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Entry
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- *611170 - STERILE ALPHA MOTIF DOMAIN-CONTAINING PROTEIN 9-LIKE; SAMD9L
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- OMIM
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<p>
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<span class="h4">*611170</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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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<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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<a href="#geneFunction">Gene Function</a>
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<a href="#cytogenetics">Cytogenetics</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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<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/611170">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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<a href="#creationDate"><strong>Creation Date</strong></a>
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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="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=ENSG00000177409;t=ENST00000318238" 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=219285" 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=611170" 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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<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=ENSG00000177409;t=ENST00000318238" 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_001303496,NM_001303497,NM_001303498,NM_001303500,NM_001350082,NM_001350083,NM_001350084,NM_001350085,NM_152703" 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_152703" 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=611170" 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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<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=10798&isoform_id=10798_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/SAMD9L" 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/21739761,21756886,27371136,33319793,37781076,37781078,37781080,37781082,37781084,51094899,51339291,68525487,117558679,117558792,118142860,119597230,119597231,146325547,194385566,194388298,745399085,745399093,745399104,745399111,929654817,1174097916,1174097918,1174097920,1174097922" 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/Q8IVG5" 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 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=219285" 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=ENSG00000177409;t=ENST00000318238" 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=SAMD9L" 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=SAMD9L" 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+219285" 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/SAMD9L" 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:219285" 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/219285" 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=chr7&hgg_gene=ENST00000318238.9&hgg_start=93130056&hgg_end=93148385&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>
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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://medlineplus.gov/genetics/gene/samd9l" 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=611170[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=611170[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://gnomad.broadinstitute.org/gene/ENSG00000177409" 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=SAMD9L" 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=SAMD9L" 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=SAMD9L" 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="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SAMD9L&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/PA25949" 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:1349" 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:1343184" 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/SAMD9L#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:1343184" 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/219285/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=219285" 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-130530-738" 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="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">
|
|
<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://reactome.org/content/query?q=SAMD9L&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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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 768556005<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
611170
|
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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>
|
|
<h3>
|
|
<span class="mim-font">
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|
STERILE ALPHA MOTIF DOMAIN-CONTAINING PROTEIN 9-LIKE; SAMD9L
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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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<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">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SAMD9L" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SAMD9L</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/7/414?start=-3&limit=10&highlight=414">7q21.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:93130056-93148385&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'})">7:93,130,056-93,148,385</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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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="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
|
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Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=619806,159550,252270" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
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</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
|
</thead>
|
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<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/7/414?start=-3&limit=10&highlight=414">
|
|
7q21.2
|
|
</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
?Spinocerebellar ataxia 49
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
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</span>
|
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</td>
|
|
<td>
|
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<span class="mim-font">
|
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<a href="/entry/619806"> 619806 </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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|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Ataxia-pancytopenia syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/159550"> 159550 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
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</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Monosomy 7 myelodysplasia and leukemia syndrome 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/252270"> 252270 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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>
|
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
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<p>The SAMD9L gene encodes a protein that negatively regulates cell proliferation (summary by <a href="#11" class="mim-tip-reference" title="Tesi, B., Davidsson, J., Voss, M., Rahikkala, E., Holmes, T. D., Chiang, S. C. C., Komulainen-Ebrahim, J., Gorcenco, S., Nilsson, A. R., Ripperger, T., Kokkonen, H., Bryder, D., and 13 others. <strong>Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms.</strong> Blood 129: 2266-2279, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28202457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28202457</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28202457[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-2016-10-743302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28202457">Tesi et al., 2017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28202457" 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>During their analysis of the SAMD9 gene (<a href="/entry/610456">610456</a>), <a href="#5" class="mim-tip-reference" title="Li, C. F., MacDonald, J. R., Wei, R. Y., Ray, J., Lau, K., Kandel, C., Koffman, R., Bell, S., Scherer, S. W., Alman, B. A. <strong>Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse.</strong> BMC Genomics 8: 92, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17407603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17407603</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17407603[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/10.1186/1471-2164-8-92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17407603">Li et al. (2007)</a> identified SAMD9L. They amplified full-length SAMD9L by PCR of an aggressive fibromatosis tumor cDNA library. The deduced protein contains an N-terminal SAM domain. Database analysis indicated that SAMD9L can undergo alternative splicing leading to an alternative coding region. PCR analysis detected SAMD9L in all adult and fetal human tissues examined except some tumor tissues. Orthologs of SAMD9L were detected in all mammals examined but not in chicken, frog, or fish species. The authors noted that while Samd9 is absent from the mouse genome due to a mouse-specific gene rearrangement, Samd9l is found in the mouse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17407603" 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 PCR, <a href="#4" class="mim-tip-reference" title="Jiang, Q., Quaynor, B., Sun, A., Li, Q., Matsui, H., Honda, H., Inaba, T., Sprecher, E., Uitto, J. <strong>The Samd9L gene: transcriptional regulation and tissue-specific expression in mouse development.</strong> J. Invest. Derm. 131: 1428-1434, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21412262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21412262</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21412262[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/jid.2011.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21412262">Jiang et al. (2011)</a> detected expression of Samd9l in most of 20 mouse tissues examined, with highest expression in kidney, followed by spleen, stomach, and adrenal gland. Samd9l expression was low during mouse embryonic development, but it increased gradually in kidney to adult levels after birth. Immunohistochemical analysis of wildtype mouse kidney and kidney from heterozygous mice expressing LacZ from the Samd9l promoter revealed Samd9l expression in proximal and distal tubules, but not in glomeruli. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21412262" 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="#3" class="mim-tip-reference" title="Corral-Juan, M., Casquero, P., Giraldo-Restrepo, N., Laurie, S., Martinez-Pineiro, A., Mateo-Montero, R. C., Ispierto, L., Vilas, D., Tolosa, E., Volpini, V., Alvarez-Ramo, R., Sanchez, I., Matilla-Duenas, A. <strong>New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).</strong> Brain Commun. 4: fcac030, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35310830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35310830</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35310830[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/10.1093/braincomms/fcac030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35310830">Corral-Juan et al. (2022)</a> found expression of the SAMD9L gene in a punctate pattern consistent with mitochondrial localization in the soma of cerebellar Purkinje cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35310830" 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="#5" class="mim-tip-reference" title="Li, C. F., MacDonald, J. R., Wei, R. Y., Ray, J., Lau, K., Kandel, C., Koffman, R., Bell, S., Scherer, S. W., Alman, B. A. <strong>Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse.</strong> BMC Genomics 8: 92, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17407603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17407603</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17407603[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/10.1186/1471-2164-8-92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17407603">Li et al. (2007)</a> determined that the SAMD9L gene contains 6 exons spanning 17.6 kb. It has a TATA signal and 2 predicted LEF (LEF1; <a href="/entry/153245">153245</a>)-binding elements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17407603" 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="#5" class="mim-tip-reference" title="Li, C. F., MacDonald, J. R., Wei, R. Y., Ray, J., Lau, K., Kandel, C., Koffman, R., Bell, S., Scherer, S. W., Alman, B. A. <strong>Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse.</strong> BMC Genomics 8: 92, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17407603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17407603</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17407603[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/10.1186/1471-2164-8-92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17407603">Li et al. (2007)</a> mapped the SAMD9L gene to chromosome 7q21.2, 5-prime upstream of the SAMD9 gene. The mouse Samd9l gene maps to proximal chromosome 6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17407603" 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>Using a reporter gene assay, <a href="#4" class="mim-tip-reference" title="Jiang, Q., Quaynor, B., Sun, A., Li, Q., Matsui, H., Honda, H., Inaba, T., Sprecher, E., Uitto, J. <strong>The Samd9L gene: transcriptional regulation and tissue-specific expression in mouse development.</strong> J. Invest. Derm. 131: 1428-1434, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21412262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21412262</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21412262[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/jid.2011.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21412262">Jiang et al. (2011)</a> identified regulatory elements as close as 87 bp upstream of the transcriptional start site of mouse Samd9l. NIH3T3 mouse fibroblast nuclear extracts tested against 96 transcription factors revealed that the Samd9l upstream region bound to Rreb1 (<a href="/entry/602209">602209</a>) and E47 (TCF3; <a href="/entry/147141">147141</a>). Real-time PCR of NIH3T3 mouse fibroblasts showed that calcitonin (CALCA; <a href="/entry/114130">114130</a>) increased expression of Samd9l, which was preceded by significant upregulation of Rreb1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21412262" 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 in vitro studies, <a href="#11" class="mim-tip-reference" title="Tesi, B., Davidsson, J., Voss, M., Rahikkala, E., Holmes, T. D., Chiang, S. C. C., Komulainen-Ebrahim, J., Gorcenco, S., Nilsson, A. R., Ripperger, T., Kokkonen, H., Bryder, D., and 13 others. <strong>Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms.</strong> Blood 129: 2266-2279, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28202457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28202457</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28202457[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-2016-10-743302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28202457">Tesi et al. (2017)</a> found that stimulation of CD34+ hematopoietic stem cells with IFNA (<a href="/entry/147660">147660</a>) or IFNG (<a href="/entry/147570">147570</a>) induced SAMD9L expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28202457" 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>Using microarray-based comparative genomic hybridization (CGH) analysis, <a href="#1" class="mim-tip-reference" title="Asou, H., Matsui, H., Ozaki, Y., Nagamachi, A., Nakamura, M., Aki, D., Inaba, T. <strong>Identification of a common microdeletion cluster in 7q21.3 subband among patients with myeloid leukemia and myelodysplastic syndrome.</strong> Biochem. Biophys. Res. Commun. 383: 245-251, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19358830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19358830</a>] [<a href="https://doi.org/10.1016/j.bbrc.2009.04.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19358830">Asou et al. (2009)</a> identified a common microdeletion involving chromosome 7q21.2-q21.3 in 8 of 21 JMML patients with normal karyotype. The microdeletion was verified by quantitative PCR analysis and involved 3 contiguous genes, SAMD9 (<a href="/entry/610456">610456</a>), SAMD9L, and HEPACAM2 (<a href="/entry/614133">614133</a>). These 3 genes were heterozygously deleted at high frequency in both adult and childhood myeloid leukemia and were commonly lost with larger chromosome 7 deletions (see <a href="/entry/252270">252270</a>) in 15 of 61 adult myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19358830" 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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In affected members of 2 unrelated families with ataxia-pancytopenia syndrome (ATXPC; <a href="/entry/159550">159550</a>), including the family originally reported by <a href="#6" class="mim-tip-reference" title="Li, F. P., Potter, N. U., Buchanan, G. R., Vawter, G., Whang-Peng, J., Rosen, R. B. <strong>A family with acute leukemia, hypoplastic anemia and cerebellar ataxia: association with bone marrow C-monosomy.</strong> Am. J. Med. 65: 933-940, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/283689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">283689</a>] [<a href="https://doi.org/10.1016/0002-9343(78)90744-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="283689">Li et al. (1978)</a>, <a href="#2" class="mim-tip-reference" title="Chen, D.-H., Below, J. E., Shimamura, A., Keel, S. B., Matsushita, M., Wolff, J., Sul, Y., Bonkowski, E., Castella, M., Taniguchi, T., Nickerson, D., Papayannopoulou, T., Bird, T. D., Raskind, W. H. <strong>Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L.</strong> Am. J. Hum. Genet. 98: 1146-1158, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27259050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27259050</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27259050[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/10.1016/j.ajhg.2016.04.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27259050">Chen et al. (2016)</a> identified 2 different heterozygous missense mutations in the SAMD9L gene (H880Q, <a href="#0001">611170.0001</a> and C1196S, <a href="#0002">611170.0002</a>). The mutation in the first family was found by a combination of linkage analysis and exome sequencing. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27259050+283689" 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 affected members of 2 unrelated families with ATXPC, <a href="#11" class="mim-tip-reference" title="Tesi, B., Davidsson, J., Voss, M., Rahikkala, E., Holmes, T. D., Chiang, S. C. C., Komulainen-Ebrahim, J., Gorcenco, S., Nilsson, A. R., Ripperger, T., Kokkonen, H., Bryder, D., and 13 others. <strong>Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms.</strong> Blood 129: 2266-2279, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28202457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28202457</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28202457[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-2016-10-743302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28202457">Tesi et al. (2017)</a> identified germline heterozygous gain-of-function mutations in the SAMD9L gene (R986C, <a href="#0003">611170.0003</a> and I891T, <a href="#0004">611170.0004</a>). The mutations, which were found by whole-exome or Sanger sequencing, segregated with the disorder in the family, although there was variable expressivity. In vitro functional expression studies in cells transfected with the mutations showed that they augmented the growth-suppressing activity of SAMD9L and halted cell proliferation compared to wildtype, consistent with a gain-of-function effect. Some patients developed MDS associated with monosomy 7; loss of chromosome 7 in these patients eliminated the SAMD9L mutations, suggesting that the SAMD9L mutations were not themselves conducive to tumor cell propagation, but that cytogenetic events eradicating the chromosome may explain the predisposition to MDS. This would be an example of 'adaptation by aneuploidy.' In contrast, other family members had less severe or limited manifestations associated with uniparental disomy of 7q or revertant SAMD9L mosaicism that likely mitigated the pathogenic effects of the familial mutations by acting as loss-of-function alleles. In in vitro studies, <a href="#11" class="mim-tip-reference" title="Tesi, B., Davidsson, J., Voss, M., Rahikkala, E., Holmes, T. D., Chiang, S. C. C., Komulainen-Ebrahim, J., Gorcenco, S., Nilsson, A. R., Ripperger, T., Kokkonen, H., Bryder, D., and 13 others. <strong>Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms.</strong> Blood 129: 2266-2279, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28202457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28202457</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28202457[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-2016-10-743302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28202457">Tesi et al. (2017)</a> found that stimulation of CD34+ hematopoietic stem cells with IFNA or IFNG induced SAMD9L expression. These findings provided a mechanism by which an immune response may lead to cytopenia, thus providing a basis for the selection of somatic SAMD9L revertant mutants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28202457" 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><strong><em>Monosomy 7 Myelodysplasia and Leukemia Syndrome 1</em></strong></p><p>
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In affected members of 4 unrelated families with variable manifestations of myelodysplasia and leukemia syndrome-1 (M7MLS1; <a href="/entry/252270">252270</a>), <a href="#12" class="mim-tip-reference" title="Wong, J. C., Bryant, V., Lamprecht, T., Ma, J., Walsh, M., Schwartz, J., del pilar Alzamora, M., Mullighan C. G., Loh, M. L., Ribeiro, R., Downing, J. R., Carroll, W. L., Davis, J., Gold, S., Rogers, R. C., Israels S., Yanofsky, R., Shannon K., Klco, J. M. <strong>Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.</strong> JCI Insight 3: 121086, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30046003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30046003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30046003[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/10.1172/jci.insight.121086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30046003">Wong et al. (2018)</a> identified heterozygous missense mutations in the SAMD9L gene (<a href="#0001">611170.0001</a>; <a href="#0003">611170.0003</a>; <a href="#0005">611170.0005</a>-<a href="#0006">611170.0006</a>). The mutations, which were filtered against public databases, segregated with the disorders in the families. In vitro functional expression studies in HEK293T cells transfected with the mutations showed that they suppressed cell cycle progression and impaired cellular growth and proliferation stronger than wildtype, consistent with a gain-of-function effect. Most patients had monosomy 7, although the phenotype was variable. The sibs in family 1 had AML, ultimately resulting in early death, whereas the patients in families 3-5 had milder hematologic abnormalities and long survival. In contrast to the patients in family 1, none of the patients in families 3, 4, or 5 had somatic mutations in genes associated with the development of MDS or AML. In addition, several patients in families 3-5 had resolution of monosomy 7 without treatment, and most had additional acquired variants in the SAMD9L gene that were demonstrated or predicted to mitigate the effects of the pathogenic germline mutation. The findings emphasized the phenotypic heterogeneity resulting from complex genetic mechanisms, including germline mutation, monosomy 7, acquired SAMD9L revertant variants, and acquired somatic changes in other genes associated with the development of MDS or AML. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30046003" 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="Schwartz, J. R., Ma, J., Lamprecht, T., Walsh, M., Wang, S., Bryant, C., Song, G., Wu, G., Easton, J., Kesserwan, C., Nichols, K. E., Mullighan, C. G., Ribeiro, R. C., Klco, J. M. <strong>The genomic landscape of pediatric myelodysplastic syndromes.</strong> Nature Commun. 8: 1557, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29146900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29146900</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29146900[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/s41467-017-01590-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29146900">Schwartz et al. (2017)</a> identified a germline heterozygous S626L variant in the SAMD9L gene (<a href="#0007">611170.0007</a>) in 2 related pediatric patients (SJ018222 and SJ018225) with M7MLS1. Although the authors classified S626L as a 'variant of uncertain significance,' they stated that in vitro functional expression studies were consistent with a gain-of-function activity leading to decreased cell proliferation. The patients did not have ataxia or a cerebellar syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29146900" 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><strong><em>Myelodysplastic Syndrome</em></strong></p><p>
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Among 799 adults with various myeloid neoplasms, including presumed acquired myelodysplastic syndrome (MDS; <a href="/entry/614286">614286</a>), bone marrow failure, and other related disorders, <a href="#8" class="mim-tip-reference" title="Nagata, Y., Narumi, S., Guan, Y., Przychodzen, B. P., Hirsch, C. M., Makishima, H., Shima, H., Aly, M., Pastor, V., Kuzmanovic, T., Radivoyevitch, T., Adema, V., and 12 others. <strong>Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes.</strong> Blood 132: 2309-2313, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30322869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30322869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30322869[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-2017-05-787390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30322869">Nagata et al. (2018)</a> identified 14 different heterozygous germline variants in the SAMD9L gene. The patients and variants were ascertained from public whole-exome sequencing databases. Most of the SAMD9L variants were missense, although there were a few frameshifts. The variants occurred throughout the gene, but tended to be located more in the N terminus compared to pediatric cases. In vitro functional expression studies of some, but not all, of the missense variants resulted in enhanced cell proliferation compared to controls, indicating a loss-of-function (LOF) effect. These variants were not subject to somatic reversion, as observed in pediatric patients with gain-of-function mutations in the SAMD9L gene. Many MDS patients had secondary somatic hits in other genes that likely contributed to the development of the disorder. <a href="#8" class="mim-tip-reference" title="Nagata, Y., Narumi, S., Guan, Y., Przychodzen, B. P., Hirsch, C. M., Makishima, H., Shima, H., Aly, M., Pastor, V., Kuzmanovic, T., Radivoyevitch, T., Adema, V., and 12 others. <strong>Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes.</strong> Blood 132: 2309-2313, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30322869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30322869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30322869[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-2017-05-787390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30322869">Nagata et al. (2018)</a> hypothesized that the late onset of MDS in these patients resulted from protracted acquisition of secondary hits in other genes associated with myeloid malignancies. Similar LOF variants in the SAMD9 gene were also identified. Overall, germline mutations in one or the other of these 2 genes were identified in about 4% of patients with adult-onset MDS and 3% with bone marrow failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30322869" 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><strong><em>Spinocerebellar Ataxia 49</em></strong></p><p>
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In 9 affected individuals from a multigenerational Spanish family (M-SCA) with spinocerebellar ataxia-49 (SCA49; <a href="/entry/619806">619806</a>), <a href="#3" class="mim-tip-reference" title="Corral-Juan, M., Casquero, P., Giraldo-Restrepo, N., Laurie, S., Martinez-Pineiro, A., Mateo-Montero, R. C., Ispierto, L., Vilas, D., Tolosa, E., Volpini, V., Alvarez-Ramo, R., Sanchez, I., Matilla-Duenas, A. <strong>New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).</strong> Brain Commun. 4: fcac030, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35310830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35310830</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35310830[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/10.1093/braincomms/fcac030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35310830">Corral-Juan et al. (2022)</a> identified a heterozygous missense mutation in the SAMD9L gene (S626L; <a href="#0007">611170.0007</a>). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed decreased levels of SAMD9L compared to controls. Further analysis of patient fibroblasts showed increased mitochondrial replication and increased ATP levels compared to controls, suggesting mitochondrial stress, although there were no mtDNA alterations. There was also evidence of dysregulation of the lysosomal/autophagy pathway with diffuse mitochondrial crests and mitophagy; fibroblasts had a dilated endoplasmic reticulum and increased numbers of lysosomes. The authors postulated that the mutation prevented proper protein folding, leading to abnormal mitochondrial clearance by mitophagy and compensatory mitochondrial biogenesis. The mechanism could be haploinsufficiency or a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35310830" 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="#4" class="mim-tip-reference" title="Jiang, Q., Quaynor, B., Sun, A., Li, Q., Matsui, H., Honda, H., Inaba, T., Sprecher, E., Uitto, J. <strong>The Samd9L gene: transcriptional regulation and tissue-specific expression in mouse development.</strong> J. Invest. Derm. 131: 1428-1434, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21412262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21412262</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21412262[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/jid.2011.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21412262">Jiang et al. (2011)</a> found that both Samd9l +/- and Samd9l -/- mice showed increased susceptibility to myelogenous leukemia after 20 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21412262" 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="Nagamachi, A., Matsui, H., Asou, H., Ozaki, Y., Aki, D., Kanai, A., Takubo, K., Suda, T., Nakamura, T., Wolff, L., Honda, H., Inaba, T. <strong>Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7.</strong> Cancer Cell 24: 305-317, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24029230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24029230</a>] [<a href="https://doi.org/10.1016/j.ccr.2013.08.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24029230">Nagamachi et al. (2013)</a> found that both Samd9l -/- and Samd9l +/- mice developed myeloid disorders and died at significantly higher frequency than wildtype mice. Samd9l +/- mice expressed Samd9l mRNA in kidney at about 45% of the level in wildtype mice, and protein expression in Samd9l mice was also decreased 4-fold. Infection with MOL4070A retrovirus accelerated disease latency and frequency in Samd9l -/- and Samd9l +/- mice, and almost all Samd9l -/- and Samd9l +/- mice died of nonlymphoid hematopoietic neoplasms much earlier than mice that developed spontaneous myeloid malignancies. Samd9l deficiency enhanced reconstitution ability of stem cells and/or early hematopoietic progenitors and sensitized hematopoietic progenitors to cytokines, as Samd9l facilitated degradation of cytokine receptors through homotypic fusion of endosomes. The authors noted that because humans also have the SAMD9 gene, which is absent in mouse and encodes a protein that compensates for loss of SAMD9L, loss of 1 copy each of SAMD9 and SAMD9L in patients with monosomy 7 and interstitial deletion of 7q may not correspond to Samd9l +/- mice. However, simultaneous reduction of SAMD9 and SAMD9L mRNA by loss of 7q in humans suggested that SMAD9/SAMD9L function in human cells harboring monosomy 7 and interstitial deletion of 7q is parallel to Samd9l function in Samd9l +/- mouse cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24029230" 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="#3" class="mim-tip-reference" title="Corral-Juan, M., Casquero, P., Giraldo-Restrepo, N., Laurie, S., Martinez-Pineiro, A., Mateo-Montero, R. C., Ispierto, L., Vilas, D., Tolosa, E., Volpini, V., Alvarez-Ramo, R., Sanchez, I., Matilla-Duenas, A. <strong>New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).</strong> Brain Commun. 4: fcac030, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35310830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35310830</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35310830[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/10.1093/braincomms/fcac030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35310830">Corral-Juan et al. (2022)</a> found that zebrafish expressing the human SAMD9L S262L mutation (<a href="#0007">611170.0007</a>) had impaired locomotor activity and decreased head turning, indicating vestibular and sensory dysfunction, compared to controls. The protein showed mitochondrial localization in neurons of zebrafish larvae, including in the spinal cord, peripheral nerves, and hindbrain, where it located with ATP5B (<a href="/entry/102910">102910</a>). Mutant fish showed increased levels of the mitochondrial fusion protein DRP1 (<a href="/entry/603850">603850</a>) compared to controls, suggesting mitochondrial biogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35310830" 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=611170[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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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> rs878855336 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs878855336;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/rs878855336?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=rs878855336" 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=rs878855336" 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=RCV000234838 OR RCV001270307 OR RCV003556291 OR RCV004737387" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000234838, RCV001270307, RCV003556291, RCV004737387" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000234838...</a>
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<p><strong><em>Ataxia-Pancytopenia Syndrome</em></strong></p><p>
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In affected members of a family (UW-AP) of Irish, German, and Native American ancestry with ataxia-pancytopenia syndrome (ATXPC; <a href="/entry/159550">159550</a>), <a href="#2" class="mim-tip-reference" title="Chen, D.-H., Below, J. E., Shimamura, A., Keel, S. B., Matsushita, M., Wolff, J., Sul, Y., Bonkowski, E., Castella, M., Taniguchi, T., Nickerson, D., Papayannopoulou, T., Bird, T. D., Raskind, W. H. <strong>Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L.</strong> Am. J. Hum. Genet. 98: 1146-1158, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27259050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27259050</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27259050[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/10.1016/j.ajhg.2016.04.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27259050">Chen et al. (2016)</a> identified a heterozygous c.2640C-A transversion (c.2640C-A, NM_152703.3) in the SAMD9L gene, resulting in a his880-to-gln (H880Q) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 131), 1000 Genomes Project, Exome Variant Server, or ExAC databases. Functional studies of the variant were not performed. Patient lymphoblastoid cells were initially heterozygous for the mutation, but 2 cell lines showed loss of heterozygosity (LOH) for the mutant allele after 3 weeks to 6 months in culture, indicating that these patients were somatic mosaic for the mutation in their hematopoietic systems. The findings demonstrated a selective growth advantage in cultured cells without the mutant allele, suggesting a role for SAMD9L in the regulation of cell proliferation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27259050" 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><strong><em>Monosomy 7 Myelodysplasia and Leukemia Syndrome 1</em></strong></p><p>
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In 2 sibs (family 1) with monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; <a href="/entry/252270">252270</a>), <a href="#12" class="mim-tip-reference" title="Wong, J. C., Bryant, V., Lamprecht, T., Ma, J., Walsh, M., Schwartz, J., del pilar Alzamora, M., Mullighan C. G., Loh, M. L., Ribeiro, R., Downing, J. R., Carroll, W. L., Davis, J., Gold, S., Rogers, R. C., Israels S., Yanofsky, R., Shannon K., Klco, J. M. <strong>Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.</strong> JCI Insight 3: 121086, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30046003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30046003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30046003[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/10.1172/jci.insight.121086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30046003">Wong et al. (2018)</a> identified a heterozygous germline H880Q mutation in the SAMD9L gene that was inherited from their asymptomatic father. HEK293T cells transfected with the H880Q mutation showed suppression of cell cycle progression compared to wildtype, suggesting a gain-of-function effect. The father was found to carry a Q569P variant in SAMD9L that was in cis with H880Q and was able to partially mitigate the cell cycle abnormalities. Both sibs developed AML. Bone marrow examination of both sibs showed deletion of the paternal copy of chromosome 7, yielding monosomy 7. Deep sequencing showed that the SAMD9L gene was present at a low frequency (less than 5%) in the bone marrow of both children, indicating selective loss of the chromosome harboring the SAMD9L mutation. Leukemic cells in both affected sibs showed acquisition of somatic mutations in other genes, including RUNX1, SETBP1, BRAF, and KRAS, which likely contributed to leukemogenesis. Both patients died. The family was previously reported as family 1 by <a href="#10" class="mim-tip-reference" title="Shannon, K. M., Turhan, A. G., Chang, S. S. Y., Bowcock, A. M., Rogers, P. C. J., Carroll, W. L., Cowan, M. J., Glader, B. E., Eaves, C. J., Eaves, A. C., Kan, Y. W. <strong>Familial bone marrow monosomy 7: evidence that the predisposing locus is not on the long arm of chromosome 7.</strong> J. Clin. Invest. 84: 984-989, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2569483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2569483</a>] [<a href="https://doi.org/10.1172/JCI114262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2569483">Shannon et al. (1989)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30046003+2569483" 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>.0002 ATAXIA-PANCYTOPENIA SYNDROME</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">rs878855337 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs878855337;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=rs878855337" 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=rs878855337" 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=RCV000234841" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000234841" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000234841</a>
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<p>In 3 affected members of a Chinese family with ataxia-pancytopenia syndrome (ATXPC; <a href="/entry/159550">159550</a>) originally reported by <a href="#6" class="mim-tip-reference" title="Li, F. P., Potter, N. U., Buchanan, G. R., Vawter, G., Whang-Peng, J., Rosen, R. B. <strong>A family with acute leukemia, hypoplastic anemia and cerebellar ataxia: association with bone marrow C-monosomy.</strong> Am. J. Med. 65: 933-940, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/283689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">283689</a>] [<a href="https://doi.org/10.1016/0002-9343(78)90744-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="283689">Li et al. (1978)</a>, <a href="#2" class="mim-tip-reference" title="Chen, D.-H., Below, J. E., Shimamura, A., Keel, S. B., Matsushita, M., Wolff, J., Sul, Y., Bonkowski, E., Castella, M., Taniguchi, T., Nickerson, D., Papayannopoulou, T., Bird, T. D., Raskind, W. H. <strong>Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L.</strong> Am. J. Hum. Genet. 98: 1146-1158, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27259050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27259050</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27259050[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/10.1016/j.ajhg.2016.04.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27259050">Chen et al. (2016)</a> identified a heterozygous c.3587G-C transversion (c.3587G-C, NM_152703.3) in the SAMD9L gene, resulting in a cys1196-to-ser (C1196S) substitution at a highly conserved residue. The mutation was not found in the dbSNP (build 131), 1000 Genomes Project, or ExAC databases. Functional studies of the variant were not performed. Loss of the variant allele was not observed in cultured fibroblasts from these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27259050+283689" 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>.0003 ATAXIA-PANCYTOPENIA SYNDROME</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">rs1554341158 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554341158;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=rs1554341158" 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=rs1554341158" 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=RCV000515805 OR RCV001270308 OR RCV001557094" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000515805, RCV001270308, RCV001557094" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000515805...</a>
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<p><strong><em>Ataxia-Pancytopenia Syndrome</em></strong></p><p>
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In 7 affected members of a 3-generation family of Swedish origin (family 1) with variable manifestations of ataxia-pancytopenia syndrome (ATXPC; <a href="/entry/159550">159550</a>), <a href="#11" class="mim-tip-reference" title="Tesi, B., Davidsson, J., Voss, M., Rahikkala, E., Holmes, T. D., Chiang, S. C. C., Komulainen-Ebrahim, J., Gorcenco, S., Nilsson, A. R., Ripperger, T., Kokkonen, H., Bryder, D., and 13 others. <strong>Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms.</strong> Blood 129: 2266-2279, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28202457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28202457</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28202457[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-2016-10-743302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28202457">Tesi et al. (2017)</a> identified a heterozygous c.2956C-T transition (c.2956C-T, ENST00000318238) in the SAMD9L gene, resulting in an arg986-to-cys (R986C) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the ExAC database. In vitro functional expression studies in cells transfected with the mutation showed that it augmented the growth-suppressing activity of SAMD9L and halted cell proliferation compared to wildtype, consistent with a gain-of-function effect. The proband was a 6-year-old boy with pancytopenia and myelodysplastic syndrome (MDS) who also had monosomy 7. He underwent bone marrow transplantation and later developed neurologic symptoms. His grandfather developed MDS at age 56 years: he did not have monosomy 7. He had mildly impaired balance. None of the other affected family members had MDS, but several had transient thrombocytopenia or pancytopenia, often associated with uniparental disomy of chromosome 7q or a revertant SAMD9L variant. One unaffected 38-year-old woman who carried the R986C mutation also carried a T233N variant in the SAMD9L gene, which represented a disease-modifying loss-of-function variant that presumably mitigated the effects of the R986C mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28202457" 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><strong><em>Monosomy 7 Myelodysplasia and Leukemia Syndrome 1</em></strong></p><p>
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In 2 sisters (family 3) with monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; <a href="/entry/252270">252270</a>), <a href="#12" class="mim-tip-reference" title="Wong, J. C., Bryant, V., Lamprecht, T., Ma, J., Walsh, M., Schwartz, J., del pilar Alzamora, M., Mullighan C. G., Loh, M. L., Ribeiro, R., Downing, J. R., Carroll, W. L., Davis, J., Gold, S., Rogers, R. C., Israels S., Yanofsky, R., Shannon K., Klco, J. M. <strong>Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.</strong> JCI Insight 3: 121086, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30046003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30046003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30046003[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/10.1172/jci.insight.121086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30046003">Wong et al. (2018)</a> identified a germline heterozygous R986C mutation in the SAMD9L gene. In vitro cellular studies demonstrated a growth-suppressive effect of the mutation. The proband presented with MDS and monosomy 7. She underwent successful bone marrow transplantation and was well at age 27 years. Genetic studies of her sister, who had no overt hematologic abnormalities, detected a focal somatic deletion of 7q11-q36, which contains the SAMD9L gene, in 7 of 27 metaphase cells. She died of an unrelated cause at age 27 years. Their unaffected mother also carried the R986C mutation. All 3 individuals carried additional, but different, putative revertant variants in the SAMD9L gene (F1092L, R223X, R843W, Y568C, and E276X) that were demonstrated or predicted to abrogate the growth-suppressive properties of the R986C substitution. The authors postulated that the relatively mild clinical course in this family may have been due to the additional revertant SAMD9L variants or to a low level of monosomy 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30046003" 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">rs1554341277 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554341277;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=rs1554341277" 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=rs1554341277" 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=RCV000515793" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000515793" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000515793</a>
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<p>In a mother and her 2 sons of Finnish origin (family 2) with ataxia-pancytopenia syndrome (ATXPC; <a href="/entry/159550">159550</a>), <a href="#11" class="mim-tip-reference" title="Tesi, B., Davidsson, J., Voss, M., Rahikkala, E., Holmes, T. D., Chiang, S. C. C., Komulainen-Ebrahim, J., Gorcenco, S., Nilsson, A. R., Ripperger, T., Kokkonen, H., Bryder, D., and 13 others. <strong>Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms.</strong> Blood 129: 2266-2279, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28202457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28202457</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28202457[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-2016-10-743302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28202457">Tesi et al. (2017)</a> identified a heterozygous c.2672T-C transition (c.2672T-C, ENST00000318238) in the SAMD9L gene, resulting in an ile891-to-thr (I891T) substitution at a conserved residue. The mutation, which was found by Sanger sequencing, segregated with the disorder in the family; it was not present in the ExAC database. In vitro functional expression studies in cells transfected with the mutation showed that it augmented the growth-suppressing activity of SAMD9L and halted cell proliferation compared to wildtype, consistent with a gain-of-function effect. The patients had recurrent infections suggesting mild immunodeficiency and variable neurologic features, such as nystagmus, balance problems, and attention deficit-hyperactivity disorder. Two had thrombocytopenia and pancytopenia, one with a hypoplastic bone marrow and the other with dysplastic megakaryocytes and MDS. Although both of these patients had uniparental disomy of 7q, only 1 had monosomy 7; the latter patient underwent hematopoietic stem cell transplantation. The mother also carried a revertant loss-of-function SAMD9L variant (K768X) that may have mitigated the effect of the pathogenic I891T mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28202457" 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>.0005 MONOSOMY 7 MYELODYSPLASIA AND LEUKEMIA SYNDROME 1</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">rs1792087738 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1792087738;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=rs1792087738" 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=rs1792087738" 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=RCV001270309 OR RCV003727967" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001270309, RCV003727967" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001270309...</a>
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<p>In 2 sisters (family 4) with monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; <a href="/entry/252270">252270</a>), <a href="#12" class="mim-tip-reference" title="Wong, J. C., Bryant, V., Lamprecht, T., Ma, J., Walsh, M., Schwartz, J., del pilar Alzamora, M., Mullighan C. G., Loh, M. L., Ribeiro, R., Downing, J. R., Carroll, W. L., Davis, J., Gold, S., Rogers, R. C., Israels S., Yanofsky, R., Shannon K., Klco, J. M. <strong>Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.</strong> JCI Insight 3: 121086, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30046003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30046003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30046003[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/10.1172/jci.insight.121086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30046003">Wong et al. (2018)</a> identified a heterozygous germline c.4535T-C transition (c.4535T-C, NM_152703) in the SAMD9L gene, resulting in a val1512-to-ala (V1512A) substitution. The parents were not available for testing. In vitro functional expression studies in HEK293T cells transfected with the mutation showed suppression of the cell cycle and cell growth, consistent with a gain-of-function effect. The proband in family 4 presented at 3 years of age with pneumonia, oral candidiasis, pancytopenia, and monosomy 7 in bone marrow metaphase cells. She was treated successfully with antibiotic and her blood counts recovered. At age 7 years, cytogenetic analysis of her bone marrow was normal. Her 1.5-year-old sister was in good health with normal peripheral blood counts, although bone marrow showed monosomy 7 in 9 of 10 metaphase cells. By age 4, her bone marrow cytogenetics were normal. These patients were alive and well at 19 and 21 years of age. However, each carried additional variants in the SAMD9L gene (Q780X, K1265N, and L409fs) that may have mitigated the effects of the V1512A mutation. <a href="#12" class="mim-tip-reference" title="Wong, J. C., Bryant, V., Lamprecht, T., Ma, J., Walsh, M., Schwartz, J., del pilar Alzamora, M., Mullighan C. G., Loh, M. L., Ribeiro, R., Downing, J. R., Carroll, W. L., Davis, J., Gold, S., Rogers, R. C., Israels S., Yanofsky, R., Shannon K., Klco, J. M. <strong>Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.</strong> JCI Insight 3: 121086, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30046003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30046003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30046003[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/10.1172/jci.insight.121086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30046003">Wong et al. (2018)</a> emphasized the relatively mild clinical course in these patients, who had spontaneous resolution of monosomy 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30046003" 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>.0006 MONOSOMY 7 MYELODYSPLASIA AND LEUKEMIA SYNDROME 1</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">rs1792140365 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1792140365;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=rs1792140365" 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=rs1792140365" 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=RCV001270310" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001270310" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001270310</a>
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<p>In 8 sibs (family 5) with mild manifestations of monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; <a href="/entry/252270">252270</a>), <a href="#12" class="mim-tip-reference" title="Wong, J. C., Bryant, V., Lamprecht, T., Ma, J., Walsh, M., Schwartz, J., del pilar Alzamora, M., Mullighan C. G., Loh, M. L., Ribeiro, R., Downing, J. R., Carroll, W. L., Davis, J., Gold, S., Rogers, R. C., Israels S., Yanofsky, R., Shannon K., Klco, J. M. <strong>Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.</strong> JCI Insight 3: 121086, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30046003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30046003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30046003[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/10.1172/jci.insight.121086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30046003">Wong et al. (2018)</a> identified a heterozygous germline c.3842G-A transition (c.3842G-A, NM_152703) in the SAMD9L gene, resulting in an arg1281-to-lys (R1281K) substitution. The mutation was inherited from the clinically unaffected mother. In vitro functional expression studies in HEK293T cells transfected with the mutation showed suppression of the cell cycle and cell growth, consistent with a gain-of-function effect. The patients, who ranged in age from 8 to 26 years, had variable hematologic abnormalities, including anemia, cytopenia, neutropenia, and hypocellular bone marrow with dysplastic changes. Four patients had transient monosomy 7 in bone marrow cells that resolved over time without treatment. None developed frank MDS or AML. Several family members had additional putative somatic acquired revertant variations in the SAMD9L gene that likely mitigated the effects of the pathogenic R1281K mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30046003" 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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SAMD9L, SER626LEU (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554341671;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1554341671</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1554341671 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554341671;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=rs1554341671" 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=rs1554341671" 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=RCV000498009 OR RCV001266100 OR RCV002221547 OR RCV004535565 OR RCV004787806" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000498009, RCV001266100, RCV002221547, RCV004535565, RCV004787806" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000498009...</a>
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<p>In 9 affected individuals from a multigenerational Spanish family with spinocerebellar ataxia-49 (SCA49; <a href="/entry/619806">619806</a>), <a href="#3" class="mim-tip-reference" title="Corral-Juan, M., Casquero, P., Giraldo-Restrepo, N., Laurie, S., Martinez-Pineiro, A., Mateo-Montero, R. C., Ispierto, L., Vilas, D., Tolosa, E., Volpini, V., Alvarez-Ramo, R., Sanchez, I., Matilla-Duenas, A. <strong>New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).</strong> Brain Commun. 4: fcac030, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35310830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35310830</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35310830[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/10.1093/braincomms/fcac030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35310830">Corral-Juan et al. (2022)</a> identified a heterozygous c.1877C-T transition in exon 5 the SAMD9L gene, resulting in a ser626-to-leu (S626L) substitution at a highly conserved residue in an intrinsically disordered region (IDR). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Patient fibroblast showed decreased levels of SAMD9L compared to controls. Further analysis of patient fibroblasts showed increased mitochondrial replication and increased ATP levels compared to controls, suggesting mitochondrial stress, although there were no mtDNA alterations. There was also evidence of dysregulation of the lysosomal/autophagy pathway with diffuse mitochondrial crests and mitophagy; fibroblasts had a dilated endoplasmic reticulum and increased numbers of lysosomes. Zebrafish expressing the human SAMD9L S262L mutation had impaired locomotor activity and decreased head turning, indicating vestibular and sensory dysfunction, compared to controls. The protein showed mitochondrial localization in neurons in zebrafish larvae, including in the spinal cord, peripheral nerves, and hindbrain, where it located with ATP5B (<a href="/entry/102910">102910</a>). Mutant fish showed increased levels of the mitochondrial fusion protein DRP1 (<a href="/entry/603850">603850</a>) compared to controls, suggesting mitochondrial biogenesis. The authors postulated that the mutation prevented proper protein folding, leading to abnormal mitochondrial clearance by mitophagy and compensatory mitochondrial biogenesis. The mechanism could be haploinsufficiency or a dominant-negative effect. The patients had gaze-evoked nystagmus, cerebellar ataxia, hyperreflexia, and pyramidal signs. Brain imaging showed cerebellar atrophy and diffuse myelination abnormalities. None of the patients had abnormal blood cells counts, MDS, or cytopenia, and there was no LOH of SAMD9L in white blood cells. These findings suggested that a secondary genomic event is required to develop hematologic abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35310830" 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><strong><em>Monosomy 7 Myelodysplasia and Leukemia Syndrome 1</em></strong></p><p>
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<a href="#9" class="mim-tip-reference" title="Schwartz, J. R., Ma, J., Lamprecht, T., Walsh, M., Wang, S., Bryant, C., Song, G., Wu, G., Easton, J., Kesserwan, C., Nichols, K. E., Mullighan, C. G., Ribeiro, R. C., Klco, J. M. <strong>The genomic landscape of pediatric myelodysplastic syndromes.</strong> Nature Commun. 8: 1557, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29146900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29146900</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29146900[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/s41467-017-01590-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29146900">Schwartz et al. (2017)</a> identified a germline heterozygous S626L variant in the SAMD9L gene in 2 related pediatric patients (SJ018222 and SJ018225) with monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; <a href="/entry/252270">252270</a>). Although the authors classified S626L as a 'variant of uncertain significance,' they stated that in vitro functional expression studies were consistent with a gain-of-function activity leading to decreased cell proliferation. The patients did not have ataxia or a cerebellar syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29146900" 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>REFERENCES</strong>
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[<a href="https://doi.org/10.1016/j.bbrc.2009.04.004" target="_blank">Full Text</a>]
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Chen, D.-H., Below, J. E., Shimamura, A., Keel, S. B., Matsushita, M., Wolff, J., Sul, Y., Bonkowski, E., Castella, M., Taniguchi, T., Nickerson, D., Papayannopoulou, T., Bird, T. D., Raskind, W. H.
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[<a href="https://doi.org/10.1016/j.ajhg.2016.04.009" target="_blank">Full Text</a>]
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Corral-Juan, M., Casquero, P., Giraldo-Restrepo, N., Laurie, S., Martinez-Pineiro, A., Mateo-Montero, R. C., Ispierto, L., Vilas, D., Tolosa, E., Volpini, V., Alvarez-Ramo, R., Sanchez, I., Matilla-Duenas, A.
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<strong>New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35310830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35310830</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35310830[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=35310830" 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/braincomms/fcac030" target="_blank">Full Text</a>]
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<a id="Jiang2011" class="mim-anchor"></a>
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Jiang, Q., Quaynor, B., Sun, A., Li, Q., Matsui, H., Honda, H., Inaba, T., Sprecher, E., Uitto, J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21412262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21412262</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21412262[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=21412262" 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/jid.2011.61" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1186/1471-2164-8-92" target="_blank">Full Text</a>]
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<a id="Li1978" class="mim-anchor"></a>
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Li, F. P., Potter, N. U., Buchanan, G. R., Vawter, G., Whang-Peng, J., Rosen, R. B.
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[<a href="https://doi.org/10.1016/0002-9343(78)90744-1" target="_blank">Full Text</a>]
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<a id="Nagamachi2013" class="mim-anchor"></a>
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Nagamachi, A., Matsui, H., Asou, H., Ozaki, Y., Aki, D., Kanai, A., Takubo, K., Suda, T., Nakamura, T., Wolff, L., Honda, H., Inaba, T.
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<strong>Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7.</strong>
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Cancer Cell 24: 305-317, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24029230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24029230</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24029230" 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/10.1016/j.ccr.2013.08.011" target="_blank">Full Text</a>]
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<a id="Nagata2018" class="mim-anchor"></a>
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Nagata, Y., Narumi, S., Guan, Y., Przychodzen, B. P., Hirsch, C. M., Makishima, H., Shima, H., Aly, M., Pastor, V., Kuzmanovic, T., Radivoyevitch, T., Adema, V., and 12 others.
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<strong>Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30322869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30322869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30322869[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=30322869" 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-2017-05-787390" target="_blank">Full Text</a>]
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<a id="Schwartz2017" class="mim-anchor"></a>
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Schwartz, J. R., Ma, J., Lamprecht, T., Walsh, M., Wang, S., Bryant, C., Song, G., Wu, G., Easton, J., Kesserwan, C., Nichols, K. E., Mullighan, C. G., Ribeiro, R. C., Klco, J. M.
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[<a href="https://doi.org/10.1038/s41467-017-01590-5" target="_blank">Full Text</a>]
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<a id="Shannon1989" class="mim-anchor"></a>
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Shannon, K. M., Turhan, A. G., Chang, S. S. Y., Bowcock, A. M., Rogers, P. C. J., Carroll, W. L., Cowan, M. J., Glader, B. E., Eaves, C. J., Eaves, A. C., Kan, Y. W.
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[<a href="https://doi.org/10.1172/JCI114262" target="_blank">Full Text</a>]
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<a id="Tesi2017" class="mim-anchor"></a>
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Tesi, B., Davidsson, J., Voss, M., Rahikkala, E., Holmes, T. D., Chiang, S. C. C., Komulainen-Ebrahim, J., Gorcenco, S., Nilsson, A. R., Ripperger, T., Kokkonen, H., Bryder, D., and 13 others.
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<strong>Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28202457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28202457</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28202457[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=28202457" 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-2016-10-743302" target="_blank">Full Text</a>]
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<a id="Wong2018" class="mim-anchor"></a>
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Wong, J. C., Bryant, V., Lamprecht, T., Ma, J., Walsh, M., Schwartz, J., del pilar Alzamora, M., Mullighan C. G., Loh, M. L., Ribeiro, R., Downing, J. R., Carroll, W. L., Davis, J., Gold, S., Rogers, R. C., Israels S., Yanofsky, R., Shannon K., Klco, J. M.
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<strong>Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.</strong>
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JCI Insight 3: 121086, 2018. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30046003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30046003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30046003[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=30046003" 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/10.1172/jci.insight.121086" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 03/31/2022
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Bao Lige - updated : 01/29/2021<br>Cassandra L. Kniffin - updated : 12/07/2020<br>Patricia A. Hartz - updated : 07/06/2016<br>Cassandra L. Kniffin - updated : 6/22/2016<br>Patricia A. Hartz - updated : 7/11/2011
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Patricia A. Hartz : 7/5/2007
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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alopez : 07/27/2022
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<span class="mim-text-font">
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carol : 04/08/2022<br>carol : 04/07/2022<br>ckniffin : 03/31/2022<br>alopez : 02/19/2021<br>mgross : 01/29/2021<br>carol : 12/14/2020<br>carol : 12/11/2020<br>carol : 12/10/2020<br>ckniffin : 12/07/2020<br>mgross : 07/06/2016<br>alopez : 7/6/2016<br>joanna : 7/1/2016<br>alopez : 6/30/2016<br>alopez : 6/30/2016<br>ckniffin : 6/22/2016<br>carol : 1/21/2016<br>wwang : 8/4/2011<br>terry : 7/11/2011<br>wwang : 7/5/2007
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<h3>
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<span class="mim-font">
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<strong>*</strong> 611170
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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STERILE ALPHA MOTIF DOMAIN-CONTAINING PROTEIN 9-LIKE; SAMD9L
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</h3>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SAMD9L</em></strong>
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</span>
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</p>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 768556005;
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</p>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 7q21.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:93,130,056-93,148,385 </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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</span>
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</p>
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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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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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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="3">
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<span class="mim-font">
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7q21.2
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</td>
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<td>
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<span class="mim-font">
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?Spinocerebellar ataxia 49
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</td>
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<span class="mim-font">
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619806
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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</tr>
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<span class="mim-font">
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Ataxia-pancytopenia syndrome
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</span>
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</td>
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<span class="mim-font">
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159550
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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Monosomy 7 myelodysplasia and leukemia syndrome 1
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</td>
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<td>
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<span class="mim-font">
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252270
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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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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3
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</tbody>
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</table>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<h4>
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<span class="mim-font">
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<strong>Description</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 SAMD9L gene encodes a protein that negatively regulates cell proliferation (summary by Tesi et al., 2017). </p>
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</span>
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<div>
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<br />
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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>During their analysis of the SAMD9 gene (610456), Li et al. (2007) identified SAMD9L. They amplified full-length SAMD9L by PCR of an aggressive fibromatosis tumor cDNA library. The deduced protein contains an N-terminal SAM domain. Database analysis indicated that SAMD9L can undergo alternative splicing leading to an alternative coding region. PCR analysis detected SAMD9L in all adult and fetal human tissues examined except some tumor tissues. Orthologs of SAMD9L were detected in all mammals examined but not in chicken, frog, or fish species. The authors noted that while Samd9 is absent from the mouse genome due to a mouse-specific gene rearrangement, Samd9l is found in the mouse. </p><p>Using PCR, Jiang et al. (2011) detected expression of Samd9l in most of 20 mouse tissues examined, with highest expression in kidney, followed by spleen, stomach, and adrenal gland. Samd9l expression was low during mouse embryonic development, but it increased gradually in kidney to adult levels after birth. Immunohistochemical analysis of wildtype mouse kidney and kidney from heterozygous mice expressing LacZ from the Samd9l promoter revealed Samd9l expression in proximal and distal tubules, but not in glomeruli. </p><p>Corral-Juan et al. (2022) found expression of the SAMD9L gene in a punctate pattern consistent with mitochondrial localization in the soma of cerebellar Purkinje cells. </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>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>Li et al. (2007) determined that the SAMD9L gene contains 6 exons spanning 17.6 kb. It has a TATA signal and 2 predicted LEF (LEF1; 153245)-binding elements. </p>
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</span>
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<div>
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<br />
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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>By genomic sequence analysis, Li et al. (2007) mapped the SAMD9L gene to chromosome 7q21.2, 5-prime upstream of the SAMD9 gene. The mouse Samd9l gene maps to proximal chromosome 6. </p>
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</span>
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<div>
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<br />
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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>Using a reporter gene assay, Jiang et al. (2011) identified regulatory elements as close as 87 bp upstream of the transcriptional start site of mouse Samd9l. NIH3T3 mouse fibroblast nuclear extracts tested against 96 transcription factors revealed that the Samd9l upstream region bound to Rreb1 (602209) and E47 (TCF3; 147141). Real-time PCR of NIH3T3 mouse fibroblasts showed that calcitonin (CALCA; 114130) increased expression of Samd9l, which was preceded by significant upregulation of Rreb1. </p><p>In in vitro studies, Tesi et al. (2017) found that stimulation of CD34+ hematopoietic stem cells with IFNA (147660) or IFNG (147570) induced SAMD9L expression. </p>
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</span>
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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>Cytogenetics</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>Using microarray-based comparative genomic hybridization (CGH) analysis, Asou et al. (2009) identified a common microdeletion involving chromosome 7q21.2-q21.3 in 8 of 21 JMML patients with normal karyotype. The microdeletion was verified by quantitative PCR analysis and involved 3 contiguous genes, SAMD9 (610456), SAMD9L, and HEPACAM2 (614133). These 3 genes were heterozygously deleted at high frequency in both adult and childhood myeloid leukemia and were commonly lost with larger chromosome 7 deletions (see 252270) in 15 of 61 adult myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) patients. </p>
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</span>
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<div>
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<br />
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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><strong><em>Ataxia-Pancytopenia Syndrome</em></strong></p><p>
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In affected members of 2 unrelated families with ataxia-pancytopenia syndrome (ATXPC; 159550), including the family originally reported by Li et al. (1978), Chen et al. (2016) identified 2 different heterozygous missense mutations in the SAMD9L gene (H880Q, 611170.0001 and C1196S, 611170.0002). The mutation in the first family was found by a combination of linkage analysis and exome sequencing. Functional studies of the variants were not performed. </p><p>In affected members of 2 unrelated families with ATXPC, Tesi et al. (2017) identified germline heterozygous gain-of-function mutations in the SAMD9L gene (R986C, 611170.0003 and I891T, 611170.0004). The mutations, which were found by whole-exome or Sanger sequencing, segregated with the disorder in the family, although there was variable expressivity. In vitro functional expression studies in cells transfected with the mutations showed that they augmented the growth-suppressing activity of SAMD9L and halted cell proliferation compared to wildtype, consistent with a gain-of-function effect. Some patients developed MDS associated with monosomy 7; loss of chromosome 7 in these patients eliminated the SAMD9L mutations, suggesting that the SAMD9L mutations were not themselves conducive to tumor cell propagation, but that cytogenetic events eradicating the chromosome may explain the predisposition to MDS. This would be an example of 'adaptation by aneuploidy.' In contrast, other family members had less severe or limited manifestations associated with uniparental disomy of 7q or revertant SAMD9L mosaicism that likely mitigated the pathogenic effects of the familial mutations by acting as loss-of-function alleles. In in vitro studies, Tesi et al. (2017) found that stimulation of CD34+ hematopoietic stem cells with IFNA or IFNG induced SAMD9L expression. These findings provided a mechanism by which an immune response may lead to cytopenia, thus providing a basis for the selection of somatic SAMD9L revertant mutants. </p><p><strong><em>Monosomy 7 Myelodysplasia and Leukemia Syndrome 1</em></strong></p><p>
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In affected members of 4 unrelated families with variable manifestations of myelodysplasia and leukemia syndrome-1 (M7MLS1; 252270), Wong et al. (2018) identified heterozygous missense mutations in the SAMD9L gene (611170.0001; 611170.0003; 611170.0005-611170.0006). The mutations, which were filtered against public databases, segregated with the disorders in the families. In vitro functional expression studies in HEK293T cells transfected with the mutations showed that they suppressed cell cycle progression and impaired cellular growth and proliferation stronger than wildtype, consistent with a gain-of-function effect. Most patients had monosomy 7, although the phenotype was variable. The sibs in family 1 had AML, ultimately resulting in early death, whereas the patients in families 3-5 had milder hematologic abnormalities and long survival. In contrast to the patients in family 1, none of the patients in families 3, 4, or 5 had somatic mutations in genes associated with the development of MDS or AML. In addition, several patients in families 3-5 had resolution of monosomy 7 without treatment, and most had additional acquired variants in the SAMD9L gene that were demonstrated or predicted to mitigate the effects of the pathogenic germline mutation. The findings emphasized the phenotypic heterogeneity resulting from complex genetic mechanisms, including germline mutation, monosomy 7, acquired SAMD9L revertant variants, and acquired somatic changes in other genes associated with the development of MDS or AML. </p><p>Schwartz et al. (2017) identified a germline heterozygous S626L variant in the SAMD9L gene (611170.0007) in 2 related pediatric patients (SJ018222 and SJ018225) with M7MLS1. Although the authors classified S626L as a 'variant of uncertain significance,' they stated that in vitro functional expression studies were consistent with a gain-of-function activity leading to decreased cell proliferation. The patients did not have ataxia or a cerebellar syndrome. </p><p><strong><em>Myelodysplastic Syndrome</em></strong></p><p>
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Among 799 adults with various myeloid neoplasms, including presumed acquired myelodysplastic syndrome (MDS; 614286), bone marrow failure, and other related disorders, Nagata et al. (2018) identified 14 different heterozygous germline variants in the SAMD9L gene. The patients and variants were ascertained from public whole-exome sequencing databases. Most of the SAMD9L variants were missense, although there were a few frameshifts. The variants occurred throughout the gene, but tended to be located more in the N terminus compared to pediatric cases. In vitro functional expression studies of some, but not all, of the missense variants resulted in enhanced cell proliferation compared to controls, indicating a loss-of-function (LOF) effect. These variants were not subject to somatic reversion, as observed in pediatric patients with gain-of-function mutations in the SAMD9L gene. Many MDS patients had secondary somatic hits in other genes that likely contributed to the development of the disorder. Nagata et al. (2018) hypothesized that the late onset of MDS in these patients resulted from protracted acquisition of secondary hits in other genes associated with myeloid malignancies. Similar LOF variants in the SAMD9 gene were also identified. Overall, germline mutations in one or the other of these 2 genes were identified in about 4% of patients with adult-onset MDS and 3% with bone marrow failure. </p><p><strong><em>Spinocerebellar Ataxia 49</em></strong></p><p>
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In 9 affected individuals from a multigenerational Spanish family (M-SCA) with spinocerebellar ataxia-49 (SCA49; 619806), Corral-Juan et al. (2022) identified a heterozygous missense mutation in the SAMD9L gene (S626L; 611170.0007). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed decreased levels of SAMD9L compared to controls. Further analysis of patient fibroblasts showed increased mitochondrial replication and increased ATP levels compared to controls, suggesting mitochondrial stress, although there were no mtDNA alterations. There was also evidence of dysregulation of the lysosomal/autophagy pathway with diffuse mitochondrial crests and mitophagy; fibroblasts had a dilated endoplasmic reticulum and increased numbers of lysosomes. The authors postulated that the mutation prevented proper protein folding, leading to abnormal mitochondrial clearance by mitophagy and compensatory mitochondrial biogenesis. The mechanism could be haploinsufficiency or a dominant-negative effect. </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>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>Jiang et al. (2011) found that both Samd9l +/- and Samd9l -/- mice showed increased susceptibility to myelogenous leukemia after 20 months of age. </p><p>Nagamachi et al. (2013) found that both Samd9l -/- and Samd9l +/- mice developed myeloid disorders and died at significantly higher frequency than wildtype mice. Samd9l +/- mice expressed Samd9l mRNA in kidney at about 45% of the level in wildtype mice, and protein expression in Samd9l mice was also decreased 4-fold. Infection with MOL4070A retrovirus accelerated disease latency and frequency in Samd9l -/- and Samd9l +/- mice, and almost all Samd9l -/- and Samd9l +/- mice died of nonlymphoid hematopoietic neoplasms much earlier than mice that developed spontaneous myeloid malignancies. Samd9l deficiency enhanced reconstitution ability of stem cells and/or early hematopoietic progenitors and sensitized hematopoietic progenitors to cytokines, as Samd9l facilitated degradation of cytokine receptors through homotypic fusion of endosomes. The authors noted that because humans also have the SAMD9 gene, which is absent in mouse and encodes a protein that compensates for loss of SAMD9L, loss of 1 copy each of SAMD9 and SAMD9L in patients with monosomy 7 and interstitial deletion of 7q may not correspond to Samd9l +/- mice. However, simultaneous reduction of SAMD9 and SAMD9L mRNA by loss of 7q in humans suggested that SMAD9/SAMD9L function in human cells harboring monosomy 7 and interstitial deletion of 7q is parallel to Samd9l function in Samd9l +/- mouse cells. </p><p>Corral-Juan et al. (2022) found that zebrafish expressing the human SAMD9L S262L mutation (611170.0007) had impaired locomotor activity and decreased head turning, indicating vestibular and sensory dysfunction, compared to controls. The protein showed mitochondrial localization in neurons of zebrafish larvae, including in the spinal cord, peripheral nerves, and hindbrain, where it located with ATP5B (102910). Mutant fish showed increased levels of the mitochondrial fusion protein DRP1 (603850) compared to controls, suggesting mitochondrial biogenesis. </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>ALLELIC VARIANTS</strong>
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</span>
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<strong>7 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 ATAXIA-PANCYTOPENIA SYNDROME</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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MONOSOMY 7 MYELODYSPLASIA AND LEUKEMIA SYNDROME 1, INCLUDED
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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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SAMD9L, HIS880GLN
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<br />
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SNP: rs878855336,
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gnomAD: rs878855336,
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ClinVar: RCV000234838, RCV001270307, RCV003556291, RCV004737387
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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 />
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<p><strong><em>Ataxia-Pancytopenia Syndrome</em></strong></p><p>
|
|
In affected members of a family (UW-AP) of Irish, German, and Native American ancestry with ataxia-pancytopenia syndrome (ATXPC; 159550), Chen et al. (2016) identified a heterozygous c.2640C-A transversion (c.2640C-A, NM_152703.3) in the SAMD9L gene, resulting in a his880-to-gln (H880Q) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 131), 1000 Genomes Project, Exome Variant Server, or ExAC databases. Functional studies of the variant were not performed. Patient lymphoblastoid cells were initially heterozygous for the mutation, but 2 cell lines showed loss of heterozygosity (LOH) for the mutant allele after 3 weeks to 6 months in culture, indicating that these patients were somatic mosaic for the mutation in their hematopoietic systems. The findings demonstrated a selective growth advantage in cultured cells without the mutant allele, suggesting a role for SAMD9L in the regulation of cell proliferation. </p><p><strong><em>Monosomy 7 Myelodysplasia and Leukemia Syndrome 1</em></strong></p><p>
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In 2 sibs (family 1) with monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; 252270), Wong et al. (2018) identified a heterozygous germline H880Q mutation in the SAMD9L gene that was inherited from their asymptomatic father. HEK293T cells transfected with the H880Q mutation showed suppression of cell cycle progression compared to wildtype, suggesting a gain-of-function effect. The father was found to carry a Q569P variant in SAMD9L that was in cis with H880Q and was able to partially mitigate the cell cycle abnormalities. Both sibs developed AML. Bone marrow examination of both sibs showed deletion of the paternal copy of chromosome 7, yielding monosomy 7. Deep sequencing showed that the SAMD9L gene was present at a low frequency (less than 5%) in the bone marrow of both children, indicating selective loss of the chromosome harboring the SAMD9L mutation. Leukemic cells in both affected sibs showed acquisition of somatic mutations in other genes, including RUNX1, SETBP1, BRAF, and KRAS, which likely contributed to leukemogenesis. Both patients died. The family was previously reported as family 1 by Shannon et al. (1989). </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 ATAXIA-PANCYTOPENIA SYNDROME</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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SAMD9L, CYS1196SER
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<br />
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SNP: rs878855337,
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ClinVar: RCV000234841
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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 3 affected members of a Chinese family with ataxia-pancytopenia syndrome (ATXPC; 159550) originally reported by Li et al. (1978), Chen et al. (2016) identified a heterozygous c.3587G-C transversion (c.3587G-C, NM_152703.3) in the SAMD9L gene, resulting in a cys1196-to-ser (C1196S) substitution at a highly conserved residue. The mutation was not found in the dbSNP (build 131), 1000 Genomes Project, or ExAC databases. Functional studies of the variant were not performed. Loss of the variant allele was not observed in cultured fibroblasts from these patients. </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 ATAXIA-PANCYTOPENIA SYNDROME</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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MONOSOMY 7 MYELODYSPLASIA AND LEUKEMIA SYNDROME 1, INCLUDED
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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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SAMD9L, ARG986CYS
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<br />
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SNP: rs1554341158,
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ClinVar: RCV000515805, RCV001270308, RCV001557094
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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 />
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<p><strong><em>Ataxia-Pancytopenia Syndrome</em></strong></p><p>
|
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In 7 affected members of a 3-generation family of Swedish origin (family 1) with variable manifestations of ataxia-pancytopenia syndrome (ATXPC; 159550), Tesi et al. (2017) identified a heterozygous c.2956C-T transition (c.2956C-T, ENST00000318238) in the SAMD9L gene, resulting in an arg986-to-cys (R986C) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the ExAC database. In vitro functional expression studies in cells transfected with the mutation showed that it augmented the growth-suppressing activity of SAMD9L and halted cell proliferation compared to wildtype, consistent with a gain-of-function effect. The proband was a 6-year-old boy with pancytopenia and myelodysplastic syndrome (MDS) who also had monosomy 7. He underwent bone marrow transplantation and later developed neurologic symptoms. His grandfather developed MDS at age 56 years: he did not have monosomy 7. He had mildly impaired balance. None of the other affected family members had MDS, but several had transient thrombocytopenia or pancytopenia, often associated with uniparental disomy of chromosome 7q or a revertant SAMD9L variant. One unaffected 38-year-old woman who carried the R986C mutation also carried a T233N variant in the SAMD9L gene, which represented a disease-modifying loss-of-function variant that presumably mitigated the effects of the R986C mutation. </p><p><strong><em>Monosomy 7 Myelodysplasia and Leukemia Syndrome 1</em></strong></p><p>
|
|
In 2 sisters (family 3) with monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; 252270), Wong et al. (2018) identified a germline heterozygous R986C mutation in the SAMD9L gene. In vitro cellular studies demonstrated a growth-suppressive effect of the mutation. The proband presented with MDS and monosomy 7. She underwent successful bone marrow transplantation and was well at age 27 years. Genetic studies of her sister, who had no overt hematologic abnormalities, detected a focal somatic deletion of 7q11-q36, which contains the SAMD9L gene, in 7 of 27 metaphase cells. She died of an unrelated cause at age 27 years. Their unaffected mother also carried the R986C mutation. All 3 individuals carried additional, but different, putative revertant variants in the SAMD9L gene (F1092L, R223X, R843W, Y568C, and E276X) that were demonstrated or predicted to abrogate the growth-suppressive properties of the R986C substitution. The authors postulated that the relatively mild clinical course in this family may have been due to the additional revertant SAMD9L variants or to a low level of monosomy 7. </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 ATAXIA-PANCYTOPENIA SYNDROME</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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SAMD9L, ILE891THR
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<br />
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SNP: rs1554341277,
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ClinVar: RCV000515793
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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 mother and her 2 sons of Finnish origin (family 2) with ataxia-pancytopenia syndrome (ATXPC; 159550), Tesi et al. (2017) identified a heterozygous c.2672T-C transition (c.2672T-C, ENST00000318238) in the SAMD9L gene, resulting in an ile891-to-thr (I891T) substitution at a conserved residue. The mutation, which was found by Sanger sequencing, segregated with the disorder in the family; it was not present in the ExAC database. In vitro functional expression studies in cells transfected with the mutation showed that it augmented the growth-suppressing activity of SAMD9L and halted cell proliferation compared to wildtype, consistent with a gain-of-function effect. The patients had recurrent infections suggesting mild immunodeficiency and variable neurologic features, such as nystagmus, balance problems, and attention deficit-hyperactivity disorder. Two had thrombocytopenia and pancytopenia, one with a hypoplastic bone marrow and the other with dysplastic megakaryocytes and MDS. Although both of these patients had uniparental disomy of 7q, only 1 had monosomy 7; the latter patient underwent hematopoietic stem cell transplantation. The mother also carried a revertant loss-of-function SAMD9L variant (K768X) that may have mitigated the effect of the pathogenic I891T mutation. </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>.0005 MONOSOMY 7 MYELODYSPLASIA AND LEUKEMIA SYNDROME 1</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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SAMD9L, VAL1512ALA
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<br />
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SNP: rs1792087738,
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ClinVar: RCV001270309, RCV003727967
|
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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 2 sisters (family 4) with monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; 252270), Wong et al. (2018) identified a heterozygous germline c.4535T-C transition (c.4535T-C, NM_152703) in the SAMD9L gene, resulting in a val1512-to-ala (V1512A) substitution. The parents were not available for testing. In vitro functional expression studies in HEK293T cells transfected with the mutation showed suppression of the cell cycle and cell growth, consistent with a gain-of-function effect. The proband in family 4 presented at 3 years of age with pneumonia, oral candidiasis, pancytopenia, and monosomy 7 in bone marrow metaphase cells. She was treated successfully with antibiotic and her blood counts recovered. At age 7 years, cytogenetic analysis of her bone marrow was normal. Her 1.5-year-old sister was in good health with normal peripheral blood counts, although bone marrow showed monosomy 7 in 9 of 10 metaphase cells. By age 4, her bone marrow cytogenetics were normal. These patients were alive and well at 19 and 21 years of age. However, each carried additional variants in the SAMD9L gene (Q780X, K1265N, and L409fs) that may have mitigated the effects of the V1512A mutation. Wong et al. (2018) emphasized the relatively mild clinical course in these patients, who had spontaneous resolution of monosomy 7. </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>.0006 MONOSOMY 7 MYELODYSPLASIA AND LEUKEMIA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
|
SAMD9L, ARG1281LYS
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|
|
<br />
|
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|
|
SNP: rs1792140365,
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|
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|
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|
|
ClinVar: RCV001270310
|
|
|
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|
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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 8 sibs (family 5) with mild manifestations of monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; 252270), Wong et al. (2018) identified a heterozygous germline c.3842G-A transition (c.3842G-A, NM_152703) in the SAMD9L gene, resulting in an arg1281-to-lys (R1281K) substitution. The mutation was inherited from the clinically unaffected mother. In vitro functional expression studies in HEK293T cells transfected with the mutation showed suppression of the cell cycle and cell growth, consistent with a gain-of-function effect. The patients, who ranged in age from 8 to 26 years, had variable hematologic abnormalities, including anemia, cytopenia, neutropenia, and hypocellular bone marrow with dysplastic changes. Four patients had transient monosomy 7 in bone marrow cells that resolved over time without treatment. None developed frank MDS or AML. Several family members had additional putative somatic acquired revertant variations in the SAMD9L gene that likely mitigated the effects of the pathogenic R1281K mutation. </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>.0007 SPINOCEREBELLAR ATAXIA 49 (1 family)</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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SAMD9L, SER626LEU ({dbSNP rs1554341671})
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<br />
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|
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SNP: rs1554341671,
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|
|
ClinVar: RCV000498009, RCV001266100, RCV002221547, RCV004535565, RCV004787806
|
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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 9 affected individuals from a multigenerational Spanish family with spinocerebellar ataxia-49 (SCA49; 619806), Corral-Juan et al. (2022) identified a heterozygous c.1877C-T transition in exon 5 the SAMD9L gene, resulting in a ser626-to-leu (S626L) substitution at a highly conserved residue in an intrinsically disordered region (IDR). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Patient fibroblast showed decreased levels of SAMD9L compared to controls. Further analysis of patient fibroblasts showed increased mitochondrial replication and increased ATP levels compared to controls, suggesting mitochondrial stress, although there were no mtDNA alterations. There was also evidence of dysregulation of the lysosomal/autophagy pathway with diffuse mitochondrial crests and mitophagy; fibroblasts had a dilated endoplasmic reticulum and increased numbers of lysosomes. Zebrafish expressing the human SAMD9L S262L mutation had impaired locomotor activity and decreased head turning, indicating vestibular and sensory dysfunction, compared to controls. The protein showed mitochondrial localization in neurons in zebrafish larvae, including in the spinal cord, peripheral nerves, and hindbrain, where it located with ATP5B (102910). Mutant fish showed increased levels of the mitochondrial fusion protein DRP1 (603850) compared to controls, suggesting mitochondrial biogenesis. The authors postulated that the mutation prevented proper protein folding, leading to abnormal mitochondrial clearance by mitophagy and compensatory mitochondrial biogenesis. The mechanism could be haploinsufficiency or a dominant-negative effect. The patients had gaze-evoked nystagmus, cerebellar ataxia, hyperreflexia, and pyramidal signs. Brain imaging showed cerebellar atrophy and diffuse myelination abnormalities. None of the patients had abnormal blood cells counts, MDS, or cytopenia, and there was no LOH of SAMD9L in white blood cells. These findings suggested that a secondary genomic event is required to develop hematologic abnormalities. </p><p><strong><em>Monosomy 7 Myelodysplasia and Leukemia Syndrome 1</em></strong></p><p>
|
|
Schwartz et al. (2017) identified a germline heterozygous S626L variant in the SAMD9L gene in 2 related pediatric patients (SJ018222 and SJ018225) with monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; 252270). Although the authors classified S626L as a 'variant of uncertain significance,' they stated that in vitro functional expression studies were consistent with a gain-of-function activity leading to decreased cell proliferation. The patients did not have ataxia or a cerebellar syndrome. </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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<p class="mim-text-font">
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Asou, H., Matsui, H., Ozaki, Y., Nagamachi, A., Nakamura, M., Aki, D., Inaba, T.
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<strong>Identification of a common microdeletion cluster in 7q21.3 subband among patients with myeloid leukemia and myelodysplastic syndrome.</strong>
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Biochem. Biophys. Res. Commun. 383: 245-251, 2009.
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[PubMed: 19358830]
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[Full Text: https://doi.org/10.1016/j.bbrc.2009.04.004]
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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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Chen, D.-H., Below, J. E., Shimamura, A., Keel, S. B., Matsushita, M., Wolff, J., Sul, Y., Bonkowski, E., Castella, M., Taniguchi, T., Nickerson, D., Papayannopoulou, T., Bird, T. D., Raskind, W. H.
|
|
<strong>Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L.</strong>
|
|
Am. J. Hum. Genet. 98: 1146-1158, 2016.
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[PubMed: 27259050]
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[Full Text: https://doi.org/10.1016/j.ajhg.2016.04.009]
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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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Corral-Juan, M., Casquero, P., Giraldo-Restrepo, N., Laurie, S., Martinez-Pineiro, A., Mateo-Montero, R. C., Ispierto, L., Vilas, D., Tolosa, E., Volpini, V., Alvarez-Ramo, R., Sanchez, I., Matilla-Duenas, A.
|
|
<strong>New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).</strong>
|
|
Brain Commun. 4: fcac030, 2022.
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[PubMed: 35310830]
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[Full Text: https://doi.org/10.1093/braincomms/fcac030]
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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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Jiang, Q., Quaynor, B., Sun, A., Li, Q., Matsui, H., Honda, H., Inaba, T., Sprecher, E., Uitto, J.
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<strong>The Samd9L gene: transcriptional regulation and tissue-specific expression in mouse development.</strong>
|
|
J. Invest. Derm. 131: 1428-1434, 2011.
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[PubMed: 21412262]
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[Full Text: https://doi.org/10.1038/jid.2011.61]
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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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Li, C. F., MacDonald, J. R., Wei, R. Y., Ray, J., Lau, K., Kandel, C., Koffman, R., Bell, S., Scherer, S. W., Alman, B. A.
|
|
<strong>Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse.</strong>
|
|
BMC Genomics 8: 92, 2007. Note: Electronic Article.
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[PubMed: 17407603]
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[Full Text: https://doi.org/10.1186/1471-2164-8-92]
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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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Li, F. P., Potter, N. U., Buchanan, G. R., Vawter, G., Whang-Peng, J., Rosen, R. B.
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<strong>A family with acute leukemia, hypoplastic anemia and cerebellar ataxia: association with bone marrow C-monosomy.</strong>
|
|
Am. J. Med. 65: 933-940, 1978.
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[PubMed: 283689]
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[Full Text: https://doi.org/10.1016/0002-9343(78)90744-1]
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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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Nagamachi, A., Matsui, H., Asou, H., Ozaki, Y., Aki, D., Kanai, A., Takubo, K., Suda, T., Nakamura, T., Wolff, L., Honda, H., Inaba, T.
|
|
<strong>Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7.</strong>
|
|
Cancer Cell 24: 305-317, 2013.
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[PubMed: 24029230]
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[Full Text: https://doi.org/10.1016/j.ccr.2013.08.011]
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Nagata, Y., Narumi, S., Guan, Y., Przychodzen, B. P., Hirsch, C. M., Makishima, H., Shima, H., Aly, M., Pastor, V., Kuzmanovic, T., Radivoyevitch, T., Adema, V., and 12 others.
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<strong>Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes.</strong>
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Blood 132: 2309-2313, 2018.
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[PubMed: 30322869]
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[Full Text: https://doi.org/10.1182/blood-2017-05-787390]
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Schwartz, J. R., Ma, J., Lamprecht, T., Walsh, M., Wang, S., Bryant, C., Song, G., Wu, G., Easton, J., Kesserwan, C., Nichols, K. E., Mullighan, C. G., Ribeiro, R. C., Klco, J. M.
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<strong>The genomic landscape of pediatric myelodysplastic syndromes.</strong>
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Nature Commun. 8: 1557, 2017.
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[PubMed: 29146900]
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[Full Text: https://doi.org/10.1038/s41467-017-01590-5]
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Shannon, K. M., Turhan, A. G., Chang, S. S. Y., Bowcock, A. M., Rogers, P. C. J., Carroll, W. L., Cowan, M. J., Glader, B. E., Eaves, C. J., Eaves, A. C., Kan, Y. W.
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<strong>Familial bone marrow monosomy 7: evidence that the predisposing locus is not on the long arm of chromosome 7.</strong>
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J. Clin. Invest. 84: 984-989, 1989.
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[PubMed: 2569483]
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[Full Text: https://doi.org/10.1172/JCI114262]
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Tesi, B., Davidsson, J., Voss, M., Rahikkala, E., Holmes, T. D., Chiang, S. C. C., Komulainen-Ebrahim, J., Gorcenco, S., Nilsson, A. R., Ripperger, T., Kokkonen, H., Bryder, D., and 13 others.
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<strong>Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms.</strong>
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Blood 129: 2266-2279, 2017.
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[PubMed: 28202457]
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[Full Text: https://doi.org/10.1182/blood-2016-10-743302]
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Wong, J. C., Bryant, V., Lamprecht, T., Ma, J., Walsh, M., Schwartz, J., del pilar Alzamora, M., Mullighan C. G., Loh, M. L., Ribeiro, R., Downing, J. R., Carroll, W. L., Davis, J., Gold, S., Rogers, R. C., Israels S., Yanofsky, R., Shannon K., Klco, J. M.
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<strong>Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.</strong>
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JCI Insight 3: 121086, 2018. Note: Electronic Article.
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[PubMed: 30046003]
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[Full Text: https://doi.org/10.1172/jci.insight.121086]
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Cassandra L. Kniffin - updated : 03/31/2022<br>Bao Lige - updated : 01/29/2021<br>Cassandra L. Kniffin - updated : 12/07/2020<br>Patricia A. Hartz - updated : 07/06/2016<br>Cassandra L. Kniffin - updated : 6/22/2016<br>Patricia A. Hartz - updated : 7/11/2011
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Patricia A. Hartz : 7/5/2007
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alopez : 07/27/2022<br>carol : 04/08/2022<br>carol : 04/07/2022<br>ckniffin : 03/31/2022<br>alopez : 02/19/2021<br>mgross : 01/29/2021<br>carol : 12/14/2020<br>carol : 12/11/2020<br>carol : 12/10/2020<br>ckniffin : 12/07/2020<br>mgross : 07/06/2016<br>alopez : 7/6/2016<br>joanna : 7/1/2016<br>alopez : 6/30/2016<br>alopez : 6/30/2016<br>ckniffin : 6/22/2016<br>carol : 1/21/2016<br>wwang : 8/4/2011<br>terry : 7/11/2011<br>wwang : 7/5/2007
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