3542 lines
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Entry
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- *610456 - STERILE ALPHA MOTIF DOMAIN-CONTAINING PROTEIN 9; SAMD9
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- OMIM
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<p>
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<span class="h4">*610456</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<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="#geneFunction">Gene Function</a>
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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="#molecularGenetics">Molecular Genetics</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/610456">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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<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="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel-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 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=ENSG00000205413;t=ENST00000379958" 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=54809" 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=610456" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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<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=ENSG00000205413;t=ENST00000379958" 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_001193307,NM_017654" 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_017654" 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=610456" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=11531&isoform_id=11531_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/SAMD9" 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/7019936,33316810,37674389,38201706,41351336,51094900,63100039,71153739,119597232,124375888,124376576,193784990,193784997,300863105,929654833" 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/Q5K651" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=54809" 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=ENSG00000205413;t=ENST00000379958" 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=SAMD9" 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=SAMD9" 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+54809" 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/SAMD9" 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:54809" 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/54809" 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=ENST00000379958.3&hgg_start=93099518&hgg_end=93117979&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://search.clinicalgenome.org/kb/gene-dosage/HGNC:1348" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=610456[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 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=610456[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/SAMD9/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000205413" 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=SAMD9" 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=SAMD9" 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=SAMD9" 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=SAMD9&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/PA25948" 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:1348" 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="http://v1.marrvel.org/search/gene/SAMD9#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="https://www.ncbi.nlm.nih.gov/gene/54809/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=54809" 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>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=SAMD9&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> 1162852008, 1234831009<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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610456
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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STERILE ALPHA MOTIF DOMAIN-CONTAINING PROTEIN 9; SAMD9
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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=SAMD9" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SAMD9</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">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/7/413?start=-3&limit=10&highlight=413">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=chr7:93099518-93117979&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'})">7:93,099,518-93,117,979</a> </span>
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</em>
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</strong>
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<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">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<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>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
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<a href="/clinicalSynopsis/table?mimNumber=617053,619041,610455" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
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</a>
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</span>
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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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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
|
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<a href="/geneMap/7/413?start=-3&limit=10&highlight=413">
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7q21.2
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</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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MIRAGE syndrome
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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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<a href="/entry/617053"> 617053 </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">
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<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>
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<span class="mim-font">
|
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Monosomy 7 myelodysplasia and leukemia syndrome 2
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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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<a href="/entry/619041"> 619041 </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">
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<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>
|
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<span class="mim-font">
|
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Tumoral calcinosis, familial, normophosphatemic
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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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<a href="/entry/610455"> 610455 </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 recessive">AR</abbr>
|
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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="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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</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>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/610456" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/610456" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></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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<a id="text" class="mim-anchor"></a>
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<h4>
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|
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<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<p>The SAMD9 gene encodes a protein involved in endosome fusion. It plays a role in growth factor signal transduction and negatively regulates cell proliferation (summary by <a href="#5" class="mim-tip-reference" title="Narumi, S., Amano, N., Ishii, T., Katsumata, N., Muroya, K., Adachi, M., Toyoshima, K., Tanaka, Y., Fukuzawa, R., Miyako, K., Kinjo, S., Ohga, S., and 27 others. <strong>SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.</strong> Nature Genet. 48: 792-797, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27182967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27182967</a>] [<a href="https://doi.org/10.1038/ng.3569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27182967">Narumi et al., 2016</a> and <a href="#4" 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://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>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27182967+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>
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<p><a href="#8" class="mim-tip-reference" title="Topaz, O., Indelman, M., Chefetz, I., Geiger, D., Metzker, A., Altschuler, Y., Choder, M., Bercovich, D., Uitto, J., Bergman, R., Richard, G., Sprecher, E. <strong>A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis.</strong> Am. J. Hum. Genet. 79: 759-764, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16960814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16960814</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16960814[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/508069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16960814">Topaz et al. (2006)</a> determined that the SAMD9 gene encodes a 1,589-amino acid protein that is expressed in a wide range of tissues, including skin. Quantitative real-time PCR showed that the gene is strongly expressed in endothelial cells and, to a lesser degree, in fibroblasts. <a href="#8" class="mim-tip-reference" title="Topaz, O., Indelman, M., Chefetz, I., Geiger, D., Metzker, A., Altschuler, Y., Choder, M., Bercovich, D., Uitto, J., Bergman, R., Richard, G., Sprecher, E. <strong>A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis.</strong> Am. J. Hum. Genet. 79: 759-764, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16960814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16960814</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16960814[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/508069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16960814">Topaz et al. (2006)</a> observed that apart from an N-terminal sterile alpha motif (SAM), the SAMD9 protein bore little homology to other known proteins except for the SAMD9L protein, with which it shares 58% identity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16960814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By database analysis, <a href="#3" 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> found evidence for alternative splicing of SAMD9 transcripts due to the utilization of noncanonical dinucleotides as intron 3 donor and acceptor splice sites. Use of the noncanonical site would result in an in-frame deletion, leading to exclusion of the N-terminal SAM domain. <a href="#3" 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> also noted that the SAM domain of SAMD9 lacks residues essential for RNA binding, but it has 98% homology with the SAM domain of EPHB2 (<a href="/entry/600997">600997</a>), which forms homooligomers and provides a platform for the formation of larger protein complexes. Northern blot analysis detected a 7-kb transcript in full-term placenta. PCR analysis detected SAMD9 in all human adult, fetal, and tumor tissues examined, except for fetal brain. Fluorescence-tagged SAMD9 was expressed in the cytoplasm of several transfected cell lines. <a href="#3" 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 SAMD9 orthologs in several mammalian species but not in chicken, frog, fish, or several lower eukaryotes. A notable exception was the absence of Samd9 in mouse, which appeared to have been lost during a mouse-specific gene rearrangement. <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 suppression subtractive hybridization, <a href="#3" 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> found that SAMD9 was one of the most differentially regulated genes in an aggressive fibromatosis tumor with inactivation of the APC gene (<a href="/entry/611731">611731</a>) compared with the same cells after transfection of wildtype APC. Knockdown of SAMD9 by RNA interference increased the proliferation and invasiveness of a normal lung fibroblast cell line, whereas SAMD9 overexpression reduced cell proliferation and motility, and increased apoptosis in a colon cancer cell line. SAMD9 overexpression reduced tumor volume following transplantation in immune-deficient mice. <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 quantitative RT-PCR, <a href="#2" class="mim-tip-reference" title="Chefetz, I., Amitai, D. B., Browning, S., Skorecki, K., Adir, N., Thomas, M. G., Kogleck, L., Topaz, O., Indelman, M., Uitto, J., Richard, G., Bradman, N., Sprecher, E. <strong>Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein.</strong> J. Invest. Derm. 128: 1423-1429, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18094730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18094730</a>] [<a href="https://doi.org/10.1038/sj.jid.5701203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18094730">Chefetz et al. (2008)</a> showed that SAMD9 expression in human endothelial cells increased significantly following exposure to TNFA (TNF; <a href="/entry/191160">191160</a>), a major proinflammatory cytokine and inducer of apoptosis. Analysis with inhibitors showed that SAMD9 upregulation by TNFA required p38 (MAPK14; <a href="/entry/600289">600289</a>). In addition, cellular stress induced by hyperosmotic shock markedly upregulated SAMD9 expression in endothelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18094730" 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="#3" 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 SAMD9 gene contains 3 exons, and its promoter region contains a TATA signal and 5 predicted LEF (LEF1; <a href="/entry/153245">153245</a>)-binding elements. There are also alternative transcriptional initiation sites and polyadenylation sites, and at least 2 alternative splice sites. <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><a href="#8" class="mim-tip-reference" title="Topaz, O., Indelman, M., Chefetz, I., Geiger, D., Metzker, A., Altschuler, Y., Choder, M., Bercovich, D., Uitto, J., Bergman, R., Richard, G., Sprecher, E. <strong>A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis.</strong> Am. J. Hum. Genet. 79: 759-764, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16960814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16960814</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16960814[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/508069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16960814">Topaz et al. (2006)</a> identified the SAMD9 gene within a region on chromosome 7q21-q21.3 linked to normophosphatemic familial tumoral calcinosis (<a href="/entry/610455">610455</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16960814" 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><strong><em>Normophosphatemic Familial Tumoral Calcinosis</em></strong></p><p>
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In 8 individuals with normophosphatemic familial tumoral calcinosis (NFTC; <a href="/entry/610455">610455</a>) from 5 families of Jewish Yemenite origin, <a href="#9" class="mim-tip-reference" title="Topaz, O., Shurman, D. L., Bergman, R., Indelman, M., Ratajczak, P., Mizrachi, M., Khamaysi, Z., Behar, D., Petronius, D., Friedman, V., Zelikovic, I., Raimer, S., Metzker, A., Richard, G., Sprecher, E. <strong>Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis.</strong> Nature Genet. 36: 579-581, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15133511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15133511</a>] [<a href="https://doi.org/10.1038/ng1358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15133511">Topaz et al. (2004)</a> identified a shared region of homozygosity on chromosome 7q21-q21.3. In the 8 affected individuals, the authors identified a homozygous missense mutation (K1495E; <a href="#0001">610456.0001</a>), which segregated with the disease in all families. K1495 seems to be well conserved across species, suggesting that it is of physiologic importance. The K1495E mutation caused loss of punctate expression of a GFP-SAMD9 fusion protein after transfection in HEK293 cells, indicating that this mutation interferes with SAMD9 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15133511" 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 dizygotic twins with NFTC from a Jewish Yemenite family, <a href="#2" class="mim-tip-reference" title="Chefetz, I., Amitai, D. B., Browning, S., Skorecki, K., Adir, N., Thomas, M. G., Kogleck, L., Topaz, O., Indelman, M., Uitto, J., Richard, G., Bradman, N., Sprecher, E. <strong>Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein.</strong> J. Invest. Derm. 128: 1423-1429, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18094730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18094730</a>] [<a href="https://doi.org/10.1038/sj.jid.5701203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18094730">Chefetz et al. (2008)</a> identified compound heterozygous mutations in the SAMD9 gene: the previously identified K1495E mutation and a novel nonsense mutation (R344X; <a href="/entry/610446#0005">610446.0005</a>). The mutations, which were identified by direct sequencing of the SAMD9 gene, segregated with the disorder in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18094730" 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="#2" class="mim-tip-reference" title="Chefetz, I., Amitai, D. B., Browning, S., Skorecki, K., Adir, N., Thomas, M. G., Kogleck, L., Topaz, O., Indelman, M., Uitto, J., Richard, G., Bradman, N., Sprecher, E. <strong>Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein.</strong> J. Invest. Derm. 128: 1423-1429, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18094730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18094730</a>] [<a href="https://doi.org/10.1038/sj.jid.5701203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18094730">Chefetz et al. (2008)</a> screened a large cohort of healthy unrelated individuals of Jewish Yemenite, Jewish non-Yemenite, and Yemenite non-Jewish origin for the K1495E and R344X variants in the SAMD9 gene and found that they were present only in the controls of Jewish Yemenite origin. Haplotype analysis demonstrated that the mutations arose in this population from 2 independent events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18094730" 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>MIRAGE Syndrome</em></strong></p><p>
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In 11 Japanese patients from 10 families with a syndromic form of adrenal hypoplasia (MIRAGE syndrome; <a href="/entry/617053">617053</a>), <a href="#5" class="mim-tip-reference" title="Narumi, S., Amano, N., Ishii, T., Katsumata, N., Muroya, K., Adachi, M., Toyoshima, K., Tanaka, Y., Fukuzawa, R., Miyako, K., Kinjo, S., Ohga, S., and 27 others. <strong>SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.</strong> Nature Genet. 48: 792-797, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27182967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27182967</a>] [<a href="https://doi.org/10.1038/ng.3569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27182967">Narumi et al. (2016)</a> identified heterozygosity for missense mutations in the SAMD9 gene (see, e.g., <a href="#0002">610456.0002</a>-<a href="#0004">610456.0004</a>). The mutations were shown to have arisen de novo in all families for which parental DNA was available, except for 1 family with 2 affected sibs, where parental germline mosaicism was suspected. None of the mutations were found in Japanese control samples or in public variant databases. Functional analysis in HEK293 cells demonstrated that expression of wildtype SAMD9 resulted in mild growth restriction, whereas expression of the mutations caused profound growth inhibition, consistent with an 'activating' effect. Patient fibroblasts grew more slowly than control cells and showed lower levels of phosphorylated ERK and lower EGFR expression on the plasma membrane. Genetic analysis in 2 patients with monosomy 7 (see <a href="/entry/619041">619041</a>) who developed myelodysplastic syndrome showed loss of the signal derived from the mutant allele, suggesting that there was an expansion of the cells that lost chromosome 7 carrying the mutation. Because functional analysis demonstrated potent growth-restricting activity with the SAMD9 mutants, <a href="#5" class="mim-tip-reference" title="Narumi, S., Amano, N., Ishii, T., Katsumata, N., Muroya, K., Adachi, M., Toyoshima, K., Tanaka, Y., Fukuzawa, R., Miyako, K., Kinjo, S., Ohga, S., and 27 others. <strong>SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.</strong> Nature Genet. 48: 792-797, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27182967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27182967</a>] [<a href="https://doi.org/10.1038/ng.3569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27182967">Narumi et al. (2016)</a> suggested that the loss of chromosome 7 occurred as an adaptation to the growth-restricting conditions. <a href="#5" class="mim-tip-reference" title="Narumi, S., Amano, N., Ishii, T., Katsumata, N., Muroya, K., Adachi, M., Toyoshima, K., Tanaka, Y., Fukuzawa, R., Miyako, K., Kinjo, S., Ohga, S., and 27 others. <strong>SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.</strong> Nature Genet. 48: 792-797, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27182967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27182967</a>] [<a href="https://doi.org/10.1038/ng.3569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27182967">Narumi et al. (2016)</a> stated that this appeared to be the first documentation of the 'adaptation-by-aneuploidy' mechanism in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27182967" 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 2</em></strong></p><p>
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In 3 sibs with monosomy 7 myelodysplasia and leukemia syndrome-2 (M7MLS2; <a href="/entry/619041">619041</a>), <a href="#6" class="mim-tip-reference" title="Schwartz, J. R., Wang, S., Ma, J., Lamprecht, T., Walsh, M., Song, G., Raimondi, S. C., Wu, G., Walsh, M. F., McGee, R. B., Kesserwan, C., Nichols, K. E., Cauff, B. E., Ribeiro, R. C., Wlodarski, M., Klco, J. M. <strong>Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome.</strong> Leukemia 31: 1827-1830, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28487541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28487541</a>] [<a href="https://doi.org/10.1038/leu.2017.142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28487541">Schwartz et al. (2017)</a> identified a germline heterozygous missense mutation in the SAMD9 gene (E1136Q; <a href="#0006">610456.0006</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the clinically unaffected mother. In vitro functional expression studies in 293T cells transfected with the mutation revealed decreased ERK phosphorylation when stimulated compared to controls. Bone marrow analysis showed monosomy 7 in all sibs, consistent with refractory cytopenia. Although the E1136Q variant was present in patient lymphocytes, the mutant allele was less common in the myeloid cell fraction, suggesting preferential loss of the copy of chromosome 7 that harbors the variant allele. <a href="#6" class="mim-tip-reference" title="Schwartz, J. R., Wang, S., Ma, J., Lamprecht, T., Walsh, M., Song, G., Raimondi, S. C., Wu, G., Walsh, M. F., McGee, R. B., Kesserwan, C., Nichols, K. E., Cauff, B. E., Ribeiro, R. C., Wlodarski, M., Klco, J. M. <strong>Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome.</strong> Leukemia 31: 1827-1830, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28487541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28487541</a>] [<a href="https://doi.org/10.1038/leu.2017.142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28487541">Schwartz et al. (2017)</a> concluded that the MDS observed in these patients was not due to the SAMD9 mutation per se, but likely resulted from haploinsufficiency of multiple genes on chromosome 7. The secondary loss of chromosome 7 may represent a cellular adaptation to the deleterious SAMD9 germline mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28487541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 brothers (family 2) with M7MLS2, <a href="#10" 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://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 missense mutation in the SAMD9 gene (K676E; <a href="#0007">610456.0007</a>). HEK293T cells transfected with the mutation showed reduced cell cycle progression and almost no proliferation compared to controls, consistent with a gain-of-function effect. One patient had AML and the other had MDS; both had loss of the paternal chromosome 7 in bone marrow cells. The molecular findings supported the hypothesis that the somatic loss of chromosome 7 results from selective pressure to favor the growth of hematopoietic stem cells with a SAMD9 mutation, suggesting 'adaptation by aneuploidy' as a pathogenic mechanism. The family was previously reported by <a href="#7" 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=2569483+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><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="#4" 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://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 12 different heterozygous germline variants in the SAMD9 gene. The patients and variants were ascertained from public whole-exome sequencing databases. Most of the variants were missense, although there were a few frameshift or nonsense changes. 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 SAMD9 gene. Many MDS patients had secondary somatic hits in other genes that likely contributed to the development of the disorder. <a href="#4" 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://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 SAMD9L gene were also identified. Overall, germline variants 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>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918554 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918554;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=rs121918554" 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=rs121918554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#8" class="mim-tip-reference" title="Topaz, O., Indelman, M., Chefetz, I., Geiger, D., Metzker, A., Altschuler, Y., Choder, M., Bercovich, D., Uitto, J., Bergman, R., Richard, G., Sprecher, E. <strong>A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis.</strong> Am. J. Hum. Genet. 79: 759-764, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16960814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16960814</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16960814[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/508069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16960814">Topaz et al. (2006)</a> identified homozygosity for a c.4483A-G transition in the SAMD9 gene, resulting in a lys1495-to-glu (K1495E) substitution, as the cause of normophosphatemic familial tumoral calcinosis (NFTC; <a href="/entry/610455">610455</a>) in 5 Jewish Yemenite families. The K1495E mutation caused loss of punctate expression of a GFP-SAMD9 fusion protein after transfection in HEK293 cells, indicating that this mutation interferes with SAMD9 expression. In a screening of 92 healthy, unrelated Jewish individuals born to couples who immigrated to Israel from Yemen, <a href="#8" class="mim-tip-reference" title="Topaz, O., Indelman, M., Chefetz, I., Geiger, D., Metzker, A., Altschuler, Y., Choder, M., Bercovich, D., Uitto, J., Bergman, R., Richard, G., Sprecher, E. <strong>A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis.</strong> Am. J. Hum. Genet. 79: 759-764, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16960814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16960814</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16960814[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/508069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16960814">Topaz et al. (2006)</a> found 1 individual who carried both K1495E and the disease haplotype in the heterozygous state, which corresponded to a carrier rate of approximately 0.01, fitting the expected prevalence of the disease in the Israeli Jewish Yemenite population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16960814" 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">rs1584254152 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1584254152;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=rs1584254152" 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=rs1584254152" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an unrelated Japanese boy and girl who died at ages 3 months and 7 months with MIRAGE syndrome (MIRAGE; <a href="/entry/617053">617053</a>), <a href="#5" class="mim-tip-reference" title="Narumi, S., Amano, N., Ishii, T., Katsumata, N., Muroya, K., Adachi, M., Toyoshima, K., Tanaka, Y., Fukuzawa, R., Miyako, K., Kinjo, S., Ohga, S., and 27 others. <strong>SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.</strong> Nature Genet. 48: 792-797, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27182967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27182967</a>] [<a href="https://doi.org/10.1038/ng.3569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27182967">Narumi et al. (2016)</a> identified heterozygosity for an arg459-to-gln (R459Q) substitution at a highly conserved residue in the SAMD9 gene. The boy died of cytomegalovirus- and Candida glabrata-related pneumonia, and the girl died of hypovolumic shock due to upper gastrointestinal bleeding. The mutation arose de novo in both patients, and was not found in 400 in-house Japanese control samples or in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, Human Genetic Variation, or ExAC databases. Functional analysis in HEK293 cells demonstrated that expression of wildtype SAMD9 resulted in mild growth restriction, whereas expression of the R459Q mutant caused profound growth inhibition, consistent with an 'activating' effect. Patient fibroblasts grew more slowly than control cells and showed lower levels of phosphorylated ERK and lower EGFR expression on the plasma membrane. Confocal microscopy with endosome markers revealed that the cytoplasm of patient fibroblasts was filled with giant RAB7A (see <a href="/entry/602298">602298</a>)-positive vesicles, and RAB5A (<a href="/entry/179512">179512</a>) vesicles also skewed larger in patients than controls. <a href="#5" class="mim-tip-reference" title="Narumi, S., Amano, N., Ishii, T., Katsumata, N., Muroya, K., Adachi, M., Toyoshima, K., Tanaka, Y., Fukuzawa, R., Miyako, K., Kinjo, S., Ohga, S., and 27 others. <strong>SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.</strong> Nature Genet. 48: 792-797, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27182967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27182967</a>] [<a href="https://doi.org/10.1038/ng.3569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27182967">Narumi et al. (2016)</a> suggested that the R459Q mutant caused functional as well as structural alterations of the endosome system, because the decrease in membrane EFGR was likely due to defective recycling of the receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27182967" 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">rs1584253343 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1584253343;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=rs1584253343" 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=rs1584253343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Japanese brother and sister with MIRAGE syndrome (MIRAGE; <a href="/entry/617053">617053</a>), <a href="#5" class="mim-tip-reference" title="Narumi, S., Amano, N., Ishii, T., Katsumata, N., Muroya, K., Adachi, M., Toyoshima, K., Tanaka, Y., Fukuzawa, R., Miyako, K., Kinjo, S., Ohga, S., and 27 others. <strong>SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.</strong> Nature Genet. 48: 792-797, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27182967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27182967</a>] [<a href="https://doi.org/10.1038/ng.3569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27182967">Narumi et al. (2016)</a> identified heterozygosity for an asp769-to-asn (D769N) substitution at a highly conserved residue in the SAMD9 gene. The brother was alive at age 16 years, but the sister developed monosomy 7-related myelodysplastic syndrome that transformed into acute myelogenous leukemia, and she died at age 5 years of respiratory failure associated with posttransplant lymphoproliferative disorder. Neither parent carried the mutation, and germline mosaicism was presumed to be present in 1 of the parents; the variant also was not found in 400 in-house Japanese control samples or in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, Human Genetic Variation, or ExAC databases. Functional analysis in HEK293 cells demonstrated that expression of wildtype SAMD9 resulted in mild growth restriction, whereas expression of the D769N mutant caused profound growth inhibition, consistent with an 'activating' effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27182967" 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">rs1584251938 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1584251938;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=rs1584251938" 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=rs1584251938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an unrelated Japanese girl and boy who died at ages 24 months and 34 months with MIRAGE syndrome (MIRAGE; <a href="/entry/617053">617053</a>), <a href="#5" class="mim-tip-reference" title="Narumi, S., Amano, N., Ishii, T., Katsumata, N., Muroya, K., Adachi, M., Toyoshima, K., Tanaka, Y., Fukuzawa, R., Miyako, K., Kinjo, S., Ohga, S., and 27 others. <strong>SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.</strong> Nature Genet. 48: 792-797, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27182967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27182967</a>] [<a href="https://doi.org/10.1038/ng.3569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27182967">Narumi et al. (2016)</a> identified heterozygosity for an arg1293-to-trp (R1293W) substitution at a highly conserved residue in the SAMD9 gene. The girl died suddenly after a hospital-to-hospital transfer, whereas the boy developed monosomy 7-related myelodysplastic syndrome and died from acute respiratory distress triggered by respiratory syncytial virus infection. The mutation arose de novo in both patients, and was not found in 400 in-house Japanese control samples, the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, Human Genetic Variation, or ExAC databases. Functional analysis in HEK293 cells demonstrated that expression of wildtype SAMD9 resulted in mild growth restriction, whereas expression of the R1293W mutant caused profound growth inhibition, consistent with an 'activating' effect. Patient fibroblasts grew more slowly than control cells and showed lower levels of phosphorylated ERK and lower EGFR expression on the plasma membrane. Confocal microscopy with endosome markers revealed that the cytoplasm of patient fibroblasts was filled with giant RAB7A (see <a href="/entry/602298">602298</a>)-positive vesicles, and RAB5A (<a href="/entry/179512">179512</a>) vesicles also skewed larger in patients than controls. <a href="#5" class="mim-tip-reference" title="Narumi, S., Amano, N., Ishii, T., Katsumata, N., Muroya, K., Adachi, M., Toyoshima, K., Tanaka, Y., Fukuzawa, R., Miyako, K., Kinjo, S., Ohga, S., and 27 others. <strong>SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.</strong> Nature Genet. 48: 792-797, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27182967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27182967</a>] [<a href="https://doi.org/10.1038/ng.3569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27182967">Narumi et al. (2016)</a> suggested that the R1293W mutant caused functional as well as structural alterations of the endosome system, because the decrease in membrane EFGR was likely due to defective recycling of the receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27182967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs543007243 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs543007243;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/rs543007243?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=rs543007243" 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=rs543007243" 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=RCV001194464 OR RCV001863066" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001194464, RCV001863066" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001194464...</a>
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<p>In dizygotic twins with normophosphatemic familial tumoral calcinosis (NFTC; <a href="/entry/610455">610455</a>) from a Jewish Yemenite family, <a href="#2" class="mim-tip-reference" title="Chefetz, I., Amitai, D. B., Browning, S., Skorecki, K., Adir, N., Thomas, M. G., Kogleck, L., Topaz, O., Indelman, M., Uitto, J., Richard, G., Bradman, N., Sprecher, E. <strong>Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein.</strong> J. Invest. Derm. 128: 1423-1429, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18094730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18094730</a>] [<a href="https://doi.org/10.1038/sj.jid.5701203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18094730">Chefetz et al. (2008)</a> identified compound heterozygous mutations in the SAMD9 gene: the previously identified K1495E mutation (<a href="#0001">610456.0001</a>) and a c.1030C-T transition resulting in an arg344-to-ter (R344X) substitution. The mutations, which were identified by direct sequencing of the SAMD9 gene, segregated with the disorder in the family. The R344X mutation is predicted to result in significant truncation of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18094730" 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 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs759775100 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs759775100;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/rs759775100?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=rs759775100" 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=rs759775100" 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=RCV001270305" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001270305" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001270305</a>
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<p>In 3 sibs with monosomy 7 myelodysplasia and leukemia syndrome-2 (M7MLS2; <a href="/entry/619041">619041</a>), <a href="#6" class="mim-tip-reference" title="Schwartz, J. R., Wang, S., Ma, J., Lamprecht, T., Walsh, M., Song, G., Raimondi, S. C., Wu, G., Walsh, M. F., McGee, R. B., Kesserwan, C., Nichols, K. E., Cauff, B. E., Ribeiro, R. C., Wlodarski, M., Klco, J. M. <strong>Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome.</strong> Leukemia 31: 1827-1830, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28487541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28487541</a>] [<a href="https://doi.org/10.1038/leu.2017.142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28487541">Schwartz et al. (2017)</a> identified a germline heterozygous c.3406G-C transversion (c.3406G-C, NM_017654) in the SAMD9 gene, resulting in a glu1136-to-gln (E1136Q) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the clinically unaffected mother. The mutation was not present in the ExAC database or in in-house controls. The mutation was also confirmed to be present in buccal cells from the proband. In vitro functional expression studies in 293T cells transfected with the mutation revealed decreased ERK phosphorylation when stimulated compared to controls. Bone marrow analysis showed monosomy 7 in all sibs, consistent with refractory cytopenia. Although the E1136Q variant was present in patient lymphocytes, the mutant allele was less common in the myeloid cell fraction, suggesting preferential loss of the copy of chromosome 7 that harbors the variant allele. Two sibs also carried different somatic alterations in the SAMD9 gene (R221X and F583I) that were in cis with the E1136Q mutation. Aside from hypospadias and a bifid scrotum in 1 sib, none had additional features suggestive of MIRAGE syndrome. Two of the sibs underwent bone marrow transplantation. <a href="#6" class="mim-tip-reference" title="Schwartz, J. R., Wang, S., Ma, J., Lamprecht, T., Walsh, M., Song, G., Raimondi, S. C., Wu, G., Walsh, M. F., McGee, R. B., Kesserwan, C., Nichols, K. E., Cauff, B. E., Ribeiro, R. C., Wlodarski, M., Klco, J. M. <strong>Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome.</strong> Leukemia 31: 1827-1830, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28487541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28487541</a>] [<a href="https://doi.org/10.1038/leu.2017.142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28487541">Schwartz et al. (2017)</a> concluded that the MDS observed in these patients was not due to the SAMD9 mutation per se, but that it likely resulted from haploinsufficiency of multiple genes on chromosome 7. The secondary loss of chromosome 7 may represent a cellular adaptation to the deleterious SAMD9 germline mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28487541" 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">rs1791586314 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1791586314;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=rs1791586314" 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=rs1791586314" 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=RCV001270306" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001270306" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001270306</a>
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<p>In 2 brothers (family 2) with monosomy 7 myelodysplasia and leukemia syndrome-2 (M7MLS2; <a href="/entry/619041">619041</a>), <a href="#10" 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://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 c.2026A-G transition (c.2026A-G, NM_017654) in exon 3 of the SAMD9 gene, resulting in a lys676-to-glu (K676E) substitution. The mutation, which was not present in either parent, was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. HEK293T cells transfected with the mutation showed suppressed cell cycle progression with almost no proliferation compared to controls, consistent with a gain-of-function effect. One patient had AML and the other had MDS; both had loss of the paternal chromosome 7 in bone marrow cells. The molecular findings supported the hypothesis that the somatic loss of chromosome 7 results from selective pressure to favor the growth of hematopoietic stem cells that carry the SAMD9 mutation, suggesting 'adaptation by aneuploidy' as a pathogenic mechanism. The family had previously been reported by <a href="#7" 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=2569483+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>REFERENCES</strong>
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<a id="Asou2009" class="mim-anchor"></a>
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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: <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://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'})">related citations</a>]
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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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Chefetz, I., Amitai, D. B., Browning, S., Skorecki, K., Adir, N., Thomas, M. G., Kogleck, L., Topaz, O., Indelman, M., Uitto, J., Richard, G., Bradman, N., Sprecher, E.
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<strong>Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein.</strong>
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J. Invest. Derm. 128: 1423-1429, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18094730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18094730</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18094730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.jid.5701203" target="_blank">Full Text</a>]
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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.
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<strong>Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse.</strong>
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BMC Genomics 8: 92, 2007. Note: Electronic Article.
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[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://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'})">related citations</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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Blood 132: 2309-2313, 2018.
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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://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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Narumi, S., Amano, N., Ishii, T., Katsumata, N., Muroya, K., Adachi, M., Toyoshima, K., Tanaka, Y., Fukuzawa, R., Miyako, K., Kinjo, S., Ohga, S., and 27 others.
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<strong>SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.</strong>
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Nature Genet. 48: 792-797, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27182967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27182967</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27182967" 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/ng.3569" target="_blank">Full Text</a>]
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Schwartz, J. R., Wang, S., Ma, J., Lamprecht, T., Walsh, M., Song, G., Raimondi, S. C., Wu, G., Walsh, M. F., McGee, R. B., Kesserwan, C., Nichols, K. E., Cauff, B. E., Ribeiro, R. C., Wlodarski, M., Klco, J. M.
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<strong>Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome.</strong>
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Leukemia 31: 1827-1830, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28487541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28487541</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28487541" 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/leu.2017.142" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Shannon1989" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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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>
|
|
J. Clin. Invest. 84: 984-989, 1989.
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[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://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2569483" 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/JCI114262" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Topaz2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Topaz, O., Indelman, M., Chefetz, I., Geiger, D., Metzker, A., Altschuler, Y., Choder, M., Bercovich, D., Uitto, J., Bergman, R., Richard, G., Sprecher, E.
|
|
<strong>A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis.</strong>
|
|
Am. J. Hum. Genet. 79: 759-764, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16960814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16960814</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16960814[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=16960814" 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/10.1086/508069" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Topaz2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Topaz, O., Shurman, D. L., Bergman, R., Indelman, M., Ratajczak, P., Mizrachi, M., Khamaysi, Z., Behar, D., Petronius, D., Friedman, V., Zelikovic, I., Raimer, S., Metzker, A., Richard, G., Sprecher, E.
|
|
<strong>Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis.</strong>
|
|
Nature Genet. 36: 579-581, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15133511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15133511</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15133511" 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/ng1358" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Wong2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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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://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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</p>
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</div>
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</li>
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</ol>
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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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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/07/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 10/27/2020<br>Kelly A. Przylepa - updated : 06/19/2020<br>Marla J. F. O'Neill - updated : 07/25/2016<br>Patricia A. Hartz - updated : 7/11/2011<br>Patricia A. Hartz - updated : 6/22/2007
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 9/28/2006
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 02/19/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 12/14/2020<br>carol : 12/11/2020<br>carol : 12/10/2020<br>ckniffin : 12/07/2020<br>mgross : 10/27/2020<br>carol : 06/22/2020<br>carol : 06/19/2020<br>carol : 07/25/2016<br>wwang : 08/04/2011<br>terry : 7/11/2011<br>ckniffin : 2/5/2008<br>wwang : 7/5/2007<br>terry : 6/22/2007<br>alopez : 9/28/2006
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</span>
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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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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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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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<strong>*</strong> 610456
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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; SAMD9
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SAMD9</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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1162852008, 1234831009;
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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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<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> : 7:93,099,518-93,117,979 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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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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<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>
|
|
Inheritance
|
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</th>
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<th>
|
|
Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
|
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<span class="mim-font">
|
|
7q21.2
|
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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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|
MIRAGE syndrome
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
617053
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</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">
|
|
Monosomy 7 myelodysplasia and leukemia syndrome 2
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
619041
|
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
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">
|
|
3
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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>
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<span class="mim-font">
|
|
Tumoral calcinosis, familial, normophosphatemic
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
610455
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
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</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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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>The SAMD9 gene encodes a protein involved in endosome fusion. It plays a role in growth factor signal transduction and negatively regulates cell proliferation (summary by Narumi et al., 2016 and Nagata et al., 2018). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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<span class="mim-text-font">
|
|
<p>Topaz et al. (2006) determined that the SAMD9 gene encodes a 1,589-amino acid protein that is expressed in a wide range of tissues, including skin. Quantitative real-time PCR showed that the gene is strongly expressed in endothelial cells and, to a lesser degree, in fibroblasts. Topaz et al. (2006) observed that apart from an N-terminal sterile alpha motif (SAM), the SAMD9 protein bore little homology to other known proteins except for the SAMD9L protein, with which it shares 58% identity. </p><p>By database analysis, Li et al. (2007) found evidence for alternative splicing of SAMD9 transcripts due to the utilization of noncanonical dinucleotides as intron 3 donor and acceptor splice sites. Use of the noncanonical site would result in an in-frame deletion, leading to exclusion of the N-terminal SAM domain. Li et al. (2007) also noted that the SAM domain of SAMD9 lacks residues essential for RNA binding, but it has 98% homology with the SAM domain of EPHB2 (600997), which forms homooligomers and provides a platform for the formation of larger protein complexes. Northern blot analysis detected a 7-kb transcript in full-term placenta. PCR analysis detected SAMD9 in all human adult, fetal, and tumor tissues examined, except for fetal brain. Fluorescence-tagged SAMD9 was expressed in the cytoplasm of several transfected cell lines. Li et al. (2007) identified SAMD9 orthologs in several mammalian species but not in chicken, frog, fish, or several lower eukaryotes. A notable exception was the absence of Samd9 in mouse, which appeared to have been lost during a mouse-specific gene rearrangement. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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|
|
<span class="mim-text-font">
|
|
<p>Using suppression subtractive hybridization, Li et al. (2007) found that SAMD9 was one of the most differentially regulated genes in an aggressive fibromatosis tumor with inactivation of the APC gene (611731) compared with the same cells after transfection of wildtype APC. Knockdown of SAMD9 by RNA interference increased the proliferation and invasiveness of a normal lung fibroblast cell line, whereas SAMD9 overexpression reduced cell proliferation and motility, and increased apoptosis in a colon cancer cell line. SAMD9 overexpression reduced tumor volume following transplantation in immune-deficient mice. </p><p>Using quantitative RT-PCR, Chefetz et al. (2008) showed that SAMD9 expression in human endothelial cells increased significantly following exposure to TNFA (TNF; 191160), a major proinflammatory cytokine and inducer of apoptosis. Analysis with inhibitors showed that SAMD9 upregulation by TNFA required p38 (MAPK14; 600289). In addition, cellular stress induced by hyperosmotic shock markedly upregulated SAMD9 expression in endothelial cells. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Li et al. (2007) determined that the SAMD9 gene contains 3 exons, and its promoter region contains a TATA signal and 5 predicted LEF (LEF1; 153245)-binding elements. There are also alternative transcriptional initiation sites and polyadenylation sites, and at least 2 alternative splice sites. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Topaz et al. (2006) identified the SAMD9 gene within a region on chromosome 7q21-q21.3 linked to normophosphatemic familial tumoral calcinosis (610455). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</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>Normophosphatemic Familial Tumoral Calcinosis</em></strong></p><p>
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In 8 individuals with normophosphatemic familial tumoral calcinosis (NFTC; 610455) from 5 families of Jewish Yemenite origin, Topaz et al. (2004) identified a shared region of homozygosity on chromosome 7q21-q21.3. In the 8 affected individuals, the authors identified a homozygous missense mutation (K1495E; 610456.0001), which segregated with the disease in all families. K1495 seems to be well conserved across species, suggesting that it is of physiologic importance. The K1495E mutation caused loss of punctate expression of a GFP-SAMD9 fusion protein after transfection in HEK293 cells, indicating that this mutation interferes with SAMD9 expression. </p><p>In dizygotic twins with NFTC from a Jewish Yemenite family, Chefetz et al. (2008) identified compound heterozygous mutations in the SAMD9 gene: the previously identified K1495E mutation and a novel nonsense mutation (R344X; 610446.0005). The mutations, which were identified by direct sequencing of the SAMD9 gene, segregated with the disorder in the family. </p><p>Chefetz et al. (2008) screened a large cohort of healthy unrelated individuals of Jewish Yemenite, Jewish non-Yemenite, and Yemenite non-Jewish origin for the K1495E and R344X variants in the SAMD9 gene and found that they were present only in the controls of Jewish Yemenite origin. Haplotype analysis demonstrated that the mutations arose in this population from 2 independent events. </p><p><strong><em>MIRAGE Syndrome</em></strong></p><p>
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In 11 Japanese patients from 10 families with a syndromic form of adrenal hypoplasia (MIRAGE syndrome; 617053), Narumi et al. (2016) identified heterozygosity for missense mutations in the SAMD9 gene (see, e.g., 610456.0002-610456.0004). The mutations were shown to have arisen de novo in all families for which parental DNA was available, except for 1 family with 2 affected sibs, where parental germline mosaicism was suspected. None of the mutations were found in Japanese control samples or in public variant databases. Functional analysis in HEK293 cells demonstrated that expression of wildtype SAMD9 resulted in mild growth restriction, whereas expression of the mutations caused profound growth inhibition, consistent with an 'activating' effect. Patient fibroblasts grew more slowly than control cells and showed lower levels of phosphorylated ERK and lower EGFR expression on the plasma membrane. Genetic analysis in 2 patients with monosomy 7 (see 619041) who developed myelodysplastic syndrome showed loss of the signal derived from the mutant allele, suggesting that there was an expansion of the cells that lost chromosome 7 carrying the mutation. Because functional analysis demonstrated potent growth-restricting activity with the SAMD9 mutants, Narumi et al. (2016) suggested that the loss of chromosome 7 occurred as an adaptation to the growth-restricting conditions. Narumi et al. (2016) stated that this appeared to be the first documentation of the 'adaptation-by-aneuploidy' mechanism in humans. </p><p><strong><em>Monosomy 7 Myelodysplasia and Leukemia Syndrome 2</em></strong></p><p>
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|
In 3 sibs with monosomy 7 myelodysplasia and leukemia syndrome-2 (M7MLS2; 619041), Schwartz et al. (2017) identified a germline heterozygous missense mutation in the SAMD9 gene (E1136Q; 610456.0006). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the clinically unaffected mother. In vitro functional expression studies in 293T cells transfected with the mutation revealed decreased ERK phosphorylation when stimulated compared to controls. Bone marrow analysis showed monosomy 7 in all sibs, consistent with refractory cytopenia. Although the E1136Q variant was present in patient lymphocytes, the mutant allele was less common in the myeloid cell fraction, suggesting preferential loss of the copy of chromosome 7 that harbors the variant allele. Schwartz et al. (2017) concluded that the MDS observed in these patients was not due to the SAMD9 mutation per se, but likely resulted from haploinsufficiency of multiple genes on chromosome 7. The secondary loss of chromosome 7 may represent a cellular adaptation to the deleterious SAMD9 germline mutation. </p><p>In 2 brothers (family 2) with M7MLS2, Wong et al. (2018) identified a germline heterozygous missense mutation in the SAMD9 gene (K676E; 610456.0007). HEK293T cells transfected with the mutation showed reduced cell cycle progression and almost no proliferation compared to controls, consistent with a gain-of-function effect. One patient had AML and the other had MDS; both had loss of the paternal chromosome 7 in bone marrow cells. The molecular findings supported the hypothesis that the somatic loss of chromosome 7 results from selective pressure to favor the growth of hematopoietic stem cells with a SAMD9 mutation, suggesting 'adaptation by aneuploidy' as a pathogenic mechanism. The family was previously reported by Shannon et al. (1989). </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 12 different heterozygous germline variants in the SAMD9 gene. The patients and variants were ascertained from public whole-exome sequencing databases. Most of the variants were missense, although there were a few frameshift or nonsense changes. 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 SAMD9 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 SAMD9L gene were also identified. Overall, germline variants 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>
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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>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, 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 deletions of chromosome 7 (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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<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 TUMORAL CALCINOSIS, NORMOPHOSPHATEMIC, FAMILIAL</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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SAMD9, LYS1495GLU
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<br />
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SNP: rs121918554,
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ClinVar: RCV000001288, RCV003555884
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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>Topaz et al. (2006) identified homozygosity for a c.4483A-G transition in the SAMD9 gene, resulting in a lys1495-to-glu (K1495E) substitution, as the cause of normophosphatemic familial tumoral calcinosis (NFTC; 610455) in 5 Jewish Yemenite families. The K1495E mutation caused loss of punctate expression of a GFP-SAMD9 fusion protein after transfection in HEK293 cells, indicating that this mutation interferes with SAMD9 expression. In a screening of 92 healthy, unrelated Jewish individuals born to couples who immigrated to Israel from Yemen, Topaz et al. (2006) found 1 individual who carried both K1495E and the disease haplotype in the heterozygous state, which corresponded to a carrier rate of approximately 0.01, fitting the expected prevalence of the disease in the Israeli Jewish Yemenite population. </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 MIRAGE 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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SAMD9, ARG459GLN
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<br />
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SNP: rs1584254152,
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ClinVar: RCV000239546, RCV001386011
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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 an unrelated Japanese boy and girl who died at ages 3 months and 7 months with MIRAGE syndrome (MIRAGE; 617053), Narumi et al. (2016) identified heterozygosity for an arg459-to-gln (R459Q) substitution at a highly conserved residue in the SAMD9 gene. The boy died of cytomegalovirus- and Candida glabrata-related pneumonia, and the girl died of hypovolumic shock due to upper gastrointestinal bleeding. The mutation arose de novo in both patients, and was not found in 400 in-house Japanese control samples or in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, Human Genetic Variation, or ExAC databases. Functional analysis in HEK293 cells demonstrated that expression of wildtype SAMD9 resulted in mild growth restriction, whereas expression of the R459Q mutant caused profound growth inhibition, consistent with an 'activating' effect. Patient fibroblasts grew more slowly than control cells and showed lower levels of phosphorylated ERK and lower EGFR expression on the plasma membrane. Confocal microscopy with endosome markers revealed that the cytoplasm of patient fibroblasts was filled with giant RAB7A (see 602298)-positive vesicles, and RAB5A (179512) vesicles also skewed larger in patients than controls. Narumi et al. (2016) suggested that the R459Q mutant caused functional as well as structural alterations of the endosome system, because the decrease in membrane EFGR was likely due to defective recycling of the receptor. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0003 MIRAGE 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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|
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SAMD9, ASP769ASN
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<br />
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SNP: rs1584253343,
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|
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ClinVar: RCV000239465
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|
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</span>
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</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese brother and sister with MIRAGE syndrome (MIRAGE; 617053), Narumi et al. (2016) identified heterozygosity for an asp769-to-asn (D769N) substitution at a highly conserved residue in the SAMD9 gene. The brother was alive at age 16 years, but the sister developed monosomy 7-related myelodysplastic syndrome that transformed into acute myelogenous leukemia, and she died at age 5 years of respiratory failure associated with posttransplant lymphoproliferative disorder. Neither parent carried the mutation, and germline mosaicism was presumed to be present in 1 of the parents; the variant also was not found in 400 in-house Japanese control samples or in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, Human Genetic Variation, or ExAC databases. Functional analysis in HEK293 cells demonstrated that expression of wildtype SAMD9 resulted in mild growth restriction, whereas expression of the D769N mutant caused profound growth inhibition, consistent with an 'activating' effect. </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>.0004 MIRAGE SYNDROME</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">
|
|
|
|
SAMD9, ARG1293TRP
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|
|
<br />
|
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|
|
SNP: rs1584251938,
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|
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|
|
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|
|
ClinVar: RCV000239516, RCV002508782
|
|
|
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|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an unrelated Japanese girl and boy who died at ages 24 months and 34 months with MIRAGE syndrome (MIRAGE; 617053), Narumi et al. (2016) identified heterozygosity for an arg1293-to-trp (R1293W) substitution at a highly conserved residue in the SAMD9 gene. The girl died suddenly after a hospital-to-hospital transfer, whereas the boy developed monosomy 7-related myelodysplastic syndrome and died from acute respiratory distress triggered by respiratory syncytial virus infection. The mutation arose de novo in both patients, and was not found in 400 in-house Japanese control samples, the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, Human Genetic Variation, or ExAC databases. Functional analysis in HEK293 cells demonstrated that expression of wildtype SAMD9 resulted in mild growth restriction, whereas expression of the R1293W mutant caused profound growth inhibition, consistent with an 'activating' effect. Patient fibroblasts grew more slowly than control cells and showed lower levels of phosphorylated ERK and lower EGFR expression on the plasma membrane. Confocal microscopy with endosome markers revealed that the cytoplasm of patient fibroblasts was filled with giant RAB7A (see 602298)-positive vesicles, and RAB5A (179512) vesicles also skewed larger in patients than controls. Narumi et al. (2016) suggested that the R1293W mutant caused functional as well as structural alterations of the endosome system, because the decrease in membrane EFGR was likely due to defective recycling of the receptor. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 TUMORAL CALCINOSIS, NORMOPHOSPHATEMIC, FAMILIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SAMD9, ARG344TER
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|
|
|
|
<br />
|
|
|
|
SNP: rs543007243,
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|
|
|
|
|
gnomAD: rs543007243,
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|
|
|
|
|
ClinVar: RCV001194464, RCV001863066
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In dizygotic twins with normophosphatemic familial tumoral calcinosis (NFTC; 610455) from a Jewish Yemenite family, Chefetz et al. (2008) identified compound heterozygous mutations in the SAMD9 gene: the previously identified K1495E mutation (610456.0001) and a c.1030C-T transition resulting in an arg344-to-ter (R344X) substitution. The mutations, which were identified by direct sequencing of the SAMD9 gene, segregated with the disorder in the family. The R344X mutation is predicted to result in significant truncation of the protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MONOSOMY 7 MYELODYSPLASIA AND LEUKEMIA SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SAMD9, GLU1136GLN
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|
<br />
|
|
|
|
SNP: rs759775100,
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|
|
|
gnomAD: rs759775100,
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|
|
|
|
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ClinVar: RCV001270305
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|
|
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|
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</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 sibs with monosomy 7 myelodysplasia and leukemia syndrome-2 (M7MLS2; 619041), Schwartz et al. (2017) identified a germline heterozygous c.3406G-C transversion (c.3406G-C, NM_017654) in the SAMD9 gene, resulting in a glu1136-to-gln (E1136Q) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the clinically unaffected mother. The mutation was not present in the ExAC database or in in-house controls. The mutation was also confirmed to be present in buccal cells from the proband. In vitro functional expression studies in 293T cells transfected with the mutation revealed decreased ERK phosphorylation when stimulated compared to controls. Bone marrow analysis showed monosomy 7 in all sibs, consistent with refractory cytopenia. Although the E1136Q variant was present in patient lymphocytes, the mutant allele was less common in the myeloid cell fraction, suggesting preferential loss of the copy of chromosome 7 that harbors the variant allele. Two sibs also carried different somatic alterations in the SAMD9 gene (R221X and F583I) that were in cis with the E1136Q mutation. Aside from hypospadias and a bifid scrotum in 1 sib, none had additional features suggestive of MIRAGE syndrome. Two of the sibs underwent bone marrow transplantation. Schwartz et al. (2017) concluded that the MDS observed in these patients was not due to the SAMD9 mutation per se, but that it likely resulted from haploinsufficiency of multiple genes on chromosome 7. The secondary loss of chromosome 7 may represent a cellular adaptation to the deleterious SAMD9 germline mutation. </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>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>.0007 MONOSOMY 7 MYELODYSPLASIA AND LEUKEMIA SYNDROME 2</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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SAMD9, LYS676GLU
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<br />
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SNP: rs1791586314,
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ClinVar: RCV001270306
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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 brothers (family 2) with monosomy 7 myelodysplasia and leukemia syndrome-2 (M7MLS2; 619041), Wong et al. (2018) identified a germline heterozygous c.2026A-G transition (c.2026A-G, NM_017654) in exon 3 of the SAMD9 gene, resulting in a lys676-to-glu (K676E) substitution. The mutation, which was not present in either parent, was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. HEK293T cells transfected with the mutation showed suppressed cell cycle progression with almost no proliferation compared to controls, consistent with a gain-of-function effect. One patient had AML and the other had MDS; both had loss of the paternal chromosome 7 in bone marrow cells. The molecular findings supported the hypothesis that the somatic loss of chromosome 7 results from selective pressure to favor the growth of hematopoietic stem cells that carry the SAMD9 mutation, suggesting 'adaptation by aneuploidy' as a pathogenic mechanism. The family had previously been reported 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">
|
|
<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">
|
|
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.
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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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Chefetz, I., Amitai, D. B., Browning, S., Skorecki, K., Adir, N., Thomas, M. G., Kogleck, L., Topaz, O., Indelman, M., Uitto, J., Richard, G., Bradman, N., Sprecher, E.
|
|
<strong>Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein.</strong>
|
|
J. Invest. Derm. 128: 1423-1429, 2008.
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[PubMed: 18094730]
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[Full Text: https://doi.org/10.1038/sj.jid.5701203]
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</p>
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</li>
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<li>
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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.
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<strong>Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse.</strong>
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<strong>Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes.</strong>
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Narumi, S., Amano, N., Ishii, T., Katsumata, N., Muroya, K., Adachi, M., Toyoshima, K., Tanaka, Y., Fukuzawa, R., Miyako, K., Kinjo, S., Ohga, S., and 27 others.
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<strong>SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.</strong>
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Nature Genet. 48: 792-797, 2016.
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<strong>Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis.</strong>
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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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