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<title>
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Entry
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- #163800 - SICK SINUS SYNDROME 2; SSS2
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- OMIM
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<span class="h4">#163800</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/phenotypicSeries/PS608567"> <strong>Phenotypic Series</strong> </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="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=17628&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/9300" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=166282" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:13884" 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://www.informatics.jax.org/disease/163800" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:13884" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:163800" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<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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<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>ORPHA:</strong> 166282<br />
|
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<strong>DO:</strong> 13884<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="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
|
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163800
|
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</span>
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</span>
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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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SICK SINUS SYNDROME 2; SSS2
|
|
|
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</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SICK SINUS SYNDROME 2 WITH OR WITHOUT CARDIAC NONCOMPACTION AND/OR ASCENDING AORTA DILATION<br />
|
|
ATRIAL FIBRILLATION WITH BRADYARRHYTHMIA<br />
|
|
SINUS NODE DISEASE, FAMILIAL, AUTOSOMAL DOMINANT<br />
|
|
SINUS BRADYCARDIA SYNDROME, FAMILIAL, AUTOSOMAL DOMINANT
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
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|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="phenotypeMap" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/15/361?start=-3&limit=10&highlight=361">
|
|
15q24.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Sick sinus syndrome 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/163800"> 163800 </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">
|
|
HCN4
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605206"> 605206 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/163800" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<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')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS608567" class="btn btn-info" role="button"> Phenotypic Series </a>
|
|
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/163800" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/163800" 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>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- 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 />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Heart </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Sinus bradycardia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/49710005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">49710005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R00.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R00.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2108107&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2108107</a>, <a href="https://bioportal.bioontology.org/search?q=C5235162&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5235162</a>, <a href="https://bioportal.bioontology.org/search?q=C0085610&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085610</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001688" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001688</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001688" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001688</a>]</span><br /> -
|
|
Atrial fibrillation (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/49436004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">49436004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/164889003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">164889003</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/427.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">427.31</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2926591&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2926591</a>, <a href="https://bioportal.bioontology.org/search?q=C0004238&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004238</a>, <a href="https://bioportal.bioontology.org/search?q=C0344434&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0344434</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005110" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005110</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005110" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005110</a>]</span><br /> -
|
|
Ventricular fibrillation (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/164896001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">164896001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/71908006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">71908006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I49.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I49.01</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/427.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">427.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042510&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042510</a>, <a href="https://bioportal.bioontology.org/search?q=C0344435&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0344435</a>, <a href="https://bioportal.bioontology.org/search?q=C2108112&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2108112</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001663" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001663</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001663" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001663</a>]</span><br /> -
|
|
Cardiac arrest (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397829000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397829000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/410429000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">410429000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I46" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I46</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/427.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">427.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018790&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018790</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001695" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001695</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001695" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001695</a>]</span><br /> -
|
|
Left ventricular noncompaction (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1960469&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1960469</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030682" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030682</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030682" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030682</a>]</span><br /> -
|
|
Biventricular hypertrabeculation (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4315900&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4315900</a>]</span><br /> -
|
|
Left ventricular hypertrophy (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/55827005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">55827005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0149721&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0149721</a>, <a href="https://bioportal.bioontology.org/search?q=C3484363&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3484363</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001712" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001712</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001712" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001712</a>]</span><br /> -
|
|
Mitral valve prolapse (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/409712001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">409712001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8074002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8074002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026267&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026267</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001634" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001634</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001634" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001634</a>]</span><br /> -
|
|
Mitral valve myxoid degeneration (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/42069006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">42069006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0264885&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0264885</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004764" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004764</a>]</span><br /> -
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Aortic valve regurgitation (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/60234000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">60234000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003504&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003504</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001659" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001659</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001659" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001659</a>]</span><br />
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<div>
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<span class="h5 mim-font">
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<em> Vascular </em>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Dilation of ascending aorta (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253645007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253645007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0345049&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0345049</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004970" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004970</a>]</span><br />
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </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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- Onset in utero or at birth<br />
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</span>
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<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 hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 gene (HCN4, <a href="/entry/605206#0001">605206.0001</a>)<br />
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</span>
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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 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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Sick sinus syndrome
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- <a href="/phenotypicSeries/PS608567">PS608567</a>
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- 3 Entries
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</h5>
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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/3/181?start=-3&limit=10&highlight=181"> 3p22.2 </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/608567"> Sick sinus syndrome 1 </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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<td>
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<span class="mim-font">
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<a href="/entry/608567"> 608567 </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/600163"> SCN5A </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/600163"> 600163 </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/14/90?start=-3&limit=10&highlight=90"> 14q11.2 </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/614090"> {Sick sinus syndrome 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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</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/614090"> 614090 </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/160710"> MYH6 </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/160710"> 160710 </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/15/361?start=-3&limit=10&highlight=361"> 15q24.1 </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/163800"> Sick sinus syndrome 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/163800"> 163800 </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/605206"> HCN4 </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/605206"> 605206 </a>
|
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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 class="text-right small">
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<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 sick sinus syndrome-2 (SSS2) is caused by heterozygous mutation in the cardiac pacemaker channel gene HCN4 (<a href="/entry/605206">605206</a>) on chromosome 15q24.</p><p>For a general description and a discussion of genetic heterogeneity of sick sinus syndrome (SSS), see <a href="/entry/608567">608567</a>.</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="clinicalFeatures" class="mim-anchor"></a>
|
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<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Clinical Features</strong>
|
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</span>
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</h4>
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</div>
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<div id="mimClinicalFeaturesFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#1" class="mim-tip-reference" title="Bacos, J. M., Eagan, J. T., Orgain, E. S. <strong>Congenital familial nodal rhythm.</strong> Circulation 22: 887-895, 1960.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13685714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13685714</a>] [<a href="https://doi.org/10.1161/01.cir.22.5.887" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13685714">Bacos et al. (1960)</a> presented a family in which 9 members of 3 generations exhibited nodal rhythm with bradycardia and tended to develop paroxysms of atrial fibrillation in the fourth decade of life. <a href="#13" class="mim-tip-reference" title="Surawicz, B., Hariman, R. J. <strong>Follow-up of the family with congenital absence of sinus rhythm.</strong> Am. J. Cardiol. 61: 467-469, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3341232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3341232</a>] [<a href="https://doi.org/10.1016/0002-9149(88)90309-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3341232">Surawicz and Hariman (1988)</a> provided a follow-up of this family. As predicted by <a href="#1" class="mim-tip-reference" title="Bacos, J. M., Eagan, J. T., Orgain, E. S. <strong>Congenital familial nodal rhythm.</strong> Circulation 22: 887-895, 1960.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13685714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13685714</a>] [<a href="https://doi.org/10.1161/01.cir.22.5.887" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13685714">Bacos et al. (1960)</a>, individuals in subsequent generations manifested slow heart rate with regular rhythm from birth and developed intermittent atrial fibrillation with established atrial fibrillation requiring chronic treatment later. <a href="#13" class="mim-tip-reference" title="Surawicz, B., Hariman, R. J. <strong>Follow-up of the family with congenital absence of sinus rhythm.</strong> Am. J. Cardiol. 61: 467-469, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3341232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3341232</a>] [<a href="https://doi.org/10.1016/0002-9149(88)90309-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3341232">Surawicz and Hariman (1988)</a> found that some members of the third and fourth generations suffered from more symptomatic bradycardia at a younger age than their parents which led, in some cases, to pacemaker implantation. Sudden death, presumably of cardiac origin, had occurred in 1 member of the third generation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3341232+13685714" 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="#5" class="mim-tip-reference" title="Lehmann, H., Klein, U. E. <strong>Familial sinus node dysfunction with autosomal dominant inheritance.</strong> Brit. Heart J. 40: 1314-1316, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/718774/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">718774</a>] [<a href="https://doi.org/10.1136/hrt.40.11.1314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="718774">Lehmann and Klein (1978)</a> reported a large family with sinus node dysfunction spanning 3 generations as an autosomal dominant trait. In some affected members, there was an association between the grade of mental retardation and the severity of the sinoatrial disorder. In another family, described in <a href="/entry/140450">140450</a>, brachydactyly was combined. <a href="#6" class="mim-tip-reference" title="Mackintosh, A. F., Chamberlain, D. A. <strong>Sinus node disease affecting both parents and both children.</strong> Europ. J. Cardiol. 10: 117-122, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/477701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">477701</a>]" pmid="477701">Mackintosh and Chamberlain (1979)</a> described sinus node disease affecting both parents and both children in 1 family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=718774+477701" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Beyer, F., Paul, T., Luhmer, I., Bertram, H., Kallfelz, H. C. <strong>Familiaeres idiopathisches Vorhofflimmern mit bradyarrhythmie.</strong> Z. Kardiol. 82: 674-677, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8291288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8291288</a>]" pmid="8291288">Beyer et al. (1993)</a> described a family in which a 10-year-old boy and his 20-year-old sister were found to have atrial fibrillation and bradyarrhythmia. Their father and grandfather, as well as their great-grandmother, had the same. This is clearly the same family as that reported later by <a href="#2" class="mim-tip-reference" title="Bertram, H., Paul, T., Beyer, F., Kallfelz, H. C. <strong>Familial idiopathic atrial fibrillation with bradyarrhythmia.</strong> Europ. J. Pediat. 155: 7-10, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8750801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8750801</a>] [<a href="https://doi.org/10.1007/BF02115617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8750801">Bertram et al. (1996)</a>. The 10-year-old proband had shown intrauterine and postnatal bradycardia, and atrial fibrillation was first documented electrocardiographically at 16 months of age. No structural heart defect was evident. A permanent ventricular demand pacemaker was implanted at the age of 10 years after syncope due to severe bradyarrhythmia. Idiopathic atrial fibrillation known since childhood was documented in 3 close relatives. A high-grade AV block resulting in bradyarrhythmia and the occurrence of ST-T changes in precordial leads could be demonstrated in all affected family members, suggesting a diffuse general conduction abnormality. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8291288+8750801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Nof, E., Luria, D., Brass, D., Marek, D., Lahat, H., Reznik-Wolf, H., Pras, E., Dascal, N., Eldar, M., Glikson, M. <strong>Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia.</strong> Circulation 116: 463-470, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646576</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.706887" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17646576">Nof et al. (2007)</a> studied 8 affected and 8 unaffected members of a 4-generation family with asymptomatic sinus bradycardia. Affected individuals had an average heart rate of less than 55 bpm on 24-hour ECG with a minimum of less than 36 bpm, whereas unaffected individuals had an average heart rate greater than 63 bpm and a minimum rate greater than 49 bpm. Exercise testing demonstrated normal chronotropic and exercise capacity, and all had a normally structured heart on echocardiography. There was no history of dizziness, syncope, or sudden cardiac death in the family. Electrophysiologic testing of 2 affected family members confirmed significant sinus node dysfunction, with prolonged average and corrected sinus node recovery times. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646576" 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>Clinical Variability</em></strong></p><p>
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<a href="#8" class="mim-tip-reference" title="Milano, A., Vermeer, A. M. C., Lodder, E. M., Barc, J., Verkerk, A. O., Postma, A. V., van der Bilt, I. A. C., Baars, M. J. H., van Haelst, P. L., Caliskan, K., Hoedemaekers, Y. M., Le Scouarnec, S., Redon, R., Pinto, Y. M., Christiaans, I., Wilde, A. A., Bezzina, C. R. <strong>HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.</strong> J. Am. Coll. Cardiol. 64: 745-756, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145517</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.05.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145517">Milano et al. (2014)</a> reported a large Dutch family (family A) in which affected individuals exhibited sinus bradycardia and left ventricular noncompaction (LVNC). The proband, who had a history of bradycardia with rates as low as 31 beats per minute (bpm), experienced out-of-hospital cardiac arrest due to ventricular fibrillation at age 57 years and underwent placement of an implantable cardioverter-defibrillator (ICD). Review of her previous echocardiograms showed LVNC. The proband had 3 sibs and 2 nephews who also had bradycardia and LVNC. Sinus bradycardia was detected in utero in 1 of the nephews, and he and 2 of the affected sibs had pacemakers implanted due to symptomatic bradycardia. In addition, 2 of the proband's sibs underwent mitral valve reconstruction due to mitral valve prolapse (MVP). <a href="#8" class="mim-tip-reference" title="Milano, A., Vermeer, A. M. C., Lodder, E. M., Barc, J., Verkerk, A. O., Postma, A. V., van der Bilt, I. A. C., Baars, M. J. H., van Haelst, P. L., Caliskan, K., Hoedemaekers, Y. M., Le Scouarnec, S., Redon, R., Pinto, Y. M., Christiaans, I., Wilde, A. A., Bezzina, C. R. <strong>HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.</strong> J. Am. Coll. Cardiol. 64: 745-756, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145517</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.05.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145517">Milano et al. (2014)</a> studied 3 more families with a similar phenotype. The 53-year-old proband of family B presented after she collapsed in the shower, and cardiovascular examination revealed bradycardia, LVNC, and myxoid degeneration of the mitral valve. She also had polymorphic ventricular extrasystoles during exercise, and later developed atrial fibrillation. Her son was also affected. In family C, the 74-year-old proband presented with atrial fibrillation and LVNC. His 2 sons had bradycardia and LVNC; 1 son had severe bradycardia documented on Holter monitoring, involving 12 episodes of standstill with a maximum duration of 2.88 seconds. Both sons also exhibited left ventricular hypertrophy, with interventricular septa measuring 13 mm. In the fourth family (family D), a 36-year-old man had severe sinus bradycardia and LVNC as well as moderate aortic valve regurgitation. His mother had a pacemaker for bradycardia, but echocardiography reports were unavailable. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25145517" 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="#12" class="mim-tip-reference" title="Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D. <strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong> J. Am. Coll. Cardiol. 64: 757-767, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145518</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.06.1155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145518">Schweizer et al. (2014)</a> studied a 4-generation German family with sinus node dysfunction and myocardial noncompaction, in which the index patient was a 23-year-old man who had syncope resulting in a car accident. He was aware of bradycardia since childhood, with dizziness, fatigue, and palpitations. Resting ECG showed sinus bradycardia and first-degree atrioventricular block, and Holter monitor revealed heart rates as low as 21 bpm, with an average heart rate of 34 bpm. Echocardiography showed LVNC as well as MVP. The proband's mother and his 16-year-old sister also had sinus node dysfunction, LVNC, and MVP. His deceased maternal grandmother, granduncle, and great-grandfather all had a history of sinus bradycardia and congestive heart failure, for which they had received pacemakers in the fifth decade of life. <a href="#12" class="mim-tip-reference" title="Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D. <strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong> J. Am. Coll. Cardiol. 64: 757-767, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145518</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.06.1155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145518">Schweizer et al. (2014)</a> noted that the presence of marked hypertrabeculations and MVP in the 2 youngest patients supported a congenital origin for the structural defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25145518" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I. <strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong> J. Am. Coll. Cardiol. 67: 2313-2315, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173043</a>] [<a href="https://doi.org/10.1016/j.jacc.2016.01.086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27173043">Vermeer et al. (2016)</a> reported a family with bradycardia, LVNC, and MVP due to a mutation in the HCN4 gene, in which 6 of 7 affected individuals studied also exhibited dilation of the ascending aorta. Review of the patients described by <a href="#8" class="mim-tip-reference" title="Milano, A., Vermeer, A. M. C., Lodder, E. M., Barc, J., Verkerk, A. O., Postma, A. V., van der Bilt, I. A. C., Baars, M. J. H., van Haelst, P. L., Caliskan, K., Hoedemaekers, Y. M., Le Scouarnec, S., Redon, R., Pinto, Y. M., Christiaans, I., Wilde, A. A., Bezzina, C. R. <strong>HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.</strong> J. Am. Coll. Cardiol. 64: 745-756, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145517</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.05.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145517">Milano et al. (2014)</a> and <a href="#12" class="mim-tip-reference" title="Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D. <strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong> J. Am. Coll. Cardiol. 64: 757-767, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145518</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.06.1155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145518">Schweizer et al. (2014)</a> revealed dilation of the ascending aorta in 13 of the 18 patients who had images of sufficient quality to be assessed, for an overall detection rate of 77%. Multiple regression analysis showed that HCN4 mutation carriers have a significantly larger age-related increase in aortic diameter than control individuals, and <a href="#15" class="mim-tip-reference" title="Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I. <strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong> J. Am. Coll. Cardiol. 67: 2313-2315, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173043</a>] [<a href="https://doi.org/10.1016/j.jacc.2016.01.086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27173043">Vermeer et al. (2016)</a> suggested that aortic diameter should be monitored in HCN4 mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27173043+25145518+25145517" 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>Sick sinus syndrome-2 shows an autosomal dominant pattern of inheritance (<a href="#10" class="mim-tip-reference" title="Schulze-Bahr, E., Neu, A., Friederich, P., Kaupp, U. B., Breithardt, G., Pongs, O., Isbrandt, D. <strong>Pacemaker channel dysfunction in a patient with sinus node disease.</strong> J. Clin. Invest. 111: 1537-1545, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12750403[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12750403">Schulze-Bahr et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12750403" 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 a 66-year-old woman with marked sinus bradycardia (41 bpm) and intermittent atrial fibrillation who suffered a severe syncopal episode, <a href="#10" class="mim-tip-reference" title="Schulze-Bahr, E., Neu, A., Friederich, P., Kaupp, U. B., Breithardt, G., Pongs, O., Isbrandt, D. <strong>Pacemaker channel dysfunction in a patient with sinus node disease.</strong> J. Clin. Invest. 111: 1537-1545, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12750403[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12750403">Schulze-Bahr et al. (2003)</a> identified heterozygosity for a 1-bp deletion (<a href="/entry/605206#0002">605206.0002</a>) in the pacemaker channel gene HCN4. Family history was unremarkable, and the mutation was not found in her 3 unaffected children or in 362 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12750403" 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 a 43-year-old woman with syncope and a 24-hour ECG showing severe bradycardia (39 bpm on average), cardiac arrest for 40 seconds followed by polymorphic ventricular tachycardia and torsade de pointes, <a href="#14" class="mim-tip-reference" title="Ueda, K., Nakamura, K., Hayashi, T., Inagaki, N., Takahashi, M., Arimura, T., Morita, H., Higashiuesato, Y., Hirano, Y., Yasunami, M., Takishita, S., Yamashina, A., Ohe, T., Sunamori, M., Hiraoka, M., Kimura, A. <strong>Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia.</strong> J. Biol. Chem. 279: 27194-27198, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15123648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15123648</a>] [<a href="https://doi.org/10.1074/jbc.M311953200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15123648">Ueda et al. (2004)</a> identified heterozygosity for a mutation (D553N; <a href="/entry/605206#0003">605206.0003</a>) in the HCN4 gene. The patient's resting ECG showed flat T waves and a QTc of 670 ms. The mutation was also found in her affected sister and son, but was not present in 380 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15123648" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Milanesi, R., Baruscotti, M., Gnecchi-Ruscone, T., DiFrancesco, D. <strong>Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel.</strong> New Eng. J. Med. 354: 151-157, 2006. Note: Erratum: New Eng. J. Med. 354: 2520 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407510</a>] [<a href="https://doi.org/10.1056/NEJMoa052475" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16407510">Milanesi et al. (2006)</a> screened the HCN4 gene in 52 patients with bradycardia and identified a mutation (S672R; <a href="/entry/605206#0001">605206.0001</a>) in affected members of a 3-generation Italian family with asymptomatic sinus bradycardia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16407510" 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 8 affected members of a 4-generation family with asymptomatic sinus bradycardia, <a href="#9" class="mim-tip-reference" title="Nof, E., Luria, D., Brass, D., Marek, D., Lahat, H., Reznik-Wolf, H., Pras, E., Dascal, N., Eldar, M., Glikson, M. <strong>Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia.</strong> Circulation 116: 463-470, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646576</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.706887" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17646576">Nof et al. (2007)</a> identified a heterozygous mutation in the HCN4 gene (G480R; <a href="/entry/605206#0004">605206.0004</a>). The mutation was not found in 8 unaffected family members or 100 unrelated control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646576" 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="#11" class="mim-tip-reference" title="Schweizer, P. A., Duhme, N., Thomas, D., Becker, R., Zehelein, J., Draguhn, A., Bruehl, C., Katus, H. A., Koenen, M. <strong>cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control.</strong> Circ. Arrhythm. Electrophysiol. 3: 542-552, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20693575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20693575</a>] [<a href="https://doi.org/10.1161/CIRCEP.110.949768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20693575">Schweizer et al. (2010)</a> screened 416 patients with cardiac arrhythmias for mutation in 7 candidate genes and identified a 45-year-old German woman with marked sinus bradycardia who was heterozygous for a 13-bp insertion in the HCN4 gene (<a href="/entry/605206#0007">605206.0007</a>). Pedigree analysis identified 7 additional family members with bradycardia and sinus arrhythmias who were also heterozygous for the insertion. <a href="#11" class="mim-tip-reference" title="Schweizer, P. A., Duhme, N., Thomas, D., Becker, R., Zehelein, J., Draguhn, A., Bruehl, C., Katus, H. A., Koenen, M. <strong>cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control.</strong> Circ. Arrhythm. Electrophysiol. 3: 542-552, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20693575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20693575</a>] [<a href="https://doi.org/10.1161/CIRCEP.110.949768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20693575">Schweizer et al. (2010)</a> noted that the mutation carriers exhibited an intact capability to accelerate heart rate according to physiologic needs, and stated that these patients had no structural cardiac anomalies. However, <a href="#12" class="mim-tip-reference" title="Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D. <strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong> J. Am. Coll. Cardiol. 64: 757-767, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145518</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.06.1155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145518">Schweizer et al. (2014)</a> reevaluated the cardiac morphology of 5 affected family members and observed that although left ventricular ejection fraction was preserved and there were no overt structural anomalies, comprehensive echocardiography and/or cardiac magnetic resonance imaging revealed biventricular hypertrabeculation and mitral valve prolapse in all 5 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20693575+25145518" 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 a large Dutch family with bradycardia and LVNC, <a href="#8" class="mim-tip-reference" title="Milano, A., Vermeer, A. M. C., Lodder, E. M., Barc, J., Verkerk, A. O., Postma, A. V., van der Bilt, I. A. C., Baars, M. J. H., van Haelst, P. L., Caliskan, K., Hoedemaekers, Y. M., Le Scouarnec, S., Redon, R., Pinto, Y. M., Christiaans, I., Wilde, A. A., Bezzina, C. R. <strong>HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.</strong> J. Am. Coll. Cardiol. 64: 745-756, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145517</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.05.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145517">Milano et al. (2014)</a> performed exome sequencing and identified heterozygosity for a missense mutation in the HCN4 gene (G482R; <a href="/entry/605206#0008">605206.0008</a>) that segregated fully with disease. Analysis of the HCN4 gene in 3 additional families with bradycardia and LVNC revealed heterozygosity for 2 mutations: a Y481H substitution (<a href="/entry/605206#0009">605206.0009</a>) in affected members of 2 families, which were shown to share a common ancestral haplotype, and an A414G mutation (<a href="/entry/605206#0010">605206.0010</a>) in an affected father and 2 sons in the third family. The mutations were not found in 500 Dutch controls or in public variant databases. The probands from all 4 families were negative for mutations in 13 LVNC-associated genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25145517" 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 a German mother and 2 children with sinus node dysfunction, LVNC, and MVP, <a href="#12" class="mim-tip-reference" title="Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D. <strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong> J. Am. Coll. Cardiol. 64: 757-767, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145518</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.06.1155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145518">Schweizer et al. (2014)</a> analyzed 79 cardiomyopathy- and cardiac arrhythmia-associated candidate genes and identified heterozygosity for the G482R mutation in the HCN4 gene. In addition, the mother was homozygous and the 2 children heterozygous for a variant of unknown significance in the CSRP3 gene (W4R; see <a href="/entry/600824#0001">600824.0001</a>); the authors stated that this variant was unlikely to be a primary cause of the cardiac noncompaction phenotype, but suggested that it might make a modifying contribution. Screening of a cohort of 85 additional unrelated probands identified 2 more probands with heterozygous mutations in HCN4: 1 was the proband of the German family previously studied by <a href="#11" class="mim-tip-reference" title="Schweizer, P. A., Duhme, N., Thomas, D., Becker, R., Zehelein, J., Draguhn, A., Bruehl, C., Katus, H. A., Koenen, M. <strong>cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control.</strong> Circ. Arrhythm. Electrophysiol. 3: 542-552, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20693575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20693575</a>] [<a href="https://doi.org/10.1161/CIRCEP.110.949768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20693575">Schweizer et al. (2010)</a> with a 13-bp insertion (see <a href="/entry/605206#0007">605206.0007</a>), and 1 was a sporadic patient with an HCN4 missense mutation. The CSRP3 W4R variant was not present in either of the latter 2 patients or their families, and all of the patients with HCN4 mutations exhibited LVNC and MVP. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20693575+25145518" 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 a family with sinus bradycardia, LVNC, MVP, and dilation of the ascending aorta, <a href="#15" class="mim-tip-reference" title="Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I. <strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong> J. Am. Coll. Cardiol. 67: 2313-2315, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173043</a>] [<a href="https://doi.org/10.1016/j.jacc.2016.01.086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27173043">Vermeer et al. (2016)</a> identified the Y481H mutation in the HCN4 gene. Analysis of 46 cardiomyopathy-associated genes and 15 aortic dilation-associated genes revealed no additional mutations. <a href="#15" class="mim-tip-reference" title="Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I. <strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong> J. Am. Coll. Cardiol. 67: 2313-2315, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173043</a>] [<a href="https://doi.org/10.1016/j.jacc.2016.01.086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27173043">Vermeer et al. (2016)</a> reviewed multimodal imaging studies available from previously described patients with HCN4 mutations (<a href="#8" class="mim-tip-reference" title="Milano, A., Vermeer, A. M. C., Lodder, E. M., Barc, J., Verkerk, A. O., Postma, A. V., van der Bilt, I. A. C., Baars, M. J. H., van Haelst, P. L., Caliskan, K., Hoedemaekers, Y. M., Le Scouarnec, S., Redon, R., Pinto, Y. M., Christiaans, I., Wilde, A. A., Bezzina, C. R. <strong>HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.</strong> J. Am. Coll. Cardiol. 64: 745-756, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145517</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.05.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145517">Milano et al., 2014</a>; <a href="#12" class="mim-tip-reference" title="Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D. <strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong> J. Am. Coll. Cardiol. 64: 757-767, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145518</a>] [<a href="https://doi.org/10.1016/j.jacc.2014.06.1155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25145518">Schweizer et al., 2014</a>) and detected dilation of the ascending aorta in 13 of 18 patients with adequate studies, for an overall detection rate of 77%. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27173043+25145518+25145517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Caralis1976" class="mim-tip-reference" title="Caralis, D. G., Varghese, P. J. <strong>Familial sinoatrial node dysfunction: increased vagal tone a possible aetiology.</strong> Brit. Heart J. 38: 951-956, 1976.">Caralis and Varghese (1976)</a>
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Caralis, D. G., Varghese, P. J.
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<strong>Familial sinoatrial node dysfunction: increased vagal tone a possible aetiology.</strong>
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Brit. Heart J. 38: 951-956, 1976.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/971377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">971377</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=971377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/477701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">477701</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=477701" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</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="Milanesi2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Milanesi, R., Baruscotti, M., Gnecchi-Ruscone, T., DiFrancesco, D.
|
|
<strong>Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel.</strong>
|
|
New Eng. J. Med. 354: 151-157, 2006. Note: Erratum: New Eng. J. Med. 354: 2520 only, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407510</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16407510" 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/10.1056/NEJMoa052475" 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="Milano2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Milano, A., Vermeer, A. M. C., Lodder, E. M., Barc, J., Verkerk, A. O., Postma, A. V., van der Bilt, I. A. C., Baars, M. J. H., van Haelst, P. L., Caliskan, K., Hoedemaekers, Y. M., Le Scouarnec, S., Redon, R., Pinto, Y. M., Christiaans, I., Wilde, A. A., Bezzina, C. R.
|
|
<strong>HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.</strong>
|
|
J. Am. Coll. Cardiol. 64: 745-756, 2014.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145517</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25145517" 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.jacc.2014.05.045" 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="Nof2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nof, E., Luria, D., Brass, D., Marek, D., Lahat, H., Reznik-Wolf, H., Pras, E., Dascal, N., Eldar, M., Glikson, M.
|
|
<strong>Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia.</strong>
|
|
Circulation 116: 463-470, 2007.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646576</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646576" 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/10.1161/CIRCULATIONAHA.107.706887" 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="Schulze-Bahr2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Schulze-Bahr, E., Neu, A., Friederich, P., Kaupp, U. B., Breithardt, G., Pongs, O., Isbrandt, D.
|
|
<strong>Pacemaker channel dysfunction in a patient with sinus node disease.</strong>
|
|
J. Clin. Invest. 111: 1537-1545, 2003.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12750403[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=12750403" 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/JCI16387" 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="11" class="mim-anchor"></a>
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<a id="Schweizer2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Schweizer, P. A., Duhme, N., Thomas, D., Becker, R., Zehelein, J., Draguhn, A., Bruehl, C., Katus, H. A., Koenen, M.
|
|
<strong>cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control.</strong>
|
|
Circ. Arrhythm. Electrophysiol. 3: 542-552, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20693575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20693575</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20693575" 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/10.1161/CIRCEP.110.949768" 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="12" class="mim-anchor"></a>
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<a id="Schweizer2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D.
|
|
<strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong>
|
|
J. Am. Coll. Cardiol. 64: 757-767, 2014.
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|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25145518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25145518</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25145518" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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[<a href="https://doi.org/10.1016/j.jacc.2014.06.1155" 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="13" class="mim-anchor"></a>
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<a id="Surawicz1988" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Surawicz, B., Hariman, R. J.
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<strong>Follow-up of the family with congenital absence of sinus rhythm.</strong>
|
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Am. J. Cardiol. 61: 467-469, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3341232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3341232</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3341232" 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/10.1016/0002-9149(88)90309-8" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Ueda2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ueda, K., Nakamura, K., Hayashi, T., Inagaki, N., Takahashi, M., Arimura, T., Morita, H., Higashiuesato, Y., Hirano, Y., Yasunami, M., Takishita, S., Yamashina, A., Ohe, T., Sunamori, M., Hiraoka, M., Kimura, A.
|
|
<strong>Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia.</strong>
|
|
J. Biol. Chem. 279: 27194-27198, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15123648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15123648</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15123648" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M311953200" 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="15" class="mim-anchor"></a>
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<a id="Vermeer2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I.
|
|
<strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong>
|
|
J. Am. Coll. Cardiol. 67: 2313-2315, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173043</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27173043" 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.jacc.2016.01.086" 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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Marla J. F. O'Neill - updated : 01/12/2017
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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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Marla J. F. O'Neill - updated : 11/18/2009<br>Marla J. F. O'Neill - updated : 3/5/2008<br>Victor A. McKusick - updated : 2/1/2006<br>Cassandra L. Kniffin - reorganized : 4/28/2004<br>Victor A. McKusick - updated : 11/18/2003<br>Victor A. McKusick - updated : 5/8/1997
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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 : 6/2/1986
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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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carol : 02/23/2024
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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 : 03/06/2017<br>carol : 01/12/2017<br>carol : 05/23/2016<br>terry : 12/20/2012<br>carol : 7/15/2011<br>wwang : 11/18/2009<br>wwang : 3/5/2008<br>alopez : 2/15/2006<br>terry : 2/1/2006<br>carol : 4/28/2004<br>ckniffin : 4/15/2004<br>joanna : 4/13/2004<br>alopez : 11/25/2003<br>tkritzer : 11/20/2003<br>terry : 11/18/2003<br>alopez : 7/30/1997<br>alopez : 7/7/1997<br>mark : 6/10/1997<br>mark : 5/8/1997<br>alopez : 5/6/1997<br>mark : 3/25/1996<br>terry : 3/18/1996<br>mimadm : 12/2/1994<br>carol : 3/29/1994<br>carol : 6/26/1992<br>carol : 6/25/1992<br>supermim : 3/16/1992<br>supermim : 3/20/1990
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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> 163800
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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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SICK SINUS SYNDROME 2; SSS2
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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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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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SICK SINUS SYNDROME 2 WITH OR WITHOUT CARDIAC NONCOMPACTION AND/OR ASCENDING AORTA DILATION<br />
|
|
ATRIAL FIBRILLATION WITH BRADYARRHYTHMIA<br />
|
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SINUS NODE DISEASE, FAMILIAL, AUTOSOMAL DOMINANT<br />
|
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SINUS BRADYCARDIA SYNDROME, FAMILIAL, AUTOSOMAL DOMINANT
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>ORPHA:</strong> 166282;
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<strong>DO:</strong> 13884;
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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>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 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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<th>
|
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Gene/Locus
|
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</th>
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<th>
|
|
Gene/Locus <br /> MIM number
|
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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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15q24.1
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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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Sick sinus 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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163800
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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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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<td>
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<span class="mim-font">
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HCN4
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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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605206
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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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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that sick sinus syndrome-2 (SSS2) is caused by heterozygous mutation in the cardiac pacemaker channel gene HCN4 (605206) on chromosome 15q24.</p><p>For a general description and a discussion of genetic heterogeneity of sick sinus syndrome (SSS), see 608567.</p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Bacos et al. (1960) presented a family in which 9 members of 3 generations exhibited nodal rhythm with bradycardia and tended to develop paroxysms of atrial fibrillation in the fourth decade of life. Surawicz and Hariman (1988) provided a follow-up of this family. As predicted by Bacos et al. (1960), individuals in subsequent generations manifested slow heart rate with regular rhythm from birth and developed intermittent atrial fibrillation with established atrial fibrillation requiring chronic treatment later. Surawicz and Hariman (1988) found that some members of the third and fourth generations suffered from more symptomatic bradycardia at a younger age than their parents which led, in some cases, to pacemaker implantation. Sudden death, presumably of cardiac origin, had occurred in 1 member of the third generation. </p><p>Lehmann and Klein (1978) reported a large family with sinus node dysfunction spanning 3 generations as an autosomal dominant trait. In some affected members, there was an association between the grade of mental retardation and the severity of the sinoatrial disorder. In another family, described in 140450, brachydactyly was combined. Mackintosh and Chamberlain (1979) described sinus node disease affecting both parents and both children in 1 family. </p><p>Beyer et al. (1993) described a family in which a 10-year-old boy and his 20-year-old sister were found to have atrial fibrillation and bradyarrhythmia. Their father and grandfather, as well as their great-grandmother, had the same. This is clearly the same family as that reported later by Bertram et al. (1996). The 10-year-old proband had shown intrauterine and postnatal bradycardia, and atrial fibrillation was first documented electrocardiographically at 16 months of age. No structural heart defect was evident. A permanent ventricular demand pacemaker was implanted at the age of 10 years after syncope due to severe bradyarrhythmia. Idiopathic atrial fibrillation known since childhood was documented in 3 close relatives. A high-grade AV block resulting in bradyarrhythmia and the occurrence of ST-T changes in precordial leads could be demonstrated in all affected family members, suggesting a diffuse general conduction abnormality. </p><p>Nof et al. (2007) studied 8 affected and 8 unaffected members of a 4-generation family with asymptomatic sinus bradycardia. Affected individuals had an average heart rate of less than 55 bpm on 24-hour ECG with a minimum of less than 36 bpm, whereas unaffected individuals had an average heart rate greater than 63 bpm and a minimum rate greater than 49 bpm. Exercise testing demonstrated normal chronotropic and exercise capacity, and all had a normally structured heart on echocardiography. There was no history of dizziness, syncope, or sudden cardiac death in the family. Electrophysiologic testing of 2 affected family members confirmed significant sinus node dysfunction, with prolonged average and corrected sinus node recovery times. </p><p><strong><em>Clinical Variability</em></strong></p><p>
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Milano et al. (2014) reported a large Dutch family (family A) in which affected individuals exhibited sinus bradycardia and left ventricular noncompaction (LVNC). The proband, who had a history of bradycardia with rates as low as 31 beats per minute (bpm), experienced out-of-hospital cardiac arrest due to ventricular fibrillation at age 57 years and underwent placement of an implantable cardioverter-defibrillator (ICD). Review of her previous echocardiograms showed LVNC. The proband had 3 sibs and 2 nephews who also had bradycardia and LVNC. Sinus bradycardia was detected in utero in 1 of the nephews, and he and 2 of the affected sibs had pacemakers implanted due to symptomatic bradycardia. In addition, 2 of the proband's sibs underwent mitral valve reconstruction due to mitral valve prolapse (MVP). Milano et al. (2014) studied 3 more families with a similar phenotype. The 53-year-old proband of family B presented after she collapsed in the shower, and cardiovascular examination revealed bradycardia, LVNC, and myxoid degeneration of the mitral valve. She also had polymorphic ventricular extrasystoles during exercise, and later developed atrial fibrillation. Her son was also affected. In family C, the 74-year-old proband presented with atrial fibrillation and LVNC. His 2 sons had bradycardia and LVNC; 1 son had severe bradycardia documented on Holter monitoring, involving 12 episodes of standstill with a maximum duration of 2.88 seconds. Both sons also exhibited left ventricular hypertrophy, with interventricular septa measuring 13 mm. In the fourth family (family D), a 36-year-old man had severe sinus bradycardia and LVNC as well as moderate aortic valve regurgitation. His mother had a pacemaker for bradycardia, but echocardiography reports were unavailable. </p><p>Schweizer et al. (2014) studied a 4-generation German family with sinus node dysfunction and myocardial noncompaction, in which the index patient was a 23-year-old man who had syncope resulting in a car accident. He was aware of bradycardia since childhood, with dizziness, fatigue, and palpitations. Resting ECG showed sinus bradycardia and first-degree atrioventricular block, and Holter monitor revealed heart rates as low as 21 bpm, with an average heart rate of 34 bpm. Echocardiography showed LVNC as well as MVP. The proband's mother and his 16-year-old sister also had sinus node dysfunction, LVNC, and MVP. His deceased maternal grandmother, granduncle, and great-grandfather all had a history of sinus bradycardia and congestive heart failure, for which they had received pacemakers in the fifth decade of life. Schweizer et al. (2014) noted that the presence of marked hypertrabeculations and MVP in the 2 youngest patients supported a congenital origin for the structural defects. </p><p>Vermeer et al. (2016) reported a family with bradycardia, LVNC, and MVP due to a mutation in the HCN4 gene, in which 6 of 7 affected individuals studied also exhibited dilation of the ascending aorta. Review of the patients described by Milano et al. (2014) and Schweizer et al. (2014) revealed dilation of the ascending aorta in 13 of the 18 patients who had images of sufficient quality to be assessed, for an overall detection rate of 77%. Multiple regression analysis showed that HCN4 mutation carriers have a significantly larger age-related increase in aortic diameter than control individuals, and Vermeer et al. (2016) suggested that aortic diameter should be monitored in HCN4 mutation carriers. </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>Inheritance</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>Sick sinus syndrome-2 shows an autosomal dominant pattern of inheritance (Schulze-Bahr et al., 2003). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a 66-year-old woman with marked sinus bradycardia (41 bpm) and intermittent atrial fibrillation who suffered a severe syncopal episode, Schulze-Bahr et al. (2003) identified heterozygosity for a 1-bp deletion (605206.0002) in the pacemaker channel gene HCN4. Family history was unremarkable, and the mutation was not found in her 3 unaffected children or in 362 control chromosomes. </p><p>In a 43-year-old woman with syncope and a 24-hour ECG showing severe bradycardia (39 bpm on average), cardiac arrest for 40 seconds followed by polymorphic ventricular tachycardia and torsade de pointes, Ueda et al. (2004) identified heterozygosity for a mutation (D553N; 605206.0003) in the HCN4 gene. The patient's resting ECG showed flat T waves and a QTc of 670 ms. The mutation was also found in her affected sister and son, but was not present in 380 control chromosomes. </p><p>Milanesi et al. (2006) screened the HCN4 gene in 52 patients with bradycardia and identified a mutation (S672R; 605206.0001) in affected members of a 3-generation Italian family with asymptomatic sinus bradycardia. </p><p>In 8 affected members of a 4-generation family with asymptomatic sinus bradycardia, Nof et al. (2007) identified a heterozygous mutation in the HCN4 gene (G480R; 605206.0004). The mutation was not found in 8 unaffected family members or 100 unrelated control chromosomes. </p><p>Schweizer et al. (2010) screened 416 patients with cardiac arrhythmias for mutation in 7 candidate genes and identified a 45-year-old German woman with marked sinus bradycardia who was heterozygous for a 13-bp insertion in the HCN4 gene (605206.0007). Pedigree analysis identified 7 additional family members with bradycardia and sinus arrhythmias who were also heterozygous for the insertion. Schweizer et al. (2010) noted that the mutation carriers exhibited an intact capability to accelerate heart rate according to physiologic needs, and stated that these patients had no structural cardiac anomalies. However, Schweizer et al. (2014) reevaluated the cardiac morphology of 5 affected family members and observed that although left ventricular ejection fraction was preserved and there were no overt structural anomalies, comprehensive echocardiography and/or cardiac magnetic resonance imaging revealed biventricular hypertrabeculation and mitral valve prolapse in all 5 patients. </p><p>In a large Dutch family with bradycardia and LVNC, Milano et al. (2014) performed exome sequencing and identified heterozygosity for a missense mutation in the HCN4 gene (G482R; 605206.0008) that segregated fully with disease. Analysis of the HCN4 gene in 3 additional families with bradycardia and LVNC revealed heterozygosity for 2 mutations: a Y481H substitution (605206.0009) in affected members of 2 families, which were shown to share a common ancestral haplotype, and an A414G mutation (605206.0010) in an affected father and 2 sons in the third family. The mutations were not found in 500 Dutch controls or in public variant databases. The probands from all 4 families were negative for mutations in 13 LVNC-associated genes. </p><p>In a German mother and 2 children with sinus node dysfunction, LVNC, and MVP, Schweizer et al. (2014) analyzed 79 cardiomyopathy- and cardiac arrhythmia-associated candidate genes and identified heterozygosity for the G482R mutation in the HCN4 gene. In addition, the mother was homozygous and the 2 children heterozygous for a variant of unknown significance in the CSRP3 gene (W4R; see 600824.0001); the authors stated that this variant was unlikely to be a primary cause of the cardiac noncompaction phenotype, but suggested that it might make a modifying contribution. Screening of a cohort of 85 additional unrelated probands identified 2 more probands with heterozygous mutations in HCN4: 1 was the proband of the German family previously studied by Schweizer et al. (2010) with a 13-bp insertion (see 605206.0007), and 1 was a sporadic patient with an HCN4 missense mutation. The CSRP3 W4R variant was not present in either of the latter 2 patients or their families, and all of the patients with HCN4 mutations exhibited LVNC and MVP. </p><p>In a family with sinus bradycardia, LVNC, MVP, and dilation of the ascending aorta, Vermeer et al. (2016) identified the Y481H mutation in the HCN4 gene. Analysis of 46 cardiomyopathy-associated genes and 15 aortic dilation-associated genes revealed no additional mutations. Vermeer et al. (2016) reviewed multimodal imaging studies available from previously described patients with HCN4 mutations (Milano et al., 2014; Schweizer et al., 2014) and detected dilation of the ascending aorta in 13 of 18 patients with adequate studies, for an overall detection rate of 77%. </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>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Caralis and Varghese (1976)
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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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Bacos, J. M., Eagan, J. T., Orgain, E. S.
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<strong>Congenital familial nodal rhythm.</strong>
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Circulation 22: 887-895, 1960.
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[PubMed: 13685714]
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[Full Text: https://doi.org/10.1161/01.cir.22.5.887]
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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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Bertram, H., Paul, T., Beyer, F., Kallfelz, H. C.
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<strong>Familial idiopathic atrial fibrillation with bradyarrhythmia.</strong>
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Europ. J. Pediat. 155: 7-10, 1996.
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[PubMed: 8750801]
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[Full Text: https://doi.org/10.1007/BF02115617]
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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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Beyer, F., Paul, T., Luhmer, I., Bertram, H., Kallfelz, H. C.
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<strong>Familiaeres idiopathisches Vorhofflimmern mit bradyarrhythmie.</strong>
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Z. Kardiol. 82: 674-677, 1993.
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[PubMed: 8291288]
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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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Caralis, D. G., Varghese, P. J.
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<strong>Familial sinoatrial node dysfunction: increased vagal tone a possible aetiology.</strong>
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Brit. Heart J. 38: 951-956, 1976.
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[PubMed: 971377]
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[Full Text: https://doi.org/10.1136/hrt.38.9.951]
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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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Lehmann, H., Klein, U. E.
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<strong>Familial sinus node dysfunction with autosomal dominant inheritance.</strong>
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Brit. Heart J. 40: 1314-1316, 1978.
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[PubMed: 718774]
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[Full Text: https://doi.org/10.1136/hrt.40.11.1314]
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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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Mackintosh, A. F., Chamberlain, D. A.
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<strong>Sinus node disease affecting both parents and both children.</strong>
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Europ. J. Cardiol. 10: 117-122, 1979.
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[PubMed: 477701]
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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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Milanesi, R., Baruscotti, M., Gnecchi-Ruscone, T., DiFrancesco, D.
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<strong>Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel.</strong>
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New Eng. J. Med. 354: 151-157, 2006. Note: Erratum: New Eng. J. Med. 354: 2520 only, 2006.
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[PubMed: 16407510]
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[Full Text: https://doi.org/10.1056/NEJMoa052475]
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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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Milano, A., Vermeer, A. M. C., Lodder, E. M., Barc, J., Verkerk, A. O., Postma, A. V., van der Bilt, I. A. C., Baars, M. J. H., van Haelst, P. L., Caliskan, K., Hoedemaekers, Y. M., Le Scouarnec, S., Redon, R., Pinto, Y. M., Christiaans, I., Wilde, A. A., Bezzina, C. R.
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<strong>HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.</strong>
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J. Am. Coll. Cardiol. 64: 745-756, 2014.
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[PubMed: 25145517]
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[Full Text: https://doi.org/10.1016/j.jacc.2014.05.045]
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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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Nof, E., Luria, D., Brass, D., Marek, D., Lahat, H., Reznik-Wolf, H., Pras, E., Dascal, N., Eldar, M., Glikson, M.
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<strong>Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia.</strong>
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Circulation 116: 463-470, 2007.
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[PubMed: 17646576]
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[Full Text: https://doi.org/10.1161/CIRCULATIONAHA.107.706887]
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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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Schulze-Bahr, E., Neu, A., Friederich, P., Kaupp, U. B., Breithardt, G., Pongs, O., Isbrandt, D.
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<strong>Pacemaker channel dysfunction in a patient with sinus node disease.</strong>
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J. Clin. Invest. 111: 1537-1545, 2003.
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[PubMed: 12750403]
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[Full Text: https://doi.org/10.1172/JCI16387]
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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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Schweizer, P. A., Duhme, N., Thomas, D., Becker, R., Zehelein, J., Draguhn, A., Bruehl, C., Katus, H. A., Koenen, M.
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<strong>cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control.</strong>
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Circ. Arrhythm. Electrophysiol. 3: 542-552, 2010.
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[PubMed: 20693575]
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[Full Text: https://doi.org/10.1161/CIRCEP.110.949768]
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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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Schweizer, P. A., Schroter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., Buss, S. J., Seyler, C., Bruehl, C., Draguhn, A., Koenen, M., Meder, B., Katus, H. A., Thomas, D.
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<strong>The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.</strong>
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J. Am. Coll. Cardiol. 64: 757-767, 2014.
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[PubMed: 25145518]
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[Full Text: https://doi.org/10.1016/j.jacc.2014.06.1155]
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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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Surawicz, B., Hariman, R. J.
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<strong>Follow-up of the family with congenital absence of sinus rhythm.</strong>
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Am. J. Cardiol. 61: 467-469, 1988.
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[PubMed: 3341232]
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[Full Text: https://doi.org/10.1016/0002-9149(88)90309-8]
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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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Ueda, K., Nakamura, K., Hayashi, T., Inagaki, N., Takahashi, M., Arimura, T., Morita, H., Higashiuesato, Y., Hirano, Y., Yasunami, M., Takishita, S., Yamashina, A., Ohe, T., Sunamori, M., Hiraoka, M., Kimura, A.
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<strong>Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia.</strong>
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J. Biol. Chem. 279: 27194-27198, 2004.
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[PubMed: 15123648]
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[Full Text: https://doi.org/10.1074/jbc.M311953200]
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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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Vermeer, A. M. C., Lodder, E. M., Thomas, D., Duijkers, F. A. M., Marcelis, C., van Gorselen, E. O. F., Fortner, P., Buss, S. J., Mereles, D., Katus, H. A., Wilde, A. A. M., Bezzina, C. R., Boekholdt, S. M., Matthijs Boekholdt, S., Schweizer, P. A., Christiaans, I.
|
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<strong>Dilation of the aorta ascendens forms part of the clinical spectrum of HCN4 mutations. (Letter)</strong>
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J. Am. Coll. Cardiol. 67: 2313-2315, 2016.
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[PubMed: 27173043]
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[Full Text: https://doi.org/10.1016/j.jacc.2016.01.086]
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</p>
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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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Marla J. F. O'Neill - updated : 01/12/2017<br>Marla J. F. O'Neill - updated : 11/18/2009<br>Marla J. F. O'Neill - updated : 3/5/2008<br>Victor A. McKusick - updated : 2/1/2006<br>Cassandra L. Kniffin - reorganized : 4/28/2004<br>Victor A. McKusick - updated : 11/18/2003<br>Victor A. McKusick - updated : 5/8/1997
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Victor A. McKusick : 6/2/1986
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carol : 02/23/2024<br>carol : 03/06/2017<br>carol : 01/12/2017<br>carol : 05/23/2016<br>terry : 12/20/2012<br>carol : 7/15/2011<br>wwang : 11/18/2009<br>wwang : 3/5/2008<br>alopez : 2/15/2006<br>terry : 2/1/2006<br>carol : 4/28/2004<br>ckniffin : 4/15/2004<br>joanna : 4/13/2004<br>alopez : 11/25/2003<br>tkritzer : 11/20/2003<br>terry : 11/18/2003<br>alopez : 7/30/1997<br>alopez : 7/7/1997<br>mark : 6/10/1997<br>mark : 5/8/1997<br>alopez : 5/6/1997<br>mark : 3/25/1996<br>terry : 3/18/1996<br>mimadm : 12/2/1994<br>carol : 3/29/1994<br>carol : 6/26/1992<br>carol : 6/25/1992<br>supermim : 3/16/1992<br>supermim : 3/20/1990
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