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Entry
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- #619767 - PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 6; PFBMFT6
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- OMIM
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<p>
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<span class="h4">#619767</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/619767"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS614742"> <strong>Phenotypic Series</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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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK22301/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=619767[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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<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 class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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619767
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</span>
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</span>
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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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PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 6; PFBMFT6
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</span>
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</h3>
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<div>
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<br />
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene 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 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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</th>
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<th>
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Phenotype <br /> MIM number
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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<a href="/geneMap/17/38?start=-3&limit=10&highlight=38">
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17p13.3
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<span class="mim-font">
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Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 6
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<span class="mim-font">
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<a href="/entry/619767"> 619767 </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 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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RPA1
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<span class="mim-font">
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<a href="/entry/179835"> 179835 </a>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/619767" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<a href="/phenotypicSeries/PS614742" class="btn btn-info" role="button"> Phenotypic Series </a>
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/619767" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/619767" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</div>
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<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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<p />
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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</span>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
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<span class="h5 mim-font">
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<strong> HEAD & NECK </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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|
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<em> Mouth </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Leukoplakia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/50978000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">50978000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/274134003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">274134003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023531&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023531</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
|
|
</div>
|
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|
|
</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> RESPIRATORY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Restrictive pulmonary function <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806472&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806472</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Lung </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Pulmonary fibrosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/51615001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">51615001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0034069&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0034069</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002206" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002206</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002206" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002206</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
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|
|
|
|
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|
|
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|
|
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|
|
|
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|
|
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Reticular skin pigmentation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278107&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278107</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Nails </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Nail dystrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/87065009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">87065009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L60.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L60.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221260&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221260</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008404" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008404</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008404" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008404</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Hair </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Premature graying <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/387833009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">387833009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L67.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L67.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0263498&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0263498</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002216" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002216</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002216" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002216</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEMATOLOGY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Pancytopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/127034005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">127034005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D61.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D61.81</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/284.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">284.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0030312&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030312</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001876" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001876</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001876" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001876</a>]</span><br /> -
|
|
Hypoplastic bone marrow <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/167928002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">167928002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855710&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855710</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005528" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005528</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005528" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005528</a>]</span><br /> -
|
|
Myelodysplastic syndrome <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/109995007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">109995007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128623006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128623006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D46" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D46</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D46.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D46.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/238.75" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">238.75</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3463824&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3463824</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002863" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002863</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002863" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002863</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> IMMUNOLOGY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Lymphopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48813009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48813009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.810" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.810</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/288.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0853986&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0853986</a>, <a href="https://bioportal.bioontology.org/search?q=C0024312&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0024312</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001888" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001888</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001888" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001888</a>]</span><br /> -
|
|
Hypogammaglobulinemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/119250001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">119250001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D80.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D80.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/279.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">279.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0086438&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0086438</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004313" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004313</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004313" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004313</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Shortened telomeres in peripheral blood cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5678350&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5678350</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Highly variable phenotype <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839039&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839039</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span><br /> -
|
|
Variable age at onset (range infancy to adult)<br /> -
|
|
Variable severity and manifestations<br /> -
|
|
Incomplete penetrance <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836598&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836598</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003829</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003829</a>]</span><br /> -
|
|
De novo mutation (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2985439&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2985439</a>]</span><br /> -
|
|
Four unrelated patients have been reported (last curated February 2022)<br />
|
|
|
|
</span>
|
|
</div>
|
|
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutation in the replication protein A1, 70-kb gene (RPA1, <a href="/entry/179835#0001">179835.0001</a>)<br />
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</span>
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</div>
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</div>
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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</div>
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</div>
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</div>
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<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small">
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<div class="row">
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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<h5>
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Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related
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- <a href="/phenotypicSeries/PS614742">PS614742</a>
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- 9 Entries
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</h5>
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</div>
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</div>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
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<table class="table table-bordered table-condensed table-hover mim-table-padding">
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<thead>
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<tr>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Location</strong>
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</th>
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<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
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<strong>Phenotype</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Inheritance</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />mapping key</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />MIM number</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus<br />MIM number</strong>
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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>
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<span class="mim-font">
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<a href="/geneMap/3/848?start=-3&limit=10&highlight=848"> 3q26.2 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614743"> Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 2 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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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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<td>
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<span class="mim-font">
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<a href="/entry/614743"> 614743 </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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<a href="/entry/602322"> TERC </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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<a href="/entry/602322"> 602322 </a>
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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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<a href="/geneMap/4/643?start=-3&limit=10&highlight=643"> 4q32.2 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/620365"> Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7 </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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<td>
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<span class="mim-font">
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<a href="/entry/620365"> 620365 </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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<a href="/entry/617868"> NAF1 </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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<a href="/entry/617868"> 617868 </a>
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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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<a href="/geneMap/5/22?start=-3&limit=10&highlight=22"> 5p15.33 </a>
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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<a href="/entry/614742"> Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 1 </a>
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
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|
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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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<td>
|
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<span class="mim-font">
|
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<a href="/entry/614742"> 614742 </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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<a href="/entry/187270"> TERT </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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<a href="/entry/187270"> 187270 </a>
|
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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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|
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<a href="/geneMap/7/635?start=-3&limit=10&highlight=635"> 7q31.33 </a>
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620367"> ?Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8 </a>
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
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|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620367"> 620367 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606478"> POT1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606478"> 606478 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/12/909?start=-3&limit=10&highlight=909"> 12q24.31 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618674"> ?Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 5 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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|
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</span>
|
|
</td>
|
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<td>
|
|
<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>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618674"> 618674 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616381"> ZCCHC8 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616381"> 616381 </a>
|
|
</span>
|
|
</td>
|
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</tr>
|
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|
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
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|
|
<a href="/geneMap/15/72?start=-3&limit=10&highlight=72"> 15q14 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620400"> ?Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620400"> 620400 </a>
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606471"> NOP10 </a>
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606471"> 606471 </a>
|
|
</span>
|
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</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/16/209?start=-3&limit=10&highlight=209"> 16p13.12 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616371"> Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 4 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616371"> 616371 </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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<a href="/entry/604212"> PARN </a>
|
|
</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/604212"> 604212 </a>
|
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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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<a href="/geneMap/17/38?start=-3&limit=10&highlight=38"> 17p13.3 </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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<a href="/entry/619767"> Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 6 </a>
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
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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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|
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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/619767"> 619767 </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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<a href="/entry/179835"> RPA1 </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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<a href="/entry/179835"> 179835 </a>
|
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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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<a href="/geneMap/20/478?start=-3&limit=10&highlight=478"> 20q13.33 </a>
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|
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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/616373"> Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 3 </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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|
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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/616373"> 616373 </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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<a href="/entry/608833"> RTEL1 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/608833"> 608833 </a>
|
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</span>
|
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</td>
|
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</tr>
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</tbody>
|
|
</table>
|
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</div>
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|
|
<div class="text-right small">
|
|
<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
|
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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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<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 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
|
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<div id="mimTextFold" class="collapse in ">
|
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-6 (PFBMFT6) is caused by heterozygous mutation in the RPA1 gene (<a href="/entry/179835">179835</a>) on chromosome 17p13.</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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<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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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
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<strong>Description</strong>
|
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-6 (PFBMFT6) is characterized by highly variable symptoms mainly affecting the hematopoietic or pulmonary systems. The age of symptom onset is also highly variable, ranging from infancy to adulthood. Some affected individuals develop early-onset pancytopenia, immunodeficiency, or myelodysplasia, whereas others manifest late-onset pulmonary fibrosis. Skin, nail, or hair features resembling dyskeratosis congenita (DKC; see, e.g., DKCA1, <a href="/entry/127550">127550</a>) may also be observed. Both PFBMFT6 and DKCA are associated with shortened telomeres, thus sharing a pathogenetic mechanism (summary by <a href="#1" class="mim-tip-reference" title="Sharma, R., Sahoo, S. S., Honda, M., Granger, S. L., Goodings, C., Sanchez, L., Kunstner, A., Busch, H., Beier, F., Pruett-Miller, S. M., Valentine, M. B., Fernandez, A., and 21 others. <strong>Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.</strong> Blood 139: 1039-1051, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34767620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34767620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34767620[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood.2021011980" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34767620">Sharma et al., 2022</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34767620" 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>For a discussion of genetic heterogeneity of telomere-related pulmonary fibrosis and/or bone marrow failure, see PFBMFT1 (<a href="/entry/614742">614742</a>).</p>
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<p><a href="#1" class="mim-tip-reference" title="Sharma, R., Sahoo, S. S., Honda, M., Granger, S. L., Goodings, C., Sanchez, L., Kunstner, A., Busch, H., Beier, F., Pruett-Miller, S. M., Valentine, M. B., Fernandez, A., and 21 others. <strong>Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.</strong> Blood 139: 1039-1051, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34767620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34767620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34767620[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood.2021011980" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34767620">Sharma et al. (2022)</a> reported 4 unrelated probands with variable hematologic, pulmonary, and skin manifestations associated with short telomeres. Patient 1 was a 28-year-old woman who presented at 10 years of age with pancytopenia, hypoplastic bone marrow, and a history of congenital eye anomaly requiring enucleation as an infant. She developed a classic dyskeratosis congenita-associated mucocutaneous triad during adolescence, including leukoplakia, nail dystrophy, and reticular skin pigmentation, but did not require treatment. Her blood counts stabilized over time due to somatic reversion (see MOLECULAR GENETICS). Patient 2 presented at age 13 years with myelodysplastic syndrome (MDS) with excess blasts and a somatic NRAS mutation (G12D; <a href="/entry/164790#0007">164790.0007</a>) at 37% allelic frequency. She also had facial dysmorphism and mildly restricted pulmonary function. After undergoing hematopoietic stem cell transplant, she developed significant complications with graft-versus-host disease, necrotizing pneumonitis, recurrent infections, and pulmonary fibrosis. She died of multiorgan failure 11 months post-transplant. The unaffected father and sister of P2 also carried a RPA1 mutation, suggesting incomplete disease penetrance. Patient 3 had early hair graying and onset of progressive pulmonary fibrosis at age 58 years. Two sisters of P3 were also diagnosed with pulmonary fibrosis and died of the disease; no DNA was available. P4 was a 3-year-old girl who presented at birth with prematurity, failure to thrive, lymphopenia, and hypogammaglobulinemia. At age 3, she was stable on IgG replacement therapy. Telomere length, assessed by different methods, was decreased in the blood cells of all patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34767620" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The transmission pattern of PFBMFT6 in 2 unrelated families (families 2 and 3) reported by <a href="#1" class="mim-tip-reference" title="Sharma, R., Sahoo, S. S., Honda, M., Granger, S. L., Goodings, C., Sanchez, L., Kunstner, A., Busch, H., Beier, F., Pruett-Miller, S. M., Valentine, M. B., Fernandez, A., and 21 others. <strong>Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.</strong> Blood 139: 1039-1051, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34767620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34767620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34767620[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood.2021011980" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34767620">Sharma et al. (2022)</a> was consistent with autosomal dominant inheritance with incomplete penetrance and variable expressivity. The heterozygous mutations in the RPA1 gene that were identified in 2 patients (patients 1 and 4) with PFBMFT6 by <a href="#1" class="mim-tip-reference" title="Sharma, R., Sahoo, S. S., Honda, M., Granger, S. L., Goodings, C., Sanchez, L., Kunstner, A., Busch, H., Beier, F., Pruett-Miller, S. M., Valentine, M. B., Fernandez, A., and 21 others. <strong>Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.</strong> Blood 139: 1039-1051, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34767620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34767620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34767620[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood.2021011980" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34767620">Sharma et al. (2022)</a> occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34767620" 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>In 4 unrelated probands with PFBMFT6, <a href="#1" class="mim-tip-reference" title="Sharma, R., Sahoo, S. S., Honda, M., Granger, S. L., Goodings, C., Sanchez, L., Kunstner, A., Busch, H., Beier, F., Pruett-Miller, S. M., Valentine, M. B., Fernandez, A., and 21 others. <strong>Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.</strong> Blood 139: 1039-1051, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34767620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34767620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34767620[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood.2021011980" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34767620">Sharma et al. (2022)</a> identified heterozygous missense mutations in the RPA1 gene affecting residues in the DNA-binding domain-A (DBD-A) (E240K, <a href="/entry/179835#0001">179835.0001</a>; V227A, <a href="/entry/179835#0002">179835.0002</a>, and T270A, <a href="/entry/179835#0003">179835.0003</a>). The mutations, which were found by exome sequencing, were either absent from the gnomAD database or present at a very low frequency. Two mutations occurred de novo and 1 was inherited from an unaffected parent; familial segregation studies for patient 3 could not be determined. In vitro functional expression studies showed that the E240K and V227A variants had increased binding to ssDNA and telomeric DNA compared to controls, consistent with a gain-of-function effect. In contrast, T270A had binding properties similar to wildtype, but was postulated to have other detrimental effects. Expression of the E240K mutation into iPSC-derived hematopoietic cells resulted in shortened telomeres and impaired differentiation of hematopoietic progenitor cells, particularly of the erythroid and myeloid lineages, but also affecting CD34+ cells. Of note, patient 1 had an atypical disease course with stabilization of blood counts and mucocutaneous features without intervention over 18 years. Her bone marrow analysis at age 13 showed reduced expression of the mutant E240K variant (27%) compared to fibroblasts (50%). Two somatic events were identified in the bone marrow that interfered with expression and proliferation of the mutant E240K allele: an RPA1 truncating (K579X) mutation at 10% allelic frequency and in cis with E240K, causing degradation of germline mutant RNA, and uniparental isodisomy of chromosome 17p, resulting in replacement of the germline variant with a wildtype allele. These allelic patterns were maintained over time and likely caused a rescue effect that coincided with the lack of progressive symptoms in the patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34767620" 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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Sharma, R., Sahoo, S. S., Honda, M., Granger, S. L., Goodings, C., Sanchez, L., Kunstner, A., Busch, H., Beier, F., Pruett-Miller, S. M., Valentine, M. B., Fernandez, A., and 21 others.
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Blood 139: 1039-1051, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34767620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34767620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34767620[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=34767620" 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.2021011980" target="_blank">Full Text</a>]
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Cassandra L. Kniffin : 02/24/2022
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alopez : 05/10/2023
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ckniffin : 05/08/2023<br>alopez : 03/04/2022<br>alopez : 03/03/2022<br>alopez : 03/03/2022<br>ckniffin : 02/25/2022
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PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 6; PFBMFT6
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Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 6
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<p>A number sign (#) is used with this entry because of evidence that telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-6 (PFBMFT6) is caused by heterozygous mutation in the RPA1 gene (179835) on chromosome 17p13.</p>
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<p>Telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-6 (PFBMFT6) is characterized by highly variable symptoms mainly affecting the hematopoietic or pulmonary systems. The age of symptom onset is also highly variable, ranging from infancy to adulthood. Some affected individuals develop early-onset pancytopenia, immunodeficiency, or myelodysplasia, whereas others manifest late-onset pulmonary fibrosis. Skin, nail, or hair features resembling dyskeratosis congenita (DKC; see, e.g., DKCA1, 127550) may also be observed. Both PFBMFT6 and DKCA are associated with shortened telomeres, thus sharing a pathogenetic mechanism (summary by Sharma et al., 2022). </p><p>For a discussion of genetic heterogeneity of telomere-related pulmonary fibrosis and/or bone marrow failure, see PFBMFT1 (614742).</p>
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<p>Sharma et al. (2022) reported 4 unrelated probands with variable hematologic, pulmonary, and skin manifestations associated with short telomeres. Patient 1 was a 28-year-old woman who presented at 10 years of age with pancytopenia, hypoplastic bone marrow, and a history of congenital eye anomaly requiring enucleation as an infant. She developed a classic dyskeratosis congenita-associated mucocutaneous triad during adolescence, including leukoplakia, nail dystrophy, and reticular skin pigmentation, but did not require treatment. Her blood counts stabilized over time due to somatic reversion (see MOLECULAR GENETICS). Patient 2 presented at age 13 years with myelodysplastic syndrome (MDS) with excess blasts and a somatic NRAS mutation (G12D; 164790.0007) at 37% allelic frequency. She also had facial dysmorphism and mildly restricted pulmonary function. After undergoing hematopoietic stem cell transplant, she developed significant complications with graft-versus-host disease, necrotizing pneumonitis, recurrent infections, and pulmonary fibrosis. She died of multiorgan failure 11 months post-transplant. The unaffected father and sister of P2 also carried a RPA1 mutation, suggesting incomplete disease penetrance. Patient 3 had early hair graying and onset of progressive pulmonary fibrosis at age 58 years. Two sisters of P3 were also diagnosed with pulmonary fibrosis and died of the disease; no DNA was available. P4 was a 3-year-old girl who presented at birth with prematurity, failure to thrive, lymphopenia, and hypogammaglobulinemia. At age 3, she was stable on IgG replacement therapy. Telomere length, assessed by different methods, was decreased in the blood cells of all patients. </p>
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<p>The transmission pattern of PFBMFT6 in 2 unrelated families (families 2 and 3) reported by Sharma et al. (2022) was consistent with autosomal dominant inheritance with incomplete penetrance and variable expressivity. The heterozygous mutations in the RPA1 gene that were identified in 2 patients (patients 1 and 4) with PFBMFT6 by Sharma et al. (2022) occurred de novo. </p>
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<p>In 4 unrelated probands with PFBMFT6, Sharma et al. (2022) identified heterozygous missense mutations in the RPA1 gene affecting residues in the DNA-binding domain-A (DBD-A) (E240K, 179835.0001; V227A, 179835.0002, and T270A, 179835.0003). The mutations, which were found by exome sequencing, were either absent from the gnomAD database or present at a very low frequency. Two mutations occurred de novo and 1 was inherited from an unaffected parent; familial segregation studies for patient 3 could not be determined. In vitro functional expression studies showed that the E240K and V227A variants had increased binding to ssDNA and telomeric DNA compared to controls, consistent with a gain-of-function effect. In contrast, T270A had binding properties similar to wildtype, but was postulated to have other detrimental effects. Expression of the E240K mutation into iPSC-derived hematopoietic cells resulted in shortened telomeres and impaired differentiation of hematopoietic progenitor cells, particularly of the erythroid and myeloid lineages, but also affecting CD34+ cells. Of note, patient 1 had an atypical disease course with stabilization of blood counts and mucocutaneous features without intervention over 18 years. Her bone marrow analysis at age 13 showed reduced expression of the mutant E240K variant (27%) compared to fibroblasts (50%). Two somatic events were identified in the bone marrow that interfered with expression and proliferation of the mutant E240K allele: an RPA1 truncating (K579X) mutation at 10% allelic frequency and in cis with E240K, causing degradation of germline mutant RNA, and uniparental isodisomy of chromosome 17p, resulting in replacement of the germline variant with a wildtype allele. These allelic patterns were maintained over time and likely caused a rescue effect that coincided with the lack of progressive symptoms in the patient. </p>
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<strong>REFERENCES</strong>
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Sharma, R., Sahoo, S. S., Honda, M., Granger, S. L., Goodings, C., Sanchez, L., Kunstner, A., Busch, H., Beier, F., Pruett-Miller, S. M., Valentine, M. B., Fernandez, A., and 21 others.
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<strong>Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.</strong>
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Blood 139: 1039-1051, 2022.
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[PubMed: 34767620]
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[Full Text: https://doi.org/10.1182/blood.2021011980]
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Cassandra L. Kniffin : 02/24/2022
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alopez : 05/10/2023<br>ckniffin : 05/08/2023<br>alopez : 03/04/2022<br>alopez : 03/03/2022<br>alopez : 03/03/2022<br>ckniffin : 02/25/2022
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