstrated the strong effect of marker allele frequencies on lod scores obtained in homozygosity mapping and discussed ways to avoid false positives arising from this effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8755924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Based on linkage analysis and allelic association in Afrikaner FA families the <a href="#5" class="mim-tip-reference" title="Fanconi Anaemia/Breast Cancer Consortium. <strong>Positional cloning of the Fanconi anaemia group A gene.</strong> Nature Genet. 14: 324-328, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896564</a>] [<a href="https://doi.org/10.1038/ng1196-324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896564">Fanconi Anaemia/Breast Cancer Consortium (1996)</a> refined the map interval for FAA to the region D16S3026-D16S303 (maximum lod = 3.15 at theta = 0.00 for D16S303). They used a positional cloning strategy to isolate a candidate cDNA for the FAA gene. <a href="#23" class="mim-tip-reference" title="Lo Ten Foe, J. R., Rooimans, M. A., Bosnoyan-Collins, L., Alon, N., Wijker, M., Parker, L., Lightfoot, J., Carreau, M., Callen, D. F., Savoia, A., Cheng, N. C., van Berkel, C. G. M., Strunk. M. H. P., Gille, J. J. P., Pals, G., Kruyt, F. A. E., Pronk, J. C., Arwert, F., Buchwald, M., Joenje, H. <strong>Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA.</strong> Nature Genet. 14: 320-323, 1996. Note: Erratum: Nature Genet. 14: 488 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896563</a>] [<a href="https://doi.org/10.1038/ng1196-320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896563">Lo Ten Foe et al. (1996)</a> stated that the cDNA identified by them mapped to the telomere of chromosome 16q by fluorescence in situ hybridization (FISH). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8896564+8896563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Savoia, A., Piemontese, M. R., Savino, M., Zatterale, A., Pronk, J., Arwert, F., Joenje, H., Ramenghi, U., Dagna-Bricarelli, F., Dallapiccola, B., Zelante, L. <strong>Linkage analysis of Fanconi anaemia in Italy and mapping of the complementation group A gene.</strong> Hum. Genet. 99: 93-97, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9003502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9003502</a>] [<a href="https://doi.org/10.1007/s004390050318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9003502">Savoia et al. (1997)</a> performed linkage analysis in 11 FA-A and 16 unclassified FA Italian families using microsatellite markers. All the families were consistent with linkage at 16q24, the largest lod score being observed with D16S1320. In 2 genetic isolates common haplotypes were observed. Autozygosity mapping and haplotype analysis suggested that FAA is located distal to D16S305. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9003502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By radiation hybrid analysis and FISH, <a href="#42" class="mim-tip-reference" title="Wong, J. C. Y., Alon, N., Norga, K., Kruyt, F. A. E., Youssoufian, H., Buchwald, M. <strong>Cloning and analysis of the mouse Fanconi anemia group A cDNA and an overlapping penta zinc finger cDNA.</strong> Genomics 67: 273-283, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10936049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10936049</a>] [<a href="https://doi.org/10.1006/geno.2000.6252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10936049">Wong et al. (2000)</a> mapped the mouse Fanca gene to distal chromosome 8 in a region that shows homology of synteny to human chromosome 16q. The last 4 exons of Fanca overlap the 3-prime UTR of the Zfp276 gene (<a href="/entry/608460">608460</a>) in a tail-to-tail manner. <a href="#42" class="mim-tip-reference" title="Wong, J. C. Y., Alon, N., Norga, K., Kruyt, F. A. E., Youssoufian, H., Buchwald, M. <strong>Cloning and analysis of the mouse Fanconi anemia group A cDNA and an overlapping penta zinc finger cDNA.</strong> Genomics 67: 273-283, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10936049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10936049</a>] [<a href="https://doi.org/10.1006/geno.2000.6252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10936049">Wong et al. (2000)</a> determined that the human FANCA gene also overlaps the ZFP276 gene in a tail-to-tail manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10936049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Goldammer, T., Kata, S. R., Brunner, R. M., Dorroch, U., Sanftleben, H., Schwerin, M., Womack, J. E. <strong>A comparative radiation hybrid map of bovine chromosome 18 and homologous chromosomes in human and mice.</strong> Proc. Nat. Acad. Sci. 99: 2106-2111, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854506</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11854506[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.042688699" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854506">Goldammer et al. (2002)</a> constructed a comprehensive, high-resolution comparative map of bovine chromosome 18. Conserved synteny between cattle, human, and mouse was found for 76 genes of bovine chromosome 18 and human chromosomes 16 and 19, and for 34 genes of bovine chromosome 18 and mouse chromosomes 7 and 8. The authors found that the FANCA gene is in a gene cluster near the telomere of human 16q and near the centromere of bovine 18. Other genes in this syntenic cluster included APRT (<a href="/entry/102600">102600</a>), SPG7 (<a href="/entry/602783">602783</a>), GALNS (<a href="/entry/612222">612222</a>), and CDK10 (<a href="/entry/603464">603464</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11854506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The fact that there are several FA complementation groups displaying similar phenotypes suggested that FA genes are functionally related. The FA genes FAA and FAC (<a href="/entry/227645">227645</a>) encode proteins that are unrelated to each other or to other proteins in the databases. <a href="#19" class="mim-tip-reference" title="Kupfer, G. M., Naf, D., Suliman, A., Pulsipher, M., D'Andrea, A. D. <strong>The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex.</strong> Nature Genet. 17: 487-490, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398857</a>] [<a href="https://doi.org/10.1038/ng1297-487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398857">Kupfer et al. (1997)</a> demonstrated that FAA and FAC bind each other and form a complex. Protein binding correlated with the functional activity of FAA and FAC, as patient-derived mutant FAC, leu554 to pro (<a href="/entry/227645#0001">227645.0001</a>), failed to bind FAA. Although unbound FAA and FAC localized predominantly to the cytoplasm, the FAA-FAC complex was found in similar abundance in both cytoplasm and nucleus. The results confirmed the interrelatedness of the FA genes in a pathway and suggested the cooperation of FAA and FAC in a nuclear function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9398857" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Garcia-Higuera, I., Kuang, Y., Naf, D., Wasik, J., D'Andrea, A. D. <strong>Fanconi anemia proteins FANCA, FANCC, and FANCG/XRCC9 interact in a functional nuclear complex.</strong> Molec. Cell. Biol. 19: 4866-4873, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10373536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10373536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10373536[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.19.7.4866" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10373536">Garcia-Higuera et al. (1999)</a> determined that FANCG is required for binding between FANCA and FANCC and that all 3 proteins are components of a nuclear protein complex. The N-terminal nuclear localization signal of FANCA was required for FANCG binding, FANCC binding, and for complementation of mitomycin C sensitivity in FAA lymphocytes, as well as for nuclear localization. Analysis of the protein interactions formed by lymphoblasts from each of the complementation groups suggested that the interaction between FANCA and FANCG is constitutive and is not regulated by FANCC or by the products of other FA genes. In contrast, the binding of FANCC required FANCA/FANCG binding and the products of other FA genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10373536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Otsuki, T., Kajigaya, S., Ozawa, K., Liu, J. M. <strong>SNX5, a new member of the sorting nexin family, binds to the Fanconi anemia complementation group A protein.</strong> Biochem. Biophys. Res. Commun. 265: 630-635, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10600472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10600472</a>] [<a href="https://doi.org/10.1006/bbrc.1999.1731" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10600472">Otsuki et al. (1999)</a> identified a sorting nexin protein, SNX5 (<a href="/entry/605937">605937</a>), as a FANCA-binding protein. They found that overexpression of SNX5 increased FANCA protein levels and suggested that FANCA may affect SNX5 traffic with cell surface receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10600472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Otsuki, T., Furukawa, Y., Ikeda, K., Endo, H., Yamashita, T., Shinohara, A., Iwamatsu, A., Ozawa, K., Liu, J. M. <strong>Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex.</strong> Hum. Molec. Genet. 10: 2651-2660, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11726552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11726552</a>] [<a href="https://doi.org/10.1093/hmg/10.23.2651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11726552">Otsuki et al. (2001)</a> used yeast 2-hybrid analysis and immunofluorescence to identify an interaction between FANCA and the brm-related gene-1 (BRG1; <a href="/entry/603254">603254</a>) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity. The authors suggested that FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11726552" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By in situ hybridization studies of the murine Fancc gene, <a href="#17" class="mim-tip-reference" title="Krasnoshtein, F., Buchwald, M. <strong>Developmental expression of the Fac gene correlates with congenital defects in Fanconi anemia patients.</strong> Hum. Molec. Genet. 5: 85-93, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8789444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8789444</a>] [<a href="https://doi.org/10.1093/hmg/5.1.85" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8789444">Krasnoshtein and Buchwald (1996)</a> found that Fancc is expressed initially (embryonic days 8 to 10) in the mesenchyme and its derivatives with osteogenic potential, and at later stages (embryonic days 13 to 19.5) in other cells involved in bone development. Fancc expression was also observed in the brain, whisker follicles, lung, kidney, gut, and stomach. <a href="#1" class="mim-tip-reference" title="Abu-Issa, R., Eichele, G., Youssoufian, H. <strong>Expression of the Fanconi anemia group A gene (Fanca) during mouse embryogenesis.</strong> Blood 94: 818-824, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10397750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10397750</a>]" pmid="10397750">Abu-Issa et al. (1999)</a> reasoned that a comparison of the expression patterns of Fancc and Fanca might clarify the functional relationship between these 2 subgroups and show tissue targets that are differentially sensitive to FA mutations. By in situ hybridization, they found Fanca transcripts in the whisker follicles, teeth, brain, retina, kidney, liver, and limbs. There was also a stage-specific variation in Fanca expression, particularly within the developing whiskers and the brain. Some tissues known to express Fancc (e.g., gut) failed to show Fanca expression. These observations showed that (1) Fanca is under both tissue- and stage-specific regulation in several tissues; (2) the expression pattern of Fanca is consistent with the phenotype of the human disease; and (3) Fanca expression is not necessarily coupled to that of Fancc. The presence of distinct tissue targets for FA genes suggested that some of the variability in the clinical phenotype can be attributed to the complementation group assignment. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8789444+10397750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Wong, J. C. Y., Alon, N., Norga, K., Kruyt, F. A. E., Youssoufian, H., Buchwald, M. <strong>Cloning and analysis of the mouse Fanconi anemia group A cDNA and an overlapping penta zinc finger cDNA.</strong> Genomics 67: 273-283, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10936049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10936049</a>] [<a href="https://doi.org/10.1006/geno.2000.6252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10936049">Wong et al. (2000)</a> determined that mouse Fanca could restore the drug sensitivity of human FAA lymphoblasts to mitomycin C. It did not alter the drug sensitivity of a wildtype human lymphoblast cell line. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10936049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Donahue, S. L., Campbell, C. <strong>A DNA double strand break repair defect in Fanconi anemia fibroblasts.</strong> J. Biol. Chem. 277: 46243-46247, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12361951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12361951</a>] [<a href="https://doi.org/10.1074/jbc.M207937200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12361951">Donahue and Campbell (2002)</a> found that fibroblasts from FA patients from complementation groups A, C, D2, and G were hypersensitive to restriction enzyme-induced cell death following electroporation of restriction enzymes. These fibroblasts also showed reduced efficiency in plasmid end-joining activity. Normal sensitivity and activity were restored following retrovirus-mediated expression of the respective FA cDNAs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12361951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Folias, A., Matkovic, M., Bruun, D,, Reid, S., Hejna, J., Grompe, M., D'Andrea, A., Moses, R. <strong>BRCA1 interacts directly with the Fanconi anemia protein FANCA.</strong> Hum. Molec. Genet. 11: 2591-2597, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12354784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12354784</a>] [<a href="https://doi.org/10.1093/hmg/11.21.2591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12354784">Folias et al. (2002)</a> used yeast 2-hybrid analysis and coimmunoprecipitation methods to demonstrate a direct interaction between the FANCA and BRCA1 proteins. Direct interaction with other FANC proteins was not demonstrable. The amino terminal portion of FANCA and the central part (amino acids 740-1,083) of BRCA1 contained the sites of interaction. The interaction did not depend on DNA damage, suggesting that FANCA and BRCA1 may be constitutively interacting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12354784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By coimmunoprecipitation of HeLa cell nuclear extracts, <a href="#26" class="mim-tip-reference" title="Meetei, A. R., Sechi, S., Wallisch, M., Yang, D., Young, M. K., Joenje, H., Hoatlin, M. E., Wang, W. <strong>A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.</strong> Molec. Cell. Biol. 23: 3417-3426, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12724401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12724401</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12724401[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.23.10.3417-3426.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12724401">Meetei et al. (2003)</a> identified 3 distinct multiprotein complexes associated with BLM (RECQL3; <a href="/entry/604610">604610</a>). One of the complexes, designated BRAFT, contained the Fanconi anemia core complementation group proteins FANCA, FANCG, FANCC, FANCE, and FANCF, as well as topoisomerase III-alpha (TOP3A; <a href="/entry/601243">601243</a>) and replication protein A (RPA; see <a href="/entry/179835">179835</a>). BLM complexes isolated from an FA cell line had a lower molecular mass, likely due to loss of FANCA and other FA components. BLM- and FANCA-associated complexes had DNA unwinding activity, and BLM was required for this activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12724401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Zhang, X., Li, J., Sejas, D. P., Rathbun, K. R., Bagby, G. C., Pang, Q. <strong>The Fanconi anemia proteins functionally interact with the protein kinase regulated by RNA (PKR).</strong> J. Biol. Chem. 279: 43910-43919, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15299030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15299030</a>] [<a href="https://doi.org/10.1074/jbc.M403884200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15299030">Zhang et al. (2004)</a> used immunoprecipitation and reconstituted kinase assays to show that the FANCC, FANCA, and FANCG proteins functionally interacted with and inhibited the proapoptotic kinase PKR (<a href="/entry/176871">176871</a>), a kinase that represses translation when activated. PKR showed strongest binding to the FANCC protein. PKR activity was increased in bone marrow cells of patients with Fanconi anemia with mutations in the FANCC, FANCA, and FANCG genes. All 3 of these cell lines showed significant increases in PKR bound to the FANCC protein, which correlated with increased PKR activation. The cells also showed hypersensitivity to growth repression mediated by IFN-gamma (<a href="/entry/147570">147570</a>) and TNF-alpha (<a href="/entry/191160">191160</a>). Forced expression of a patient-derived FANCC mutation increased PKR activation and cell death. <a href="#44" class="mim-tip-reference" title="Zhang, X., Li, J., Sejas, D. P., Rathbun, K. R., Bagby, G. C., Pang, Q. <strong>The Fanconi anemia proteins functionally interact with the protein kinase regulated by RNA (PKR).</strong> J. Biol. Chem. 279: 43910-43919, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15299030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15299030</a>] [<a href="https://doi.org/10.1074/jbc.M403884200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15299030">Zhang et al. (2004)</a> concluded that FA mutations cause increased binding of PKR to FANCC and increased PKR activation, leading to growth inhibition of hematopoietic progenitors and bone marrow failure in Fanconi anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15299030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Ferrer, M., Rodriguez, J. A., Spierings, E. A., de Winter, J. P., Giaccone, G., Kruyt, F. A. E. <strong>Identification of multiple nuclear export sequences in Fanconi anemia group A protein that contribute to CRM1-dependent nuclear export.</strong> Hum. Molec. Genet. 14: 1271-1281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15790592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15790592</a>] [<a href="https://doi.org/10.1093/hmg/ddi138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15790592">Ferrer et al. (2005)</a> investigated the possibility that FANCA, FANCC, and FANCG may be subjected to active export out of the nucleus. After treatment with leptomycin B, a specific inhibitor of CRM1 (XPO1; <a href="/entry/602559">602559</a>)-mediated nuclear export, the accumulation of epitope-tagged FANCA in the nucleus increased, whereas FANCC was affected to a lesser extent, and FANCG showed no response. CRM1-mediated export of FANCA was further confirmed using CRM1 cotransfection, which led to a dramatic relocalization of FANCA to the cytoplasm. Five functional leucine-rich nuclear export sequences distributed throughout the FANCA sequence were identified and characterized using an in vivo export assay. <a href="#6" class="mim-tip-reference" title="Ferrer, M., Rodriguez, J. A., Spierings, E. A., de Winter, J. P., Giaccone, G., Kruyt, F. A. E. <strong>Identification of multiple nuclear export sequences in Fanconi anemia group A protein that contribute to CRM1-dependent nuclear export.</strong> Hum. Molec. Genet. 14: 1271-1281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15790592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15790592</a>] [<a href="https://doi.org/10.1093/hmg/ddi138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15790592">Ferrer et al. (2005)</a> concluded that FANCA can be actively exported out of the nucleus by CRM1, revealing a novel mechanism to regulate the function of the FA protein complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15790592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid and coimmunoprecipitation assays, <a href="#38" class="mim-tip-reference" title="Tremblay, C. S., Huang, F. F., Habi, O., Huard, C. C., Godin, C., Levesque, G., Carreau, M. <strong>HES1 is a novel interactor of the Fanconi anemia core complex.</strong> Blood 112: 2062-2070, 2008. Note: Erratum: Blood 114: 3974 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18550849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18550849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18550849[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood-2008-04-152710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18550849">Tremblay et al. (2008)</a> found that HES1 (<a href="/entry/139605">139605</a>), a NOTCH1 (<a href="/entry/190198">190198</a>) pathway component involved in hematopoietic stem cell (HSC) self-renewal, interacted directly with FANCA, FANCF, FANCG, and FANCL, but not with other FA core complex components. Mutation analysis showed that interactions with individual FA core components required different domains within HES1. HES1 did not interact with FA core components if any of them contained an FA-related mutation, suggesting that a functional FA pathway is required for HES1 interaction. Depletion of HES1 from HeLa cells resulted in failure of normal interactions between individual FA core components, as well as altered protein levels and mislocalization of some FA core components. Depletion of HES1 also increased cell sensitivity to mitomycin C (MMC) and reduced MMC-induced monoubiquitination of FANCD2 and localization of FANCD2 to MMC-induced foci. <a href="#38" class="mim-tip-reference" title="Tremblay, C. S., Huang, F. F., Habi, O., Huard, C. C., Godin, C., Levesque, G., Carreau, M. <strong>HES1 is a novel interactor of the Fanconi anemia core complex.</strong> Blood 112: 2062-2070, 2008. Note: Erratum: Blood 114: 3974 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18550849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18550849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18550849[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood-2008-04-152710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18550849">Tremblay et al. (2008)</a> concluded that interaction with HES1 is required for normal FA core complex function in the DNA damage response. They proposed that the HSC defect in FA may result from the inability of HES1 to interact with the defective FA core complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18550849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>RT-PCR and direct sequencing of PCR products from FAA patients by the <a href="#5" class="mim-tip-reference" title="Fanconi Anaemia/Breast Cancer Consortium. <strong>Positional cloning of the Fanconi anaemia group A gene.</strong> Nature Genet. 14: 324-328, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896564</a>] [<a href="https://doi.org/10.1038/ng1196-324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896564">Fanconi Anaemia/Breast Cancer Consortium (1996)</a> led to the identification of 4 different mutations (<a href="#0001">607139.0001</a>-<a href="#0004">607139.0004</a>). The authors postulated that the introns of the FAA gene may contain repetitive unstable sequences susceptible to deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8896564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Levran, O., Erlich, T., Magdalena, N., Gregory, J. J., Batish, S. D., Verlander, P. C., Auerbach, A. D. <strong>Sequence variation in the Fanconi anemia gene FAA.</strong> Proc. Nat. Acad. Sci. 94: 13051-13056, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9371798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9371798</a>] [<a href="https://doi.org/10.1073/pnas.94.24.13051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9371798">Levran et al. (1997)</a> used SSCP analysis to screen genomic DNA from a panel of 97 racially and ethnically diverse FA patients from the International Fanconi Anemia Registry for mutations in the FAA gene. A total of 85 variant bands were detected. Forty-five of the variants were probably benign polymorphisms, of which 9 are common and can be used for various applications, including mapping studies for other genes in this region of 16q. Amplification refractory mutation system assays were developed to simplify their detection. Forty variants were considered probable pathogenic mutations. Seventeen of these were microdeletions/microinsertions associated with short direct repeats or homonucleotide tracts, a type of mutation thought to be generated by a mechanism of slipped-strand mispairing during DNA replication. A screening of 350 FA probands from the registry for 2 of these deletions (1115-1118del and 3788-3790del) revealed that they are carried on about 2% and 5% of the FA alleles, respectively. The second of these was found in a variety of ethnic groups and existed on at least 2 different haplotypes. <a href="#22" class="mim-tip-reference" title="Levran, O., Erlich, T., Magdalena, N., Gregory, J. J., Batish, S. D., Verlander, P. C., Auerbach, A. D. <strong>Sequence variation in the Fanconi anemia gene FAA.</strong> Proc. Nat. Acad. Sci. 94: 13051-13056, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9371798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9371798</a>] [<a href="https://doi.org/10.1073/pnas.94.24.13051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9371798">Levran et al. (1997)</a> suggested that FAA is hypermutable, and that slipped-strand mispairing, a mutational mechanism recognized as important for the generation of germline and somatic mutations in a variety of cancer-related genes, including p53 (<a href="/entry/191170">191170</a>), APC (<a href="/entry/611731">611731</a>), RB1 (<a href="/entry/614041">614041</a>), WT1 (<a href="/entry/194070">194070</a>), and BRCA1 (<a href="/entry/113705">113705</a>), may be a major mechanism for FAA mutagenesis. They speculated that FAA is a member of the 'caretaker' gene family according to the caretaker-gatekeeper model of <a href="#16" class="mim-tip-reference" title="Kinzler, K. W., Vogelstein, B. <strong>Gatekeepers and caretakers.</strong> Nature 386: 761-763, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9126728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9126728</a>] [<a href="https://doi.org/10.1038/386761a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9126728">Kinzler and Vogelstein (1997)</a>: inactivation of a caretaker gene results in a higher mutation rate in all genes, including gatekeeper genes that directly regulate tumor growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9371798+9126728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Levran, O., Doggett, N. A., Auerbach, A. D. <strong>Identification of Alu-mediated deletions in the Fanconi anemia gene FAA.</strong> Hum. Mutat. 12: 145-152, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9711872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9711872</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)12:3<145::AID-HUMU2>3.0.CO;2-G" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9711872">Levran et al. (1998)</a> reported the occurrence of Alu-mediated genomic deletions in the FACA gene. Two different deletions of 1.2 kb and 1.9 kb were found in patients with Fanconi anemia. Both deletions included exons 16 and 17 and removed a 156-bp segment from the transcript, causing a shorter in-frame message. Introns 15 and 17 are rich in partial and complete Alu repeats. Sequence analysis of the deletion showed that the 5-prime breakpoints occurred at different sites in the same Alu element in intron 15, while the 3-prime breakpoints were located in different Alu repeats in intron 17. Numerous Alu repeats are present in the FACA gene, suggesting that Alu-mediated recombination may be an important mechanism for the generation of Fanconi anemia-producing mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9711872" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Wijker, M., Morgan, N. V., Herterich, S., van Berkel, C. G. M., Tipping, A. J., Gross, H. J., Gille, J. J. P., Pals, G., Savino, M., Altay, C., Mohan, S., Dokal, I., and 20 others. <strong>Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene.</strong> Europ. J. Hum. Genet. 7: 52-59, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10094191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10094191</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10094191">Wijker et al. (1999)</a> investigated the molecular pathology of Fanconi anemia by screening the FAA gene for mutations in a panel of 90 patients identified by the European FA research group, EUFAR. A highly heterogeneous spectrum of mutations were identified, with 31 different mutations being detected in 34 patients. The mutations were scattered throughout the gene, and most were predicted to result in the absence of the FAA protein. A surprisingly high frequency of intragenic deletions was detected, which removed between 1 and 30 exons from the gene. Most microdeletions and insertions occurred at homopolymeric tracts or direct repeats within the coding sequence. These features had not been observed in the FAC gene (<a href="/entry/227645">227645</a>) and may indicate a higher mutation rate in FAA, which accounts for 60 to 65% of all Fanconi anemia cases. The heterogeneity of the mutation spectrum and the frequency of intragenic deletions present a considerable challenge for the molecular diagnosis of FA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10094191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#39" class="mim-tip-reference" title="Waisfisz, Q., Morgan, N. V., Savino, M., de Winter, J. P., van Berkel, C. G. M., Hoatlin, M. E., Ianzano, L., Gibson, R. A., Arwert, F., Savoia, A., Mathew, C. G., Pronk, J. C., Joenje, H. <strong>Spontaneous functional correction of homozygous Fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism.</strong> Nature Genet. 22: 379-383, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10431244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10431244</a>] [<a href="https://doi.org/10.1038/11956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10431244">Waisfisz et al. (1999)</a> demonstrated functional correction of a pathogenic microdeletion, microinsertion, and missense mutation in homozygous Fanconi anemia patients resulting from compensatory secondary sequence alterations in cis. The frameshift mutation 1615delG in FANCA was compensated by 2 additional single basepair deletions, 1637delA and 1641delT (<a href="#0005">607139.0005</a>). Another FANCA frameshift mutation, 3559insG, was compensated by 3580insCGCTG (<a href="#0006">607139.0006</a>). Although the predicted proteins were different from wildtype, their cDNAs complemented the characteristic hypersensitivity of FA cells to crosslinking agents, thus establishing a functional correction to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10431244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Reports of several large deletions of FANCA, coupled with only modest mutation-detection rates, led <a href="#27" class="mim-tip-reference" title="Morgan, N. V., Tipping, A. J., Joenje, H., Mathew, C. G. <strong>High frequency of large intragenic deletions in Fanconi anemia group A gene.</strong> Am. J. Hum. Genet. 65: 1330-1341, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10521298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10521298</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10521298[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10521298">Morgan et al. (1999)</a> to investigate whether many deletions might occur in heterozygous state and thus fail to be detected by current screening protocols. They used a 2-step screening strategy, in which small mutations were detected by fluorescent chemical cleavage of the FANCA transcript and heterozygosity for gross deletions was detected by quantitative fluorescent multiplex PCR. The authors screened 26 cell lines from FA complementation group A for FANCA mutations and detected 33 different mutations, 23 of which were novel. Mutations were observed in all 26 cell lines and included 43 of a possible 52 mutant alleles (83%). Of the mutant alleles, 40% were large intragenic deletions that removed up to 31 exons from the gene, indicating that this may be the most prevalent form of mutation in FANCA. Several common deletion breakpoints were observed, and there was a highly significant correlation between the number of breakpoints detected in a given intron and the number of Alu repeats that it contained, which suggested that Alu-mediated recombination may explain the high prevalence of deletions in FANCA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10521298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 13 Israeli non-Ashkenazi Jewish patients with FA, <a href="#36" class="mim-tip-reference" title="Tamary, H., Bar-Yam, R., Shalmon, L., Rachavi, G., Krostichevsky, M., Elhasid, R., Barak, Y., Kapelushnik, J., Yaniv, I., Auerbach, A. D., Zaizov, R. <strong>Fanconi anaemia group A (FANCA) mutations in Israeli non-Ashkenazi Jewish patients.</strong> Brit. J. Haemat. 111: 338-343, 2000. Note: Erratum: Brit. J. Haemat. 112: 829 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11091222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11091222</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2000.02323.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11091222">Tamary et al. (2000)</a> found 4 ethnic-specific mutations: 2 Moroccan mutations, 1 Tunisian mutation, and 1 Indian mutation. The tetranucleotide CCTG motif, previously identified as a mutation hotspot in FANCA and other human genes, was found in the vicinity of 2 of the mutations. All carriers within each ethnic group had the same haplotype, suggesting a common founder for each mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11091222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Although revertant mosaicism in FA had been demonstrated in cultured T cells and lymphoblastoid cell lines, the question remained whether genetic reversion ever occurs in the pluripotent lymphohematopoietic stem cell. <a href="#10" class="mim-tip-reference" title="Gregory, J. J., Jr., Wagner, J. E., Verlander, P. C., Levran, O., Batish, S. D., Eide, C. R., Steffenhagen, A., Hirsch, B., Auerbach, A. D. <strong>Somatic mosaicism in Fanconi anemia: evidence of genotypic reversion in lymphohematopoietic stem cells.</strong> Proc. Nat. Acad. Sci. 98: 2532-2537, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11226273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11226273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11226273[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.051609898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11226273">Gregory et al. (2001)</a> therefore examined each lymphohematopoietic and stromal cell lineage in an FA patient with a 2815-2816ins19 mutation in FANCA and known lymphocyte somatic mosaicism. DNA extracted from individually plucked peripheral blood T-cell colonies and marrow colony-forming unit granulocyte-macrophage and burst-forming unit erythroid cells revealed absence of the maternal FANCA exon 29 mutation in 74.0%, 80.3%, and 86.2% of colonies, respectively. These data, together with the absence of the FANCA exon 29 mutation in Epstein-Barr virus-transformed B cells and its presence in fibroblasts, indicated that genotypic reversion, most likely because of back mutation, originated in a lymphohematopoietic stem cell and not solely in a lymphocyte population. Contrary to a predicted increase in marrow cellularity resulting from reversion in a hematopoietic stem cell, pancytopenia was progressive. The subsequent development of a clonal cytogenetic abnormality in nonrevertant cells suggested that ex vivo correction of hematopoietic stem cells by gene transfer may not be sufficient for providing lifelong stable hematopoiesis in patients with FA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11226273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Revertant mosaicism improves the prognosis in patients with FA. Mechanisms of reversion include back mutation, intragenic crossover, gene conversion, and compensating deletions/insertions. <a href="#12" class="mim-tip-reference" title="Gross, M., Hanenberg, H., Lobitz, S., Friedl, R., Herterich, S., Dietrich, R., Gruhn, B., Schindler, D., Hoehn, H. <strong>Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular self-correction.</strong> Cytogenet. Genome Res. 98: 126-135, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12697994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12697994</a>] [<a href="https://doi.org/10.1159/000069805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12697994">Gross et al. (2002)</a> described the types of reversions found in 5 mosaic FA patients who were compound heterozygotes for single base mutations in FANCA or FANCC. In the 1 FANCC patient, intragenic crossover was the mechanism of self-correction. In the 4 FANCA patients, restoration to wildtype via back mutation or gene conversion of either the paternal or maternal allele was observed. The sequence environments of these mutations/reversions were indicative of high mutability, and selective advantage of bone marrow precursor cells carrying a completely restored FANCA allele might explain the surprisingly uniform pattern of these reversions. <a href="#12" class="mim-tip-reference" title="Gross, M., Hanenberg, H., Lobitz, S., Friedl, R., Herterich, S., Dietrich, R., Gruhn, B., Schindler, D., Hoehn, H. <strong>Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular self-correction.</strong> Cytogenet. Genome Res. 98: 126-135, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12697994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12697994</a>] [<a href="https://doi.org/10.1159/000069805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12697994">Gross et al. (2002)</a> also described the first example of in vitro phenotypic reversion via the emergence of a compensating missense mutation 15 amino acids downstream of the constitutional mutation, which explained the reversion to mitomycin C resistance of the respective lymphoblastoid cell line. With 1 exception (the FANCC patient), the mosaic patients showed improvement of their hematologic status during a 3- to 6-year observation, indicating a proliferative advantage of the reverted cell lineages. In patients with FA, genetic instability due to defective caretaker genes sharply increases the risk of neoplasia, but at the same time increases the chance for revertant mosaicism leading to improved bone marrow function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12697994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Joenje, H., Patel, K. J. <strong>The emerging genetic and molecular basis of Fanconi anaemia.</strong> Nature Rev. Genet. 2: 446-457, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11389461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11389461</a>] [<a href="https://doi.org/10.1038/35076590" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11389461">Joenje and Patel (2001)</a> reviewed the molecular basis of Fanconi anemia. They referred to Fanconi anemia, xeroderma pigmentosum (see <a href="/entry/278700">278700</a>), and hereditary nonpolyposis colorectal cancer (see <a href="/entry/120435">120435</a>), all of which feature genomic instability in combination with a strong predisposition to cancer, as 'caretaker-gene diseases.' The common feature of these disorders is an impaired capacity to maintain genomic integrity, which results in the accelerated accumulation of key genetic changes that promote cellular transformation and neoplasia. Cancer predisposition in these diseases is therefore an indirect result of the primary genetic defect. <a href="#11" class="mim-tip-reference" title="Grompe, M., D'Andrea, A. <strong>Fanconi anemia and DNA repair.</strong> Hum. Molec. Genet. 10: 2253-2259, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11673408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11673408</a>] [<a href="https://doi.org/10.1093/hmg/10.20.2253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11673408">Grompe and D'Andrea (2001)</a> reviewed the molecular genetics of FA and noted the presumed interaction of BRCA1 with the 8 FA complementation group proteins in a model of interstrand crosslink repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11673408+11389461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To characterize the molecular defects underlying FA in Tunisia, <a href="#2" class="mim-tip-reference" title="Bouchlaka, C., Abdelhak, S., Amouri, A., Ben Abid, H., Hadiji, S., Frikha, M., Ben Othman, T., Amri, F., Ayadi, H., Hachicha, M., Rebai, A., Saad, A., Dellagi, K., Tunisian Fanconi Anemia Study Group. <strong>Fanconi anemia in Tunisia: high prevalence of group A and identification of new FANCA mutations.</strong> J. Hum. Genet. 48: 352-361, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12827451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12827451</a>] [<a href="https://doi.org/10.1007/s10038-003-0037-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12827451">Bouchlaka et al. (2003)</a> genotyped 39 families for microsatellite markers linked to known FA genes. Haplotype analysis and homozygosity mapping assigned 43 patients belonging to 34 families to the FAA group, whereas 1 family was probably not linked to any known FA genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12827451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Systematic mutation analysis of the FANCA gene, including gene dosage assay to detect large deletions, had not previously been documented for Asian populations. <a href="#43" class="mim-tip-reference" title="Yagasaki, H., Hamanoue, S., Oda, T., Nakahata, T., Asano, S., Yamashita, T. <strong>Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population.</strong> Hum. Mutat. 24: 481-490, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523645</a>] [<a href="https://doi.org/10.1002/humu.20099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15523645">Yagasaki et al. (2004)</a> detected 48 mutant alleles of FANCA in 27 (77%) of 35 unrelated Japanese FA families with no detectable mutations in FANCC (<a href="/entry/227645">227645</a>) or FANCG (<a href="/entry/602956">602956</a>). They identified 29 different mutations (21 nucleotide substitutions or small deletions/insertions and 8 large deletions), at least 20 of which were novel. <a href="#43" class="mim-tip-reference" title="Yagasaki, H., Hamanoue, S., Oda, T., Nakahata, T., Asano, S., Yamashita, T. <strong>Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population.</strong> Hum. Mutat. 24: 481-490, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523645</a>] [<a href="https://doi.org/10.1002/humu.20099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15523645">Yagasaki et al. (2004)</a> stated that the FANCA mutational spectrum of the Japanese was different from that of other ethnic groups studied theretofore. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15523645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Based on the International Fanconi Anemia Registry (IFAR), <a href="#20" class="mim-tip-reference" title="Levran, O., Diotti, R., Pujara, K., Batish, S. D., Hanenberg, H., Auerbach, A. D. <strong>Spectrum of sequence variations in the FANCA gene: an International Fanconi Anemia Registry (IFAR) study.</strong> Hum. Mutat. 25: 142-149, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15643609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15643609</a>] [<a href="https://doi.org/10.1002/humu.20125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15643609">Levran et al. (2005)</a> reviewed the spectrum of sequence variations in the FANCA gene. They stated that the FANCA complementation group accounts for approximately 65% of all affected individuals with Fanconi anemia. Their review identified 61 novel FANCA mutations identified in FA patients registered by IFAR. They also reported on single nucleotide polymorphisms (SNPs) and concluded that the FANCA SNP data were highly useful for carrier testing, prenatal diagnosis, and preimplantation genetic diagnosis, particularly when the disease-causing mutations were unknown. By detection of apparent homozygosity for rare SNPs, 22 large genomic deletions were identified. In addition, a conserved SNP haplotype block spanning at least 60 kb of the FANCA gene was identified in individuals from various ethnic groups, suggesting an ancient origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15643609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 infertile Spanish brothers and an unrelated infertile Spanish man, who were azoospermic and exhibited Sertoli cell-only syndrome (SCO; see <a href="/entry/400042">400042</a>) on testicular histology, <a href="#18" class="mim-tip-reference" title="Krausz, C., Riera-Escamilla, A., Chianese, C., Moreno-Mendoza, D., Ars, E., Rajmil, O., Pujol, R., Bogliolo, M., Blanco, I., Rodriguez, I., Badell, I., Ruiz-Castane, E., Surralles, J. <strong>From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia.</strong> Genet. Med. 21: 189-194, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29904161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29904161</a>] [<a href="https://doi.org/10.1038/s41436-018-0037-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29904161">Krausz et al. (2019)</a> identified homozygosity and compound heterozygosity for mutations in the FANCA gene (<a href="#0013">607139.0013</a>-<a href="#0015">607139.0015</a>). Laboratory evaluation showed low platelets, red blood cells, and leukocytes in 1 brother and the unrelated man; DEB-induced chromosomal breakage results were consistent with somatic mosaicism in the other brother. The authors suggested that screening for FANCA variants in infertile men with SCO might identify undiagnosed FA patients before the appearance of severe clinical manifestations of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29904161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The <a href="#5" class="mim-tip-reference" title="Fanconi Anaemia/Breast Cancer Consortium. <strong>Positional cloning of the Fanconi anaemia group A gene.</strong> Nature Genet. 14: 324-328, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896564</a>] [<a href="https://doi.org/10.1038/ng1196-324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896564">Fanconi Anaemia/Breast Cancer Consortium (1996)</a> identified a 274-bp deletion of the FANCA gene in an Italian patient with Fanconi anemia (FANCA; <a href="/entry/227650">227650</a>), which resulted in the loss of nucleotides 1671 to 1944, a frameshift, and the creation of a premature termination codon 6 residues downstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8896564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397507552 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397507552;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs397507552?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397507552" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397507552" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003609 OR RCV000463426 OR RCV001091063 OR RCV004742211" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003609, RCV000463426, RCV001091063, RCV004742211" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003609...</a>
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<p>In 2 members of a family of British origin with Fanconi anemia (FANCA; <a href="/entry/227650">227650</a>), the <a href="#5" class="mim-tip-reference" title="Fanconi Anaemia/Breast Cancer Consortium. <strong>Positional cloning of the Fanconi anaemia group A gene.</strong> Nature Genet. 14: 324-328, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896564</a>] [<a href="https://doi.org/10.1038/ng1196-324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896564">Fanconi Anaemia/Breast Cancer Consortium (1996)</a> identified a deletion of 1 of 2 direct repeats of the sequence TTGG at nucleotides 1155-1162 of the FANCA gene. The deletion resulted in a frameshift and the production of a termination codon 42 residues downstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8896564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003610" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003610" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003610</a>
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<p>The <a href="#5" class="mim-tip-reference" title="Fanconi Anaemia/Breast Cancer Consortium. <strong>Positional cloning of the Fanconi anaemia group A gene.</strong> Nature Genet. 14: 324-328, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896564</a>] [<a href="https://doi.org/10.1038/ng1196-324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896564">Fanconi Anaemia/Breast Cancer Consortium (1996)</a> identified in 2 families with Fanconi anemia (FANCA; <a href="/entry/227650">227650</a>) a deletion in the FANCA gene of 156 bp (from nucleotides 1515 to 1670) that spans 2 exons. One patient was of African American origin and one was of northern European origin (and a compound heterozygote for another deletion; see <a href="#0004">607139.0004</a>). This 156-bp deletion did not result in a frameshift but led to the deletion of 52 amino acids from the protein. The deletion was not found in 70 control chromosomes, suggesting to the investigators that it did not represent alternative splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8896564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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FANCA, 113-BP DEL, NT938
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<p>A patient of northern European origin with Fanconi anemia (FANCA; <a href="/entry/227650">227650</a>) was found by the <a href="#5" class="mim-tip-reference" title="Fanconi Anaemia/Breast Cancer Consortium. <strong>Positional cloning of the Fanconi anaemia group A gene.</strong> Nature Genet. 14: 324-328, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896564</a>] [<a href="https://doi.org/10.1038/ng1196-324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896564">Fanconi Anaemia/Breast Cancer Consortium (1996)</a> to be compound heterozygous for 2 mutations in the FANCA gene: a 113-bp deletion spanning nucleotides 938 to 1050, and a 156-bp deletion (<a href="#0003">607139.0003</a>). The 113-bp deletion removes a single exon from the coding sequence and creates a premature stop codon 2 residues downstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8896564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs778507965 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs778507965;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs778507965?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs778507965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs778507965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003612 OR RCV001046987 OR RCV003228892" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003612, RCV001046987, RCV003228892" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003612...</a>
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<p>In a patient with Fanconi anemia (FANCA; <a href="/entry/227650">227650</a>), <a href="#39" class="mim-tip-reference" title="Waisfisz, Q., Morgan, N. V., Savino, M., de Winter, J. P., van Berkel, C. G. M., Hoatlin, M. E., Ianzano, L., Gibson, R. A., Arwert, F., Savoia, A., Mathew, C. G., Pronk, J. C., Joenje, H. <strong>Spontaneous functional correction of homozygous Fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism.</strong> Nature Genet. 22: 379-383, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10431244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10431244</a>] [<a href="https://doi.org/10.1038/11956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10431244">Waisfisz et al. (1999)</a> identified homozygous deletion of a G at nucleotide 1615 in exon 17 of the FANCA gene. Sequence analysis revealed 2 de novo single-basepair deletions at 1 allele, 1637delA and 1641delT, in exon 18. A cDNA containing the three 1-bp deletions transfected into an FAA lymphoblastoid cell line complemented the phenotype to the same extent as a construct expressing wildtype FANCA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10431244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs747851434 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs747851434;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs747851434?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs747851434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs747851434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003613 OR RCV000630905 OR RCV001818121 OR RCV003398432" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003613, RCV000630905, RCV001818121, RCV003398432" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003613...</a>
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<p>In a patient with Fanconi anemia (FANCA; <a href="/entry/227650">227650</a>), <a href="#39" class="mim-tip-reference" title="Waisfisz, Q., Morgan, N. V., Savino, M., de Winter, J. P., van Berkel, C. G. M., Hoatlin, M. E., Ianzano, L., Gibson, R. A., Arwert, F., Savoia, A., Mathew, C. G., Pronk, J. C., Joenje, H. <strong>Spontaneous functional correction of homozygous Fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism.</strong> Nature Genet. 22: 379-383, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10431244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10431244</a>] [<a href="https://doi.org/10.1038/11956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10431244">Waisfisz et al. (1999)</a> found a 3559insG frameshift in exon 36 of the FANCA gene on both alleles. An additional de novo insertion (3580insCGCTG or 3576insGCTGC) in the same exon restored the open reading frame. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10431244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003614" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003614" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003614</a>
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<p><a href="#37" class="mim-tip-reference" title="Tipping, A. J., Pearson, T., Morgan, N. V., Gibson, R. A., Kuyt, L. P., Havenga, C., Gluckman, E., Joenje, H., de Ravel, T., Jansen, S., Mathew, C. G. <strong>Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa.</strong> Proc. Nat. Acad. Sci. 98: 5734-5739, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11344308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11344308</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11344308[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.091402398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11344308">Tipping et al. (2001)</a> identified an intragenic deletion of exons 12-31 of the FANCA gene as accounting for 60% of Fanconi anemia chromosomes in 46 unrelated Afrikaner FA (see FANCA, <a href="/entry/227650">227650</a>) patients. Two other mutations, also deletions, accounted for an additional 20%. By genealogic investigation of 12 Afrikaner families with FA, they traced the major deletion to a French Huguenot couple who arrived at the Cape in 1688. The same mutation and haplotype was found in an FANCA patient from the western Ruhr region of Germany. It was thus possible that the major founder mutation was introduced into South Africa from that region. Rhinelanders were a substantial component of the crew of the ships of the Dutch East India Company, and about one-third of the original European population of the Cape were of German origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11344308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776570 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776570;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587776570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003615" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003615" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003615</a>
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<p>In a Tunisian patient with Fanconi anemia (FANCA; <a href="/entry/227650">227650</a>), <a href="#2" class="mim-tip-reference" title="Bouchlaka, C., Abdelhak, S., Amouri, A., Ben Abid, H., Hadiji, S., Frikha, M., Ben Othman, T., Amri, F., Ayadi, H., Hachicha, M., Rebai, A., Saad, A., Dellagi, K., Tunisian Fanconi Anemia Study Group. <strong>Fanconi anemia in Tunisia: high prevalence of group A and identification of new FANCA mutations.</strong> J. Hum. Genet. 48: 352-361, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12827451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12827451</a>] [<a href="https://doi.org/10.1007/s10038-003-0037-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12827451">Bouchlaka et al. (2003)</a> identified homozygosity for a 1-bp deletion, 1606delT, in exon 17 of the FANCA gene. The deletion resulted in a shift in the reading frame and production of a termination codon 21 amino acids downstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12827451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907930 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907930;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121907930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121907930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Tunisian family with Fanconi anemia (FANCA; <a href="/entry/227650">227650</a>), <a href="#2" class="mim-tip-reference" title="Bouchlaka, C., Abdelhak, S., Amouri, A., Ben Abid, H., Hadiji, S., Frikha, M., Ben Othman, T., Amri, F., Ayadi, H., Hachicha, M., Rebai, A., Saad, A., Dellagi, K., Tunisian Fanconi Anemia Study Group. <strong>Fanconi anemia in Tunisia: high prevalence of group A and identification of new FANCA mutations.</strong> J. Hum. Genet. 48: 352-361, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12827451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12827451</a>] [<a href="https://doi.org/10.1007/s10038-003-0037-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12827451">Bouchlaka et al. (2003)</a> identified a 513G-A transition in exon 5 of the FANCA gene. This change resulted in a trp171-to-ter (W171X) substitution, and therefore to a premature termination of the FANCA protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12827451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs794726660 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794726660;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs794726660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs794726660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003617 OR RCV001851619" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003617, RCV001851619" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003617...</a>
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<p>In 2 presumably unrelated Japanese patients with Fanconi anemia (FANCA; <a href="/entry/227650">227650</a>), <a href="#43" class="mim-tip-reference" title="Yagasaki, H., Hamanoue, S., Oda, T., Nakahata, T., Asano, S., Yamashita, T. <strong>Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population.</strong> Hum. Mutat. 24: 481-490, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523645</a>] [<a href="https://doi.org/10.1002/humu.20099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15523645">Yagasaki et al. (2004)</a> found a 5-bp deletion (AAACA) at cDNA nucleotides 3720-3724 in exon 37 of the FANCA gene (3720_3724del). In 1 case the mutation was homozygous. The mutation resulted in aberrant splicing which caused skipping of exon 37. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15523645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs752160950 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs752160950;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs752160950?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs752160950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs752160950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000173013 OR RCV000630944" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000173013, RCV000630944" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000173013...</a>
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<p>In a cell line derived from a proband with Fanconi anemia of complementation group A (FANCA; <a href="/entry/227650">227650</a>), <a href="#33" class="mim-tip-reference" title="Singh, T. R., Bakker, S. T., Agarwal, S., Jansen, M., Grassman, E., Godthelp, B. C., Ali, A. M., Du, C., Rooimans, M. A., Fan, Q., Wahengbam, K., Steltenpool, J., Andreassen, P. R., Williams, D. A., Joenje, H., de Winter, J. P., Meetei, A. R. <strong>Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M.</strong> Blood 114: 174-180, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19423727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19423727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19423727[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood-2009-02-207811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19423727">Singh et al. (2009)</a> identified compound heterozygous mutations in the FANCA gene: a c.2557C-T transition, resulting in an arg853-to-ter (R853X) substitution, and a G-to-A transition in intron 7 (IVS7+5G-A; <a href="#0012">607139.0012</a>), resulting in a 30-bp insertion in the FANCA mRNA, which adds 10 amino acids between residues 236 and 237 of the protein. Expression of the mutant FANCA protein was unable to restore FANDC2 monoubiquitination in FANCA-deficient lymphoblasts, demonstrating that the splice site mutation is pathogenic. Each unaffected parent was heterozygous for 1 of the mutations. This patient had a sib (EUFA867) who had no clinical symptoms of Fanconi anemia but whose cell lines carried the same biallelic FANCA mutations. Both patients were originally reported by <a href="#25" class="mim-tip-reference" title="Meetei, A. R., Medhurst, A. L., Ling, C., Xue, Y., Singh, T. R., Bier, P., Steltenpool, J., Stone, S., Dokal, I., Mathew, C. G., Hoatlin, M., Joenje, H., de Winter, J. P., Wang, W. <strong>A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.</strong> Nature Genet. 37: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16116422[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng1626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116422">Meetei et al. (2005)</a> as having Fanconi anemia, complementation group M due to compound heterozygous mutations in the FAAP250 gene (FANCM; <a href="/entry/609644">609644</a>). However, <a href="#33" class="mim-tip-reference" title="Singh, T. R., Bakker, S. T., Agarwal, S., Jansen, M., Grassman, E., Godthelp, B. C., Ali, A. M., Du, C., Rooimans, M. A., Fan, Q., Wahengbam, K., Steltenpool, J., Andreassen, P. R., Williams, D. A., Joenje, H., de Winter, J. P., Meetei, A. R. <strong>Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M.</strong> Blood 114: 174-180, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19423727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19423727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19423727[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood-2009-02-207811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19423727">Singh et al. (2009)</a> stated that the proband only carried 1 of the FAAP250 mutations, which in retrospect reclassified this patient as having FANCA. The clinically unaffected sib carried both biallelic mutations in the FANCA gene and biallelic variants in the FAAP250 gene (see <a href="/entry/609644#0001">609644.0001</a> and <a href="/entry/609644#0002">609644.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16116422+19423727" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs759877008 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs759877008;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs759877008?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs759877008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs759877008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000474895 OR RCV000673202 OR RCV001821265" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000474895, RCV000673202, RCV001821265" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000474895...</a>
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<p>For discussion of the IVS7+5G-A mutation in the FANCA gene that was found in compound heterozygous state in a patient with Fanconi anemia of complementation group A (FANCA; <a href="/entry/227650">227650</a>) by <a href="#33" class="mim-tip-reference" title="Singh, T. R., Bakker, S. T., Agarwal, S., Jansen, M., Grassman, E., Godthelp, B. C., Ali, A. M., Du, C., Rooimans, M. A., Fan, Q., Wahengbam, K., Steltenpool, J., Andreassen, P. R., Williams, D. A., Joenje, H., de Winter, J. P., Meetei, A. R. <strong>Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M.</strong> Blood 114: 174-180, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19423727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19423727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19423727[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood-2009-02-207811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19423727">Singh et al. (2009)</a>, see <a href="#0011">607139.0011</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19423727" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs372254398 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs372254398;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs372254398?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs372254398" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs372254398" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000671284 OR RCV000803258 OR RCV003478396 OR RCV004742565" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000671284, RCV000803258, RCV003478396, RCV004742565" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000671284...</a>
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<p>In 2 infertile Spanish brothers from a consanguineous family with nonobstructive azoospermia and Sertoli cell-only syndrome on testicular biopsy, 1 of whom also had low erythrocyte, leukocyte, and platelet counts (FANCA; <a href="/entry/227650">227650</a>), <a href="#18" class="mim-tip-reference" title="Krausz, C., Riera-Escamilla, A., Chianese, C., Moreno-Mendoza, D., Ars, E., Rajmil, O., Pujol, R., Bogliolo, M., Blanco, I., Rodriguez, I., Badell, I., Ruiz-Castane, E., Surralles, J. <strong>From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia.</strong> Genet. Med. 21: 189-194, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29904161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29904161</a>] [<a href="https://doi.org/10.1038/s41436-018-0037-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29904161">Krausz et al. (2019)</a> identified homozygosity for a c.2639G-A transition (c.2639G-A, NM_000135.2) in exon 28 of the FANCA gene, resulting in an arg880-to-gln (R880Q) substitution. The DEB-induced chromosomal breakage test was consistent with somatic mosaicism in the proband (patient 04-170), whereas his brother had typical complete Fanconi anemia. DNA from their parents was unavailable for segregation analysis; however, the authors noted that the R880Q variant had previously been reported in a Spanish patient with Fanconi anemia (<a href="#3" class="mim-tip-reference" title="Castella, M., Pujol, R., Callen, E., Trujillo, J. P., Casado, J. A., Gille, H., Lach, F. P., Auerbach, A. D., Schindler, D., Benitez, J., Porto, B., Ferro, T., and 20 others. <strong>Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations.</strong> Blood 117: 3759-3769, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21273304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21273304</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21273304[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood-2010-08-299917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21273304">Castella et al., 2011</a>) and was also present in heterozygosity and homozygosity in 8 patients in the Rockefeller University FA Mutation Database. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29904161+21273304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397507553 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397507553;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs397507553?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397507553" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397507553" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000033896 OR RCV000120945 OR RCV000231918 OR RCV000485336 OR RCV003924889" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033896, RCV000120945, RCV000231918, RCV000485336, RCV003924889" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033896...</a>
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<p>In a Spanish man (patient 14-339) with nonobstructive azoospermia and Sertoli cell-only syndrome on testicular biopsy, who also had low erythrocyte, leukocyte, and platelet counts and elevated mean corpuscular volume (FANCA; <a href="/entry/227650">227650</a>), <a href="#18" class="mim-tip-reference" title="Krausz, C., Riera-Escamilla, A., Chianese, C., Moreno-Mendoza, D., Ars, E., Rajmil, O., Pujol, R., Bogliolo, M., Blanco, I., Rodriguez, I., Badell, I., Ruiz-Castane, E., Surralles, J. <strong>From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia.</strong> Genet. Med. 21: 189-194, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29904161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29904161</a>] [<a href="https://doi.org/10.1038/s41436-018-0037-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29904161">Krausz et al. (2019)</a> identified compound heterozygosity for an in-frame 3-bp deletion (c.3788_3790delTCT, NM_000135.2) in exon 38 of the FANCA gene, causing deletion of a single residue (phe1263del), and a c.3913C-T transition in exon 39, resulting in a leu1305-to-phe (L1305F; <a href="#0015">607139.0015</a>) substitution. The DEB-induced chromosomal breakage test was consistent with somatic mosaicism in the proband. His normozoospermic brother, who had blood counts within the normal range, was heterozygous for the L1305F mutation. The authors stated that both mutations had previously been reported in many patients with Fanconi anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29904161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs753700179 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs753700179;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs753700179?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs753700179" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs753700179" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000672199 OR RCV001222479" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000672199, RCV001222479" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000672199...</a>
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<p>For discussion of the c.3913C-T transition (c.3913C-T, NM_000135.2) in exon 39 of the FANCA gene, resulting in a leu1305-to-phe (L1305F) substitution, that was found in compound heterozygous state in a patient with Fanconi anemia (FANCA; <a href="/entry/227650">227650</a>) by <a href="#18" class="mim-tip-reference" title="Krausz, C., Riera-Escamilla, A., Chianese, C., Moreno-Mendoza, D., Ars, E., Rajmil, O., Pujol, R., Bogliolo, M., Blanco, I., Rodriguez, I., Badell, I., Ruiz-Castane, E., Surralles, J. <strong>From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia.</strong> Genet. Med. 21: 189-194, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29904161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29904161</a>] [<a href="https://doi.org/10.1038/s41436-018-0037-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29904161">Krausz et al. (2019)</a>, see <a href="#0014">607139.0014</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29904161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Expression of the Fanconi anemia group A gene (Fanca) during mouse embryogenesis.</strong>
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Blood 94: 818-824, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10397750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10397750</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10397750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bouchlaka, C., Abdelhak, S., Amouri, A., Ben Abid, H., Hadiji, S., Frikha, M., Ben Othman, T., Amri, F., Ayadi, H., Hachicha, M., Rebai, A., Saad, A., Dellagi, K., Tunisian Fanconi Anemia Study Group.
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<strong>Fanconi anemia in Tunisia: high prevalence of group A and identification of new FANCA mutations.</strong>
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J. Hum. Genet. 48: 352-361, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12827451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12827451</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12827451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10038-003-0037-z" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M207937200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi138" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/11.21.2591" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1297-487" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)12:3<145::AID-HUMU2>3.0.CO;2-G" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1626" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/MCB.23.10.3417-3426.2003" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/302627" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/10.23.2651" target="_blank">Full Text</a>]
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<a id="35" class="mim-anchor"></a>
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<a id="Steinlein1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Steinlein, O., Fischer, C., Keil, R., Smigrodzki, R., Vogel, F.
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<strong>D20S19, linked to low voltage EEG, benign neonatal convulsions, and Fanconi anaemia, maps to a region of enhanced recombination and is localized between CpG islands.</strong>
|
|
Hum. Molec. Genet. 1: 325-329, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303209</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1303209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/1.5.325" target="_blank">Full Text</a>]
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</p>
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<a id="36" class="mim-anchor"></a>
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<a id="Tamary2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tamary, H., Bar-Yam, R., Shalmon, L., Rachavi, G., Krostichevsky, M., Elhasid, R., Barak, Y., Kapelushnik, J., Yaniv, I., Auerbach, A. D., Zaizov, R.
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<strong>Fanconi anaemia group A (FANCA) mutations in Israeli non-Ashkenazi Jewish patients.</strong>
|
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Brit. J. Haemat. 111: 338-343, 2000. Note: Erratum: Brit. J. Haemat. 112: 829 only, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11091222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11091222</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11091222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1046/j.1365-2141.2000.02323.x" target="_blank">Full Text</a>]
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<a id="37" class="mim-anchor"></a>
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<a id="Tipping2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tipping, A. J., Pearson, T., Morgan, N. V., Gibson, R. A., Kuyt, L. P., Havenga, C., Gluckman, E., Joenje, H., de Ravel, T., Jansen, S., Mathew, C. G.
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<strong>Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa.</strong>
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Proc. Nat. Acad. Sci. 98: 5734-5739, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11344308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11344308</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11344308[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11344308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.091402398" target="_blank">Full Text</a>]
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<a id="38" class="mim-anchor"></a>
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<a id="Tremblay2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tremblay, C. S., Huang, F. F., Habi, O., Huard, C. C., Godin, C., Levesque, G., Carreau, M.
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<strong>HES1 is a novel interactor of the Fanconi anemia core complex.</strong>
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Blood 112: 2062-2070, 2008. Note: Erratum: Blood 114: 3974 only, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18550849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18550849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18550849[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18550849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1182/blood-2008-04-152710" target="_blank">Full Text</a>]
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<a id="Waisfisz1999" class="mim-anchor"></a>
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<div class="">
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Waisfisz, Q., Morgan, N. V., Savino, M., de Winter, J. P., van Berkel, C. G. M., Hoatlin, M. E., Ianzano, L., Gibson, R. A., Arwert, F., Savoia, A., Mathew, C. G., Pronk, J. C., Joenje, H.
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<strong>Spontaneous functional correction of homozygous Fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism.</strong>
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Nature Genet. 22: 379-383, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10431244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10431244</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10431244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/11956" target="_blank">Full Text</a>]
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<a id="40" class="mim-anchor"></a>
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<a id="Wijker1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wijker, M., Morgan, N. V., Herterich, S., van Berkel, C. G. M., Tipping, A. J., Gross, H. J., Gille, J. J. P., Pals, G., Savino, M., Altay, C., Mohan, S., Dokal, I., and 20 others.
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<strong>Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene.</strong>
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Europ. J. Hum. Genet. 7: 52-59, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10094191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10094191</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10094191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200248" target="_blank">Full Text</a>]
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<a id="41" class="mim-anchor"></a>
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<a id="Wong2003" class="mim-anchor"></a>
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Wong, J. C. Y., Alon, N., Mckerlie, C., Huang, J. R., Meyn, M. S., Buchwald, M.
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<strong>Targeted disruption of exons 1 to 6 of the Fanconi anemia group A gene leads to growth retardation, strain-specific microphthalmia, meiotic defects and primordial germ cell hypoplasia.</strong>
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Hum. Molec. Genet. 12: 2063-2076, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12913077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12913077</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12913077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg219" target="_blank">Full Text</a>]
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<a id="42" class="mim-anchor"></a>
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<a id="Wong2000" class="mim-anchor"></a>
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Wong, J. C. Y., Alon, N., Norga, K., Kruyt, F. A. E., Youssoufian, H., Buchwald, M.
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<strong>Cloning and analysis of the mouse Fanconi anemia group A cDNA and an overlapping penta zinc finger cDNA.</strong>
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Genomics 67: 273-283, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10936049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10936049</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10936049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.2000.6252" target="_blank">Full Text</a>]
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<a id="43" class="mim-anchor"></a>
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<a id="Yagasaki2004" class="mim-anchor"></a>
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Yagasaki, H., Hamanoue, S., Oda, T., Nakahata, T., Asano, S., Yamashita, T.
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<strong>Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population.</strong>
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Hum. Mutat. 24: 481-490, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523645</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15523645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.20099" target="_blank">Full Text</a>]
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<a id="44" class="mim-anchor"></a>
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<a id="Zhang2004" class="mim-anchor"></a>
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Zhang, X., Li, J., Sejas, D. P., Rathbun, K. R., Bagby, G. C., Pang, Q.
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<strong>The Fanconi anemia proteins functionally interact with the protein kinase regulated by RNA (PKR).</strong>
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J. Biol. Chem. 279: 43910-43919, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15299030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15299030</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15299030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M403884200" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 02/14/2019
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 6/22/2015<br>Patricia A. Hartz - updated : 8/28/2009<br>George E. Tiller - updated : 5/30/2008<br>Cassandra L. Kniffin - updated : 11/21/2005<br>George E. Tiller - updated : 6/6/2005<br>Victor A. McKusick - updated : 3/7/2005<br>Patricia A. Hartz - updated : 1/18/2005<br>Victor A. McKusick - updated : 1/10/2005<br>Cassandra L. Kniffin - updated : 12/16/2004<br>Victor A. McKusick - updated : 11/19/2004<br>Patricia A. Hartz - updated : 2/11/2004<br>George E. Tiller - updated : 2/3/2004<br>Victor A. McKusick - updated : 8/27/2003<br>Victor A. McKusick - updated : 5/16/2003<br>Patricia A. Hartz - updated : 1/24/2003
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Creation Date:
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Cassandra L. Kniffin : 8/5/2002
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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carol : 01/11/2022
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<span class="mim-text-font">
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carol : 02/14/2019<br>carol : 06/23/2015<br>carol : 6/22/2015<br>ckniffin : 6/22/2015<br>carol : 2/18/2015<br>carol : 9/2/2014<br>carol : 9/24/2013<br>terry : 4/4/2013<br>terry : 1/2/2013<br>terry : 5/29/2012<br>carol : 7/13/2011<br>alopez : 6/17/2011<br>mgross : 10/14/2009<br>terry : 8/28/2009<br>carol : 8/27/2008<br>wwang : 6/3/2008<br>terry : 5/30/2008<br>ckniffin : 2/5/2008<br>carol : 8/6/2007<br>wwang : 11/21/2005<br>alopez : 10/20/2005<br>alopez : 6/6/2005<br>mgross : 4/13/2005<br>tkritzer : 3/11/2005<br>terry : 3/7/2005<br>alopez : 2/10/2005<br>wwang : 1/25/2005<br>mgross : 1/18/2005<br>terry : 1/10/2005<br>tkritzer : 12/29/2004<br>ckniffin : 12/16/2004<br>alopez : 11/30/2004<br>alopez : 11/29/2004<br>terry : 11/19/2004<br>joanna : 3/19/2004<br>mgross : 2/11/2004<br>cwells : 2/3/2004<br>cwells : 9/2/2003<br>terry : 8/27/2003<br>tkritzer : 5/27/2003<br>terry : 5/16/2003<br>cwells : 1/24/2003<br>ckniffin : 1/24/2003<br>ckniffin : 1/2/2003<br>ckniffin : 8/13/2002<br>ckniffin : 8/12/2002<br>ckniffin : 8/6/2002
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<strong>*</strong> 607139
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<div>
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<h3>
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<span class="mim-font">
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FANCA GENE; FANCA
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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FACA; FAA
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<strong><em>HGNC Approved Gene Symbol: FANCA</em></strong>
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<strong>
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Cytogenetic location: 16q24.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:89,737,549-89,816,647 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</h4>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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Location
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<th>
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Phenotype
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</th>
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Phenotype <br /> MIM number
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</thead>
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<tbody>
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<td rowspan="1">
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<span class="mim-font">
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16q24.3
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</td>
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<td>
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<span class="mim-font">
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Fanconi anemia, complementation group A
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</span>
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</td>
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<td>
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<span class="mim-font">
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227650
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</span>
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<span class="mim-font">
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Autosomal recessive
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</span>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tbody>
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</table>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Soulier et al. (2005) noted that the FANCA, -C (613899), -E (613976), -F (613897), -G (602956), and -L (608111) proteins are part of a nuclear multiprotein core complex which triggers activating monoubiquitination of the FANCD2 (613984) protein during S phase of the growth cycle and after exposure to DNA crosslinking agents. The FA/BRCA pathway is involved in the repair of DNA damage. FANCM (609644) is also part of the FA core complex (Meetei et al., 2005). </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lo Ten Foe et al. (1996) used a cDNA expression library to complement the mitomycin C-sensitive phenotype of Fanconi anemia (see 227650) lymphoblastoid cells. By this method they identified a cDNA clone that corrected the cross-linker hypersensitivity of FANCA cells but not of FANCC (227645) cells. The cDNA clone for the gene (called FAA by them) has an open reading frame of 4,368 bp and encodes a 1,455-amino acid polypeptide predicted to contain 2 overlapping bipartite nuclear localization signals and a partial leucine zipper consensus sequence, suggesting that the protein is localized in the nucleus. Northern blot analysis detected a 5.5-kb transcript in controls and in FA patients from complementation groups other than FAA. In an FAA cell line, the 5.5-kb band was virtually undetectable, suggesting reduced transcription or reduced stability of the FAA mRNA transcript. </p><p>Through exon trapping and cDNA selection the Fanconi Anaemia/Breast Cancer Consortium (1996) identified a candidate cDNA clone for FAA and through searches in the dbEST database they identified additional overlapping cDNA clones. Sequencing of these clones revealed a full-length FAA candidate gene that encodes a polypeptide of 1,455 amino acids. Sequence analysis revealed that the full-length cDNA isolated by positional cloning was identical to the cDNA clone isolated by complementation and reported by Lo Ten Foe et al. (1996), except that the clone isolated by positional cloning had an additional 13 bp of 5-prime untranslated sequence and 2 amino acid substitutions (S501G and I717M). </p><p>Wong et al. (2000) cloned mouse Fanca. The deduced 1,439-amino acid protein shares 65% identity with human FANCA. The C-terminal partial leucine zipper and most of the N-terminal bipartite nuclear localization signal of human FANCA are conserved in mouse Fanca. Northern blot analysis detected several Fanca transcripts expressed in all adult mouse tissues examined and during all stages of embryonic development. The most abundant transcript was 1.6 kb and showed highest expression in intestine, liver, lung, and spleen. A 3.8-kb transcript was unique to brain, while a 4.5-kb transcript was expressed in all tissues except brain. In vitro transcription and translation of mouse Fanca cDNA yielded a protein with an apparent molecular mass of 161 kD. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Ianzano et al. (1997) determined that the FANCA gene contains 43 exons and spans approximately 80 kb. The exon sizes range from 34 to 188 bp. The authors also described 3 alternative splicing events resulting in the loss of exon 37, a 23-bp deletion at the 5-prime end of exon 41, and a GCAG insertion at the 3-prime portion of exon 41. Ianzano et al. (1997) noted that instead of TATA or CAAT boxes, the 5-prime region upstream of the putative transcription start site of FANCA has a GC-rich region, which is typical of housekeeping genes. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Although some studies suggested that the FA locus was on chromosome 20q (Mann et al., 1991; Steinlein et al., 1992), Pronk et al. (1995) determined that the FA1 gene (which they called FAA) is linked to microsatellite markers on 16q24.3. Pronk et al. (1995) established a panel of families classified as Fanconi anemia type A by complementation analysis, and used them to search for the FAA gene by linkage analysis. Pronk et al. (1995) found strong evidence of allelic association between the disease and the marker D16S303 in the Afrikaner population of South Africa, indicating founder effect, which had previously been suggested by Rosendorff et al. (1987). </p><p>Gschwend et al. (1996) used homozygosity mapping in the study of 23 inbred families with Fanconi anemia and identified linkage to a locus near marker D16S520 at 16q24.3. Although approximately 65% of the families displayed clear linkage to D16S250, the authors found strong evidence of genetic heterogeneity. Family ascertainment was biased against the previously identified FAC gene on chromosome 9, and no linkage was observed to that locus. Simultaneous search analysis suggested to Gschwend et al. (1996) several additional chromosomal regions that could account for a small fraction of Fanconi anemia in the families studied, but the sample size was insufficient to provide statistical significance. They also demonstrated the strong effect of marker allele frequencies on lod scores obtained in homozygosity mapping and discussed ways to avoid false positives arising from this effect. </p><p>Based on linkage analysis and allelic association in Afrikaner FA families the Fanconi Anaemia/Breast Cancer Consortium (1996) refined the map interval for FAA to the region D16S3026-D16S303 (maximum lod = 3.15 at theta = 0.00 for D16S303). They used a positional cloning strategy to isolate a candidate cDNA for the FAA gene. Lo Ten Foe et al. (1996) stated that the cDNA identified by them mapped to the telomere of chromosome 16q by fluorescence in situ hybridization (FISH). </p><p>Savoia et al. (1997) performed linkage analysis in 11 FA-A and 16 unclassified FA Italian families using microsatellite markers. All the families were consistent with linkage at 16q24, the largest lod score being observed with D16S1320. In 2 genetic isolates common haplotypes were observed. Autozygosity mapping and haplotype analysis suggested that FAA is located distal to D16S305. </p><p>By radiation hybrid analysis and FISH, Wong et al. (2000) mapped the mouse Fanca gene to distal chromosome 8 in a region that shows homology of synteny to human chromosome 16q. The last 4 exons of Fanca overlap the 3-prime UTR of the Zfp276 gene (608460) in a tail-to-tail manner. Wong et al. (2000) determined that the human FANCA gene also overlaps the ZFP276 gene in a tail-to-tail manner. </p><p>Goldammer et al. (2002) constructed a comprehensive, high-resolution comparative map of bovine chromosome 18. Conserved synteny between cattle, human, and mouse was found for 76 genes of bovine chromosome 18 and human chromosomes 16 and 19, and for 34 genes of bovine chromosome 18 and mouse chromosomes 7 and 8. The authors found that the FANCA gene is in a gene cluster near the telomere of human 16q and near the centromere of bovine 18. Other genes in this syntenic cluster included APRT (102600), SPG7 (602783), GALNS (612222), and CDK10 (603464). </p>
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</span>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The fact that there are several FA complementation groups displaying similar phenotypes suggested that FA genes are functionally related. The FA genes FAA and FAC (227645) encode proteins that are unrelated to each other or to other proteins in the databases. Kupfer et al. (1997) demonstrated that FAA and FAC bind each other and form a complex. Protein binding correlated with the functional activity of FAA and FAC, as patient-derived mutant FAC, leu554 to pro (227645.0001), failed to bind FAA. Although unbound FAA and FAC localized predominantly to the cytoplasm, the FAA-FAC complex was found in similar abundance in both cytoplasm and nucleus. The results confirmed the interrelatedness of the FA genes in a pathway and suggested the cooperation of FAA and FAC in a nuclear function. </p><p>Garcia-Higuera et al. (1999) determined that FANCG is required for binding between FANCA and FANCC and that all 3 proteins are components of a nuclear protein complex. The N-terminal nuclear localization signal of FANCA was required for FANCG binding, FANCC binding, and for complementation of mitomycin C sensitivity in FAA lymphocytes, as well as for nuclear localization. Analysis of the protein interactions formed by lymphoblasts from each of the complementation groups suggested that the interaction between FANCA and FANCG is constitutive and is not regulated by FANCC or by the products of other FA genes. In contrast, the binding of FANCC required FANCA/FANCG binding and the products of other FA genes. </p><p>Otsuki et al. (1999) identified a sorting nexin protein, SNX5 (605937), as a FANCA-binding protein. They found that overexpression of SNX5 increased FANCA protein levels and suggested that FANCA may affect SNX5 traffic with cell surface receptors. </p><p>Otsuki et al. (2001) used yeast 2-hybrid analysis and immunofluorescence to identify an interaction between FANCA and the brm-related gene-1 (BRG1; 603254) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity. The authors suggested that FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair. </p><p>By in situ hybridization studies of the murine Fancc gene, Krasnoshtein and Buchwald (1996) found that Fancc is expressed initially (embryonic days 8 to 10) in the mesenchyme and its derivatives with osteogenic potential, and at later stages (embryonic days 13 to 19.5) in other cells involved in bone development. Fancc expression was also observed in the brain, whisker follicles, lung, kidney, gut, and stomach. Abu-Issa et al. (1999) reasoned that a comparison of the expression patterns of Fancc and Fanca might clarify the functional relationship between these 2 subgroups and show tissue targets that are differentially sensitive to FA mutations. By in situ hybridization, they found Fanca transcripts in the whisker follicles, teeth, brain, retina, kidney, liver, and limbs. There was also a stage-specific variation in Fanca expression, particularly within the developing whiskers and the brain. Some tissues known to express Fancc (e.g., gut) failed to show Fanca expression. These observations showed that (1) Fanca is under both tissue- and stage-specific regulation in several tissues; (2) the expression pattern of Fanca is consistent with the phenotype of the human disease; and (3) Fanca expression is not necessarily coupled to that of Fancc. The presence of distinct tissue targets for FA genes suggested that some of the variability in the clinical phenotype can be attributed to the complementation group assignment. </p><p>Wong et al. (2000) determined that mouse Fanca could restore the drug sensitivity of human FAA lymphoblasts to mitomycin C. It did not alter the drug sensitivity of a wildtype human lymphoblast cell line. </p><p>Donahue and Campbell (2002) found that fibroblasts from FA patients from complementation groups A, C, D2, and G were hypersensitive to restriction enzyme-induced cell death following electroporation of restriction enzymes. These fibroblasts also showed reduced efficiency in plasmid end-joining activity. Normal sensitivity and activity were restored following retrovirus-mediated expression of the respective FA cDNAs. </p><p>Folias et al. (2002) used yeast 2-hybrid analysis and coimmunoprecipitation methods to demonstrate a direct interaction between the FANCA and BRCA1 proteins. Direct interaction with other FANC proteins was not demonstrable. The amino terminal portion of FANCA and the central part (amino acids 740-1,083) of BRCA1 contained the sites of interaction. The interaction did not depend on DNA damage, suggesting that FANCA and BRCA1 may be constitutively interacting. </p><p>By coimmunoprecipitation of HeLa cell nuclear extracts, Meetei et al. (2003) identified 3 distinct multiprotein complexes associated with BLM (RECQL3; 604610). One of the complexes, designated BRAFT, contained the Fanconi anemia core complementation group proteins FANCA, FANCG, FANCC, FANCE, and FANCF, as well as topoisomerase III-alpha (TOP3A; 601243) and replication protein A (RPA; see 179835). BLM complexes isolated from an FA cell line had a lower molecular mass, likely due to loss of FANCA and other FA components. BLM- and FANCA-associated complexes had DNA unwinding activity, and BLM was required for this activity. </p><p>Zhang et al. (2004) used immunoprecipitation and reconstituted kinase assays to show that the FANCC, FANCA, and FANCG proteins functionally interacted with and inhibited the proapoptotic kinase PKR (176871), a kinase that represses translation when activated. PKR showed strongest binding to the FANCC protein. PKR activity was increased in bone marrow cells of patients with Fanconi anemia with mutations in the FANCC, FANCA, and FANCG genes. All 3 of these cell lines showed significant increases in PKR bound to the FANCC protein, which correlated with increased PKR activation. The cells also showed hypersensitivity to growth repression mediated by IFN-gamma (147570) and TNF-alpha (191160). Forced expression of a patient-derived FANCC mutation increased PKR activation and cell death. Zhang et al. (2004) concluded that FA mutations cause increased binding of PKR to FANCC and increased PKR activation, leading to growth inhibition of hematopoietic progenitors and bone marrow failure in Fanconi anemia. </p><p>Ferrer et al. (2005) investigated the possibility that FANCA, FANCC, and FANCG may be subjected to active export out of the nucleus. After treatment with leptomycin B, a specific inhibitor of CRM1 (XPO1; 602559)-mediated nuclear export, the accumulation of epitope-tagged FANCA in the nucleus increased, whereas FANCC was affected to a lesser extent, and FANCG showed no response. CRM1-mediated export of FANCA was further confirmed using CRM1 cotransfection, which led to a dramatic relocalization of FANCA to the cytoplasm. Five functional leucine-rich nuclear export sequences distributed throughout the FANCA sequence were identified and characterized using an in vivo export assay. Ferrer et al. (2005) concluded that FANCA can be actively exported out of the nucleus by CRM1, revealing a novel mechanism to regulate the function of the FA protein complex. </p><p>Using yeast 2-hybrid and coimmunoprecipitation assays, Tremblay et al. (2008) found that HES1 (139605), a NOTCH1 (190198) pathway component involved in hematopoietic stem cell (HSC) self-renewal, interacted directly with FANCA, FANCF, FANCG, and FANCL, but not with other FA core complex components. Mutation analysis showed that interactions with individual FA core components required different domains within HES1. HES1 did not interact with FA core components if any of them contained an FA-related mutation, suggesting that a functional FA pathway is required for HES1 interaction. Depletion of HES1 from HeLa cells resulted in failure of normal interactions between individual FA core components, as well as altered protein levels and mislocalization of some FA core components. Depletion of HES1 also increased cell sensitivity to mitomycin C (MMC) and reduced MMC-induced monoubiquitination of FANCD2 and localization of FANCD2 to MMC-induced foci. Tremblay et al. (2008) concluded that interaction with HES1 is required for normal FA core complex function in the DNA damage response. They proposed that the HSC defect in FA may result from the inability of HES1 to interact with the defective FA core complex. </p>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>RT-PCR and direct sequencing of PCR products from FAA patients by the Fanconi Anaemia/Breast Cancer Consortium (1996) led to the identification of 4 different mutations (607139.0001-607139.0004). The authors postulated that the introns of the FAA gene may contain repetitive unstable sequences susceptible to deletion. </p><p>Levran et al. (1997) used SSCP analysis to screen genomic DNA from a panel of 97 racially and ethnically diverse FA patients from the International Fanconi Anemia Registry for mutations in the FAA gene. A total of 85 variant bands were detected. Forty-five of the variants were probably benign polymorphisms, of which 9 are common and can be used for various applications, including mapping studies for other genes in this region of 16q. Amplification refractory mutation system assays were developed to simplify their detection. Forty variants were considered probable pathogenic mutations. Seventeen of these were microdeletions/microinsertions associated with short direct repeats or homonucleotide tracts, a type of mutation thought to be generated by a mechanism of slipped-strand mispairing during DNA replication. A screening of 350 FA probands from the registry for 2 of these deletions (1115-1118del and 3788-3790del) revealed that they are carried on about 2% and 5% of the FA alleles, respectively. The second of these was found in a variety of ethnic groups and existed on at least 2 different haplotypes. Levran et al. (1997) suggested that FAA is hypermutable, and that slipped-strand mispairing, a mutational mechanism recognized as important for the generation of germline and somatic mutations in a variety of cancer-related genes, including p53 (191170), APC (611731), RB1 (614041), WT1 (194070), and BRCA1 (113705), may be a major mechanism for FAA mutagenesis. They speculated that FAA is a member of the 'caretaker' gene family according to the caretaker-gatekeeper model of Kinzler and Vogelstein (1997): inactivation of a caretaker gene results in a higher mutation rate in all genes, including gatekeeper genes that directly regulate tumor growth. </p><p>Levran et al. (1998) reported the occurrence of Alu-mediated genomic deletions in the FACA gene. Two different deletions of 1.2 kb and 1.9 kb were found in patients with Fanconi anemia. Both deletions included exons 16 and 17 and removed a 156-bp segment from the transcript, causing a shorter in-frame message. Introns 15 and 17 are rich in partial and complete Alu repeats. Sequence analysis of the deletion showed that the 5-prime breakpoints occurred at different sites in the same Alu element in intron 15, while the 3-prime breakpoints were located in different Alu repeats in intron 17. Numerous Alu repeats are present in the FACA gene, suggesting that Alu-mediated recombination may be an important mechanism for the generation of Fanconi anemia-producing mutations. </p><p>Wijker et al. (1999) investigated the molecular pathology of Fanconi anemia by screening the FAA gene for mutations in a panel of 90 patients identified by the European FA research group, EUFAR. A highly heterogeneous spectrum of mutations were identified, with 31 different mutations being detected in 34 patients. The mutations were scattered throughout the gene, and most were predicted to result in the absence of the FAA protein. A surprisingly high frequency of intragenic deletions was detected, which removed between 1 and 30 exons from the gene. Most microdeletions and insertions occurred at homopolymeric tracts or direct repeats within the coding sequence. These features had not been observed in the FAC gene (227645) and may indicate a higher mutation rate in FAA, which accounts for 60 to 65% of all Fanconi anemia cases. The heterogeneity of the mutation spectrum and the frequency of intragenic deletions present a considerable challenge for the molecular diagnosis of FA. </p><p>Waisfisz et al. (1999) demonstrated functional correction of a pathogenic microdeletion, microinsertion, and missense mutation in homozygous Fanconi anemia patients resulting from compensatory secondary sequence alterations in cis. The frameshift mutation 1615delG in FANCA was compensated by 2 additional single basepair deletions, 1637delA and 1641delT (607139.0005). Another FANCA frameshift mutation, 3559insG, was compensated by 3580insCGCTG (607139.0006). Although the predicted proteins were different from wildtype, their cDNAs complemented the characteristic hypersensitivity of FA cells to crosslinking agents, thus establishing a functional correction to wildtype. </p><p>Reports of several large deletions of FANCA, coupled with only modest mutation-detection rates, led Morgan et al. (1999) to investigate whether many deletions might occur in heterozygous state and thus fail to be detected by current screening protocols. They used a 2-step screening strategy, in which small mutations were detected by fluorescent chemical cleavage of the FANCA transcript and heterozygosity for gross deletions was detected by quantitative fluorescent multiplex PCR. The authors screened 26 cell lines from FA complementation group A for FANCA mutations and detected 33 different mutations, 23 of which were novel. Mutations were observed in all 26 cell lines and included 43 of a possible 52 mutant alleles (83%). Of the mutant alleles, 40% were large intragenic deletions that removed up to 31 exons from the gene, indicating that this may be the most prevalent form of mutation in FANCA. Several common deletion breakpoints were observed, and there was a highly significant correlation between the number of breakpoints detected in a given intron and the number of Alu repeats that it contained, which suggested that Alu-mediated recombination may explain the high prevalence of deletions in FANCA. </p><p>In 13 Israeli non-Ashkenazi Jewish patients with FA, Tamary et al. (2000) found 4 ethnic-specific mutations: 2 Moroccan mutations, 1 Tunisian mutation, and 1 Indian mutation. The tetranucleotide CCTG motif, previously identified as a mutation hotspot in FANCA and other human genes, was found in the vicinity of 2 of the mutations. All carriers within each ethnic group had the same haplotype, suggesting a common founder for each mutation. </p><p>Although revertant mosaicism in FA had been demonstrated in cultured T cells and lymphoblastoid cell lines, the question remained whether genetic reversion ever occurs in the pluripotent lymphohematopoietic stem cell. Gregory et al. (2001) therefore examined each lymphohematopoietic and stromal cell lineage in an FA patient with a 2815-2816ins19 mutation in FANCA and known lymphocyte somatic mosaicism. DNA extracted from individually plucked peripheral blood T-cell colonies and marrow colony-forming unit granulocyte-macrophage and burst-forming unit erythroid cells revealed absence of the maternal FANCA exon 29 mutation in 74.0%, 80.3%, and 86.2% of colonies, respectively. These data, together with the absence of the FANCA exon 29 mutation in Epstein-Barr virus-transformed B cells and its presence in fibroblasts, indicated that genotypic reversion, most likely because of back mutation, originated in a lymphohematopoietic stem cell and not solely in a lymphocyte population. Contrary to a predicted increase in marrow cellularity resulting from reversion in a hematopoietic stem cell, pancytopenia was progressive. The subsequent development of a clonal cytogenetic abnormality in nonrevertant cells suggested that ex vivo correction of hematopoietic stem cells by gene transfer may not be sufficient for providing lifelong stable hematopoiesis in patients with FA. </p><p>Revertant mosaicism improves the prognosis in patients with FA. Mechanisms of reversion include back mutation, intragenic crossover, gene conversion, and compensating deletions/insertions. Gross et al. (2002) described the types of reversions found in 5 mosaic FA patients who were compound heterozygotes for single base mutations in FANCA or FANCC. In the 1 FANCC patient, intragenic crossover was the mechanism of self-correction. In the 4 FANCA patients, restoration to wildtype via back mutation or gene conversion of either the paternal or maternal allele was observed. The sequence environments of these mutations/reversions were indicative of high mutability, and selective advantage of bone marrow precursor cells carrying a completely restored FANCA allele might explain the surprisingly uniform pattern of these reversions. Gross et al. (2002) also described the first example of in vitro phenotypic reversion via the emergence of a compensating missense mutation 15 amino acids downstream of the constitutional mutation, which explained the reversion to mitomycin C resistance of the respective lymphoblastoid cell line. With 1 exception (the FANCC patient), the mosaic patients showed improvement of their hematologic status during a 3- to 6-year observation, indicating a proliferative advantage of the reverted cell lineages. In patients with FA, genetic instability due to defective caretaker genes sharply increases the risk of neoplasia, but at the same time increases the chance for revertant mosaicism leading to improved bone marrow function. </p><p>Joenje and Patel (2001) reviewed the molecular basis of Fanconi anemia. They referred to Fanconi anemia, xeroderma pigmentosum (see 278700), and hereditary nonpolyposis colorectal cancer (see 120435), all of which feature genomic instability in combination with a strong predisposition to cancer, as 'caretaker-gene diseases.' The common feature of these disorders is an impaired capacity to maintain genomic integrity, which results in the accelerated accumulation of key genetic changes that promote cellular transformation and neoplasia. Cancer predisposition in these diseases is therefore an indirect result of the primary genetic defect. Grompe and D'Andrea (2001) reviewed the molecular genetics of FA and noted the presumed interaction of BRCA1 with the 8 FA complementation group proteins in a model of interstrand crosslink repair. </p><p>To characterize the molecular defects underlying FA in Tunisia, Bouchlaka et al. (2003) genotyped 39 families for microsatellite markers linked to known FA genes. Haplotype analysis and homozygosity mapping assigned 43 patients belonging to 34 families to the FAA group, whereas 1 family was probably not linked to any known FA genes. </p><p>Systematic mutation analysis of the FANCA gene, including gene dosage assay to detect large deletions, had not previously been documented for Asian populations. Yagasaki et al. (2004) detected 48 mutant alleles of FANCA in 27 (77%) of 35 unrelated Japanese FA families with no detectable mutations in FANCC (227645) or FANCG (602956). They identified 29 different mutations (21 nucleotide substitutions or small deletions/insertions and 8 large deletions), at least 20 of which were novel. Yagasaki et al. (2004) stated that the FANCA mutational spectrum of the Japanese was different from that of other ethnic groups studied theretofore. </p><p>Based on the International Fanconi Anemia Registry (IFAR), Levran et al. (2005) reviewed the spectrum of sequence variations in the FANCA gene. They stated that the FANCA complementation group accounts for approximately 65% of all affected individuals with Fanconi anemia. Their review identified 61 novel FANCA mutations identified in FA patients registered by IFAR. They also reported on single nucleotide polymorphisms (SNPs) and concluded that the FANCA SNP data were highly useful for carrier testing, prenatal diagnosis, and preimplantation genetic diagnosis, particularly when the disease-causing mutations were unknown. By detection of apparent homozygosity for rare SNPs, 22 large genomic deletions were identified. In addition, a conserved SNP haplotype block spanning at least 60 kb of the FANCA gene was identified in individuals from various ethnic groups, suggesting an ancient origin. </p><p>In 2 infertile Spanish brothers and an unrelated infertile Spanish man, who were azoospermic and exhibited Sertoli cell-only syndrome (SCO; see 400042) on testicular histology, Krausz et al. (2019) identified homozygosity and compound heterozygosity for mutations in the FANCA gene (607139.0013-607139.0015). Laboratory evaluation showed low platelets, red blood cells, and leukocytes in 1 brother and the unrelated man; DEB-induced chromosomal breakage results were consistent with somatic mosaicism in the other brother. The authors suggested that screening for FANCA variants in infertile men with SCO might identify undiagnosed FA patients before the appearance of severe clinical manifestations of the disease. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Wong et al. (2003) generated Fanca -/- mice in which Fanca exons 1 through 6 were replaced by a beta-galactosidase reporter construct. Homozygotes displayed FA-like phenotypes including growth retardation, microphthalmia, craniofacial malformations (not found in other Fanca mouse models), and hypogonadism. Homozygous females demonstrated premature reproductive senescence and an increased incidence of ovarian cysts. The fertility defects in homozygotes may be related to a diminished population of primordial germ cells during migration into the gonadal ridges. Homozygous males exhibited an elevated frequency of mispaired meiotic chromosomes and increased apoptosis in germ cells, implicating a role for Fanca in meiotic recombination. The authors suggested that the FA pathway may play a role in the maintenance of reproductive germ cells and in meiotic recombination. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>15 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FANCA, 274-BP DEL
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<br />
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ClinVar: RCV000003608
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>The Fanconi Anaemia/Breast Cancer Consortium (1996) identified a 274-bp deletion of the FANCA gene in an Italian patient with Fanconi anemia (FANCA; 227650), which resulted in the loss of nucleotides 1671 to 1944, a frameshift, and the creation of a premature termination codon 6 residues downstream. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FANCA, 4-BP DEL, NT1155
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<br />
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SNP: rs397507552,
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gnomAD: rs397507552,
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ClinVar: RCV000003609, RCV000463426, RCV001091063, RCV004742211
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 members of a family of British origin with Fanconi anemia (FANCA; 227650), the Fanconi Anaemia/Breast Cancer Consortium (1996) identified a deletion of 1 of 2 direct repeats of the sequence TTGG at nucleotides 1155-1162 of the FANCA gene. The deletion resulted in a frameshift and the production of a termination codon 42 residues downstream. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FANCA, 156-BP DEL, NT1515
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<br />
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ClinVar: RCV000003610
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>The Fanconi Anaemia/Breast Cancer Consortium (1996) identified in 2 families with Fanconi anemia (FANCA; 227650) a deletion in the FANCA gene of 156 bp (from nucleotides 1515 to 1670) that spans 2 exons. One patient was of African American origin and one was of northern European origin (and a compound heterozygote for another deletion; see 607139.0004). This 156-bp deletion did not result in a frameshift but led to the deletion of 52 amino acids from the protein. The deletion was not found in 70 control chromosomes, suggesting to the investigators that it did not represent alternative splicing. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FANCA, 113-BP DEL, NT938
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<br />
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ClinVar: RCV000003611
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>A patient of northern European origin with Fanconi anemia (FANCA; 227650) was found by the Fanconi Anaemia/Breast Cancer Consortium (1996) to be compound heterozygous for 2 mutations in the FANCA gene: a 113-bp deletion spanning nucleotides 938 to 1050, and a 156-bp deletion (607139.0003). The 113-bp deletion removes a single exon from the coding sequence and creates a premature stop codon 2 residues downstream. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FANCA, 1-NT DEL, 1615G
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<br />
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SNP: rs778507965,
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gnomAD: rs778507965,
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ClinVar: RCV000003612, RCV001046987, RCV003228892
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with Fanconi anemia (FANCA; 227650), Waisfisz et al. (1999) identified homozygous deletion of a G at nucleotide 1615 in exon 17 of the FANCA gene. Sequence analysis revealed 2 de novo single-basepair deletions at 1 allele, 1637delA and 1641delT, in exon 18. A cDNA containing the three 1-bp deletions transfected into an FAA lymphoblastoid cell line complemented the phenotype to the same extent as a construct expressing wildtype FANCA. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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|
FANCA, 1-NT DEL, 3559G
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<br />
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SNP: rs747851434,
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|
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gnomAD: rs747851434,
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|
|
ClinVar: RCV000003613, RCV000630905, RCV001818121, RCV003398432
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|
</span>
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|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Fanconi anemia (FANCA; 227650), Waisfisz et al. (1999) found a 3559insG frameshift in exon 36 of the FANCA gene on both alleles. An additional de novo insertion (3580insCGCTG or 3576insGCTGC) in the same exon restored the open reading frame. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
|
FANCA, EX12-31DEL
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|
|
<br />
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|
|
ClinVar: RCV000003614
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|
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|
|
</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Tipping et al. (2001) identified an intragenic deletion of exons 12-31 of the FANCA gene as accounting for 60% of Fanconi anemia chromosomes in 46 unrelated Afrikaner FA (see FANCA, 227650) patients. Two other mutations, also deletions, accounted for an additional 20%. By genealogic investigation of 12 Afrikaner families with FA, they traced the major deletion to a French Huguenot couple who arrived at the Cape in 1688. The same mutation and haplotype was found in an FANCA patient from the western Ruhr region of Germany. It was thus possible that the major founder mutation was introduced into South Africa from that region. Rhinelanders were a substantial component of the crew of the ships of the Dutch East India Company, and about one-third of the original European population of the Cape were of German origin. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
FANCA, 1-BP DEL, 1606T
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|
|
<br />
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|
|
SNP: rs587776570,
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|
|
ClinVar: RCV000003615
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Tunisian patient with Fanconi anemia (FANCA; 227650), Bouchlaka et al. (2003) identified homozygosity for a 1-bp deletion, 1606delT, in exon 17 of the FANCA gene. The deletion resulted in a shift in the reading frame and production of a termination codon 21 amino acids downstream. </p>
|
|
</span>
|
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</div>
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<div>
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|
<br />
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|
</div>
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</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
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<div>
|
|
<span class="mim-text-font">
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|
|
FANCA, TRP171TER
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|
|
<br />
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|
|
SNP: rs121907930,
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|
|
ClinVar: RCV000003616
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|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Tunisian family with Fanconi anemia (FANCA; 227650), Bouchlaka et al. (2003) identified a 513G-A transition in exon 5 of the FANCA gene. This change resulted in a trp171-to-ter (W171X) substitution, and therefore to a premature termination of the FANCA protein. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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FANCA, 5-BP DEL, NT3720
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<br />
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SNP: rs794726660,
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ClinVar: RCV000003617, RCV001851619
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 presumably unrelated Japanese patients with Fanconi anemia (FANCA; 227650), Yagasaki et al. (2004) found a 5-bp deletion (AAACA) at cDNA nucleotides 3720-3724 in exon 37 of the FANCA gene (3720_3724del). In 1 case the mutation was homozygous. The mutation resulted in aberrant splicing which caused skipping of exon 37. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0011 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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FANCA, ARG853TER
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<br />
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|
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SNP: rs752160950,
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gnomAD: rs752160950,
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ClinVar: RCV000173013, RCV000630944
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a cell line derived from a proband with Fanconi anemia of complementation group A (FANCA; 227650), Singh et al. (2009) identified compound heterozygous mutations in the FANCA gene: a c.2557C-T transition, resulting in an arg853-to-ter (R853X) substitution, and a G-to-A transition in intron 7 (IVS7+5G-A; 607139.0012), resulting in a 30-bp insertion in the FANCA mRNA, which adds 10 amino acids between residues 236 and 237 of the protein. Expression of the mutant FANCA protein was unable to restore FANDC2 monoubiquitination in FANCA-deficient lymphoblasts, demonstrating that the splice site mutation is pathogenic. Each unaffected parent was heterozygous for 1 of the mutations. This patient had a sib (EUFA867) who had no clinical symptoms of Fanconi anemia but whose cell lines carried the same biallelic FANCA mutations. Both patients were originally reported by Meetei et al. (2005) as having Fanconi anemia, complementation group M due to compound heterozygous mutations in the FAAP250 gene (FANCM; 609644). However, Singh et al. (2009) stated that the proband only carried 1 of the FAAP250 mutations, which in retrospect reclassified this patient as having FANCA. The clinically unaffected sib carried both biallelic mutations in the FANCA gene and biallelic variants in the FAAP250 gene (see 609644.0001 and 609644.0002). </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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FANCA, IVS7DS, G-A, +5
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<br />
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SNP: rs759877008,
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gnomAD: rs759877008,
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ClinVar: RCV000474895, RCV000673202, RCV001821265
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the IVS7+5G-A mutation in the FANCA gene that was found in compound heterozygous state in a patient with Fanconi anemia of complementation group A (FANCA; 227650) by Singh et al. (2009), see 607139.0011. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0013 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FANCA, ARG880GLN
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<br />
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SNP: rs372254398,
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gnomAD: rs372254398,
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ClinVar: RCV000671284, RCV000803258, RCV003478396, RCV004742565
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 infertile Spanish brothers from a consanguineous family with nonobstructive azoospermia and Sertoli cell-only syndrome on testicular biopsy, 1 of whom also had low erythrocyte, leukocyte, and platelet counts (FANCA; 227650), Krausz et al. (2019) identified homozygosity for a c.2639G-A transition (c.2639G-A, NM_000135.2) in exon 28 of the FANCA gene, resulting in an arg880-to-gln (R880Q) substitution. The DEB-induced chromosomal breakage test was consistent with somatic mosaicism in the proband (patient 04-170), whereas his brother had typical complete Fanconi anemia. DNA from their parents was unavailable for segregation analysis; however, the authors noted that the R880Q variant had previously been reported in a Spanish patient with Fanconi anemia (Castella et al., 2011) and was also present in heterozygosity and homozygosity in 8 patients in the Rockefeller University FA Mutation Database. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0014 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FANCA, 3-BP DEL, 3788TCT
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<br />
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SNP: rs397507553,
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gnomAD: rs397507553,
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ClinVar: RCV000033896, RCV000120945, RCV000231918, RCV000485336, RCV003924889
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Spanish man (patient 14-339) with nonobstructive azoospermia and Sertoli cell-only syndrome on testicular biopsy, who also had low erythrocyte, leukocyte, and platelet counts and elevated mean corpuscular volume (FANCA; 227650), Krausz et al. (2019) identified compound heterozygosity for an in-frame 3-bp deletion (c.3788_3790delTCT, NM_000135.2) in exon 38 of the FANCA gene, causing deletion of a single residue (phe1263del), and a c.3913C-T transition in exon 39, resulting in a leu1305-to-phe (L1305F; 607139.0015) substitution. The DEB-induced chromosomal breakage test was consistent with somatic mosaicism in the proband. His normozoospermic brother, who had blood counts within the normal range, was heterozygous for the L1305F mutation. The authors stated that both mutations had previously been reported in many patients with Fanconi anemia. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0015 FANCONI ANEMIA, COMPLEMENTATION GROUP A</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FANCA, LEU1305PHE
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<br />
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SNP: rs753700179,
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gnomAD: rs753700179,
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ClinVar: RCV000672199, RCV001222479
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.3913C-T transition (c.3913C-T, NM_000135.2) in exon 39 of the FANCA gene, resulting in a leu1305-to-phe (L1305F) substitution, that was found in compound heterozygous state in a patient with Fanconi anemia (FANCA; 227650) by Krausz et al. (2019), see 607139.0014. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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Abu-Issa, R., Eichele, G., Youssoufian, H.
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<strong>Expression of the Fanconi anemia group A gene (Fanca) during mouse embryogenesis.</strong>
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Blood 94: 818-824, 1999.
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<strong>Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations.</strong>
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Folias, A., Matkovic, M., Bruun, D,, Reid, S., Hejna, J., Grompe, M., D'Andrea, A., Moses, R.
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[PubMed: 12354784]
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[Full Text: https://doi.org/10.1093/hmg/11.21.2591]
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Garcia-Higuera, I., Kuang, Y., Naf, D., Wasik, J., D'Andrea, A. D.
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<strong>Fanconi anemia proteins FANCA, FANCC, and FANCG/XRCC9 interact in a functional nuclear complex.</strong>
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Goldammer, T., Kata, S. R., Brunner, R. M., Dorroch, U., Sanftleben, H., Schwerin, M., Womack, J. E.
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Gregory, J. J., Jr., Wagner, J. E., Verlander, P. C., Levran, O., Batish, S. D., Eide, C. R., Steffenhagen, A., Hirsch, B., Auerbach, A. D.
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Proc. Nat. Acad. Sci. 98: 2532-2537, 2001.
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Gschwend, M., Levran, O., Kruglyak, L., Ranade, K., Verlander, P. C., Shen, S., Faure, S., Weissenbach, J., Altay, C., Lander, E. S., Auerbach, A. D., Botstein, D.
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Ianzano, L., D'Apolito, M., Centra, M., Savino, M., Levran, O., Auerbach, A. D., Cleton-Jansen, A.-M., Doggett, N. A., Pronk, J. C., Tipping, A. J., Gibson, R. A., Mathew, C. G., Whitmore, S. A., Apostolou, S., Callen, D. F., Zelante, L., Savoia, A.
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Joenje, H., Patel, K. J.
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<p class="mim-text-font">
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Kinzler, K. W., Vogelstein, B.
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Nature 386: 761-763, 1997.
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<p class="mim-text-font">
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Krasnoshtein, F., Buchwald, M.
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Hum. Molec. Genet. 5: 85-93, 1996.
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[PubMed: 8789444]
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<p class="mim-text-font">
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Krausz, C., Riera-Escamilla, A., Chianese, C., Moreno-Mendoza, D., Ars, E., Rajmil, O., Pujol, R., Bogliolo, M., Blanco, I., Rodriguez, I., Badell, I., Ruiz-Castane, E., Surralles, J.
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<strong>From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia.</strong>
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Kupfer, G. M., Naf, D., Suliman, A., Pulsipher, M., D'Andrea, A. D.
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<p class="mim-text-font">
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Levran, O., Doggett, N. A., Auerbach, A. D.
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Hum. Mutat. 12: 145-152, 1998.
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</p>
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<li>
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<p class="mim-text-font">
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|
Levran, O., Erlich, T., Magdalena, N., Gregory, J. J., Batish, S. D., Verlander, P. C., Auerbach, A. D.
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|
<strong>Sequence variation in the Fanconi anemia gene FAA.</strong>
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Proc. Nat. Acad. Sci. 94: 13051-13056, 1997.
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[PubMed: 9371798]
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[Full Text: https://doi.org/10.1073/pnas.94.24.13051]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Marla J. F. O'Neill - updated : 02/14/2019<br>Cassandra L. Kniffin - updated : 6/22/2015<br>Patricia A. Hartz - updated : 8/28/2009<br>George E. Tiller - updated : 5/30/2008<br>Cassandra L. Kniffin - updated : 11/21/2005<br>George E. Tiller - updated : 6/6/2005<br>Victor A. McKusick - updated : 3/7/2005<br>Patricia A. Hartz - updated : 1/18/2005<br>Victor A. McKusick - updated : 1/10/2005<br>Cassandra L. Kniffin - updated : 12/16/2004<br>Victor A. McKusick - updated : 11/19/2004<br>Patricia A. Hartz - updated : 2/11/2004<br>George E. Tiller - updated : 2/3/2004<br>Victor A. McKusick - updated : 8/27/2003<br>Victor A. McKusick - updated : 5/16/2003<br>Patricia A. Hartz - updated : 1/24/2003
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