4701 lines
401 KiB
Text
4701 lines
401 KiB
Text
|
|
|
|
|
|
|
|
|
|
<!DOCTYPE html>
|
|
<html xmlns="http://www.w3.org/1999/xhtml" lang="en-us" xml:lang="en-us" >
|
|
|
|
<head>
|
|
|
|
|
|
|
|
<!--
|
|
################################# CRAWLER WARNING #################################
|
|
|
|
- The terms of service and the robots.txt file disallows crawling of this site,
|
|
please see https://omim.org/help/agreement for more information.
|
|
|
|
- A number of data files are available for download at https://omim.org/downloads.
|
|
|
|
- We have an API which you can learn about at https://omim.org/help/api and register
|
|
for at https://omim.org/api, this provides access to the data in JSON & XML formats.
|
|
|
|
- You should feel free to contact us at https://omim.org/contact to figure out the best
|
|
approach to getting the data you need for your work.
|
|
|
|
- WE WILL AUTOMATICALLY BLOCK YOUR IP ADDRESS IF YOU CRAWL THIS SITE.
|
|
|
|
- WE WILL ALSO AUTOMATICALLY BLOCK SUB-DOMAINS AND ADDRESS RANGES IMPLICATED IN
|
|
DISTRIBUTED CRAWLS OF THIS SITE.
|
|
|
|
################################# CRAWLER WARNING #################################
|
|
-->
|
|
|
|
|
|
|
|
<meta http-equiv="content-type" content="text/html; charset=utf-8" />
|
|
<meta http-equiv="cache-control" content="no-cache" />
|
|
<meta http-equiv="pragma" content="no-cache" />
|
|
<meta name="robots" content="index, follow" />
|
|
|
|
|
|
<meta name="viewport" content="width=device-width, initial-scale=1" />
|
|
<meta http-equiv="X-UA-Compatible" content="IE=edge" />
|
|
|
|
|
|
<meta name="title" content="Online Mendelian Inheritance in Man (OMIM)" />
|
|
<meta name="description" content="Online Mendelian Inheritance in Man (OMIM) is a comprehensive, authoritative
|
|
compendium of human genes and genetic phenotypes that is freely available and updated daily. The full-text,
|
|
referenced overviews in OMIM contain information on all known mendelian disorders and over 15,000 genes.
|
|
OMIM focuses on the relationship between phenotype and genotype. It is updated daily, and the entries
|
|
contain copious links to other genetics resources." />
|
|
<meta name="keywords" content="Mendelian Inheritance in Man, OMIM, Mendelian diseases, Mendelian disorders, genetic diseases,
|
|
genetic disorders, genetic disorders in humans, genetic phenotypes, phenotype and genotype, disease models, alleles,
|
|
genes, dna, genetics, dna testing, gene testing, clinical synopsis, medical genetics" />
|
|
<meta name="theme-color" content="#333333" />
|
|
<link rel="icon" href="/static/omim/favicon.png" />
|
|
<link rel="apple-touch-icon" href="/static/omim/favicon.png" />
|
|
<link rel="manifest" href="/static/omim/manifest.json" />
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<script id='mimBrowserCapability'>
|
|
function _0x5069(){const _0x4b1387=['91sZIeLc','mimBrowserCapability','15627zshTnf','710004yxXedd','34LxqNYj','match','disconnect','1755955rnzTod','observe','1206216ZRfBWB','575728fqgsYy','webdriver','documentElement','close','open','3086704utbakv','7984143PpiTpt'];_0x5069=function(){return _0x4b1387;};return _0x5069();}function _0xe429(_0x472ead,_0x43eb70){const _0x506916=_0x5069();return _0xe429=function(_0xe42949,_0x1aaefc){_0xe42949=_0xe42949-0x1a9;let _0xe6add8=_0x506916[_0xe42949];return _0xe6add8;},_0xe429(_0x472ead,_0x43eb70);}(function(_0x337daa,_0x401915){const _0x293f03=_0xe429,_0x5811dd=_0x337daa();while(!![]){try{const _0x3dc3a3=parseInt(_0x293f03(0x1b4))/0x1*(-parseInt(_0x293f03(0x1b6))/0x2)+parseInt(_0x293f03(0x1b5))/0x3+parseInt(_0x293f03(0x1b0))/0x4+-parseInt(_0x293f03(0x1b9))/0x5+parseInt(_0x293f03(0x1aa))/0x6+-parseInt(_0x293f03(0x1b2))/0x7*(parseInt(_0x293f03(0x1ab))/0x8)+parseInt(_0x293f03(0x1b1))/0x9;if(_0x3dc3a3===_0x401915)break;else _0x5811dd['push'](_0x5811dd['shift']());}catch(_0x4dd27b){_0x5811dd['push'](_0x5811dd['shift']());}}}(_0x5069,0x84d63),(function(){const _0x9e4c5f=_0xe429,_0x363a26=new MutationObserver(function(){const _0x458b09=_0xe429;if(document!==null){let _0x2f0621=![];navigator[_0x458b09(0x1ac)]!==![]&&(_0x2f0621=!![]);for(const _0x427dda in window){_0x427dda[_0x458b09(0x1b7)](/cdc_[a-z0-9]/ig)&&(_0x2f0621=!![]);}_0x2f0621===!![]?document[_0x458b09(0x1af)]()[_0x458b09(0x1ae)]():(_0x363a26[_0x458b09(0x1b8)](),document['getElementById'](_0x458b09(0x1b3))['remove']());}});_0x363a26[_0x9e4c5f(0x1a9)](document[_0x9e4c5f(0x1ad)],{'childList':!![]});}()));
|
|
</script>
|
|
|
|
|
|
|
|
<link rel='preconnect' href='https://cdn.jsdelivr.net' />
|
|
<link rel='preconnect' href='https://cdnjs.cloudflare.com' />
|
|
|
|
<link rel="preconnect" href="https://www.googletagmanager.com" />
|
|
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/jquery@3.7.1/dist/jquery.min.js" integrity="sha256-/JqT3SQfawRcv/BIHPThkBvs0OEvtFFmqPF/lYI/Cxo=" crossorigin="anonymous"></script>
|
|
<script src="https://cdn.jsdelivr.net/npm/jquery-migrate@3.5.2/dist/jquery-migrate.js" integrity="sha256-ThFcNr/v1xKVt5cmolJIauUHvtXFOwwqiTP7IbgP8EU=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/bootstrap@3.4.1/dist/js/bootstrap.min.js" integrity="sha256-nuL8/2cJ5NDSSwnKD8VqreErSWHtnEP9E7AySL+1ev4=" crossorigin="anonymous"></script>
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/bootstrap@3.4.1/dist/css/bootstrap.min.css" integrity="sha256-bZLfwXAP04zRMK2BjiO8iu9pf4FbLqX6zitd+tIvLhE=" crossorigin="anonymous">
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/bootstrap@3.4.1/dist/css/bootstrap-theme.min.css" integrity="sha256-8uHMIn1ru0GS5KO+zf7Zccf8Uw12IA5DrdEcmMuWLFM=" crossorigin="anonymous">
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/moment@2.29.4/min/moment.min.js" integrity="sha256-80OqMZoXo/w3LuatWvSCub9qKYyyJlK0qnUCYEghBx8=" crossorigin="anonymous"></script>
|
|
<script src="https://cdn.jsdelivr.net/npm/eonasdan-bootstrap-datetimepicker@4.17.49/build/js/bootstrap-datetimepicker.min.js" integrity="sha256-dYxUtecag9x4IaB2vUNM34sEso6rWTgEche5J6ahwEQ=" crossorigin="anonymous"></script>
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/eonasdan-bootstrap-datetimepicker@4.17.49/build/css/bootstrap-datetimepicker.min.css" integrity="sha256-9FNpuXEYWYfrusiXLO73oIURKAOVzqzkn69cVqgKMRY=" crossorigin="anonymous">
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/qtip2@3.0.3/dist/jquery.qtip.min.js" integrity="sha256-a+PRq3NbyK3G08Boio9X6+yFiHpTSIrbE7uzZvqmDac=" crossorigin="anonymous"></script>
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/qtip2@3.0.3/dist/jquery.qtip.min.css" integrity="sha256-JvdVmxv7Q0LsN1EJo2zc1rACwzatOzkyx11YI4aP9PY=" crossorigin="anonymous">
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/devbridge-autocomplete@1.4.11/dist/jquery.autocomplete.min.js" integrity="sha256-BNpu3uLkB3SwY3a2H3Ue7WU69QFdSRlJVBrDTnVKjiA=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/jquery-validation@1.21.0/dist/jquery.validate.min.js" integrity="sha256-umbTaFxP31Fv6O1itpLS/3+v5fOAWDLOUzlmvOGaKV4=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/js-cookie@3.0.5/dist/js.cookie.min.js" integrity="sha256-WCzAhd2P6gRJF9Hv3oOOd+hFJi/QJbv+Azn4CGB8gfY=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdnjs.cloudflare.com/ajax/libs/ScrollToFixed/1.0.8/jquery-scrolltofixed-min.js" integrity="sha512-ohXbv1eFvjIHMXG/jY057oHdBZ/jhthP1U3jES/nYyFdc9g6xBpjDjKIacGoPG6hY//xVQeqpWx8tNjexXWdqA==" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<script async src="https://www.googletagmanager.com/gtag/js?id=G-HMPSQC23JJ"></script>
|
|
<script>
|
|
window.dataLayer = window.dataLayer || [];
|
|
function gtag(){window.dataLayer.push(arguments);}
|
|
gtag("js", new Date());
|
|
gtag("config", "G-HMPSQC23JJ");
|
|
</script>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<script src="/static/omim/js/site.js?version=Zmk5Y1" integrity="sha256-fi9cXywxCO5p0mU1OSWcMp0DTQB4s8ncFR8j+IO840s="></script>
|
|
|
|
|
|
<link rel="stylesheet" href="/static/omim/css/site.css?version=VGE4MF" integrity="sha256-Ta80Qpm3w1S8kmnN0ornbsZxdfA32R42R4ncsbos0YU=" />
|
|
|
|
|
|
<script src="/static/omim/js/entry/entry.js?version=anMvRU" integrity="sha256-js/EBOBZzGDctUqr1VhnNPzEiA7w3HM5JbFmOj2CW84="></script>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimBootstrapDeviceSize">
|
|
<div class="visible-xs" data-mim-bootstrap-device-size="xs"></div>
|
|
<div class="visible-sm" data-mim-bootstrap-device-size="sm"></div>
|
|
<div class="visible-md" data-mim-bootstrap-device-size="md"></div>
|
|
<div class="visible-lg" data-mim-bootstrap-device-size="lg"></div>
|
|
</div>
|
|
|
|
|
|
|
|
<title>
|
|
|
|
Entry
|
|
|
|
- *603851 - PAIRED-LIKE HOMEOBOX 2B; PHOX2B
|
|
|
|
|
|
- OMIM
|
|
|
|
</title>
|
|
|
|
|
|
|
|
</head>
|
|
|
|
<body>
|
|
<div id="mimBody">
|
|
|
|
|
|
|
|
<div id="mimHeader" class="hidden-print">
|
|
|
|
|
|
|
|
<nav class="navbar navbar-inverse navbar-fixed-top mim-navbar-background">
|
|
<div class="container-fluid">
|
|
|
|
<!-- Brand and toggle get grouped for better mobile display -->
|
|
<div class="navbar-header">
|
|
<button type="button" class="navbar-toggle collapsed" data-toggle="collapse" data-target="#mimNavbarCollapse" aria-expanded="false">
|
|
<span class="sr-only"> Toggle navigation </span>
|
|
<span class="icon-bar"></span>
|
|
<span class="icon-bar"></span>
|
|
<span class="icon-bar"></span>
|
|
</button>
|
|
<a class="navbar-brand" href="/"><img alt="OMIM" src="/static/omim/icons/OMIM_davinciman.001.png" height="30" width="30"></a>
|
|
</div>
|
|
|
|
<div id="mimNavbarCollapse" class="collapse navbar-collapse">
|
|
|
|
<ul class="nav navbar-nav">
|
|
|
|
|
|
<li>
|
|
<a href="/help/about"><span class="mim-navbar-menu-font"> About </span></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimStatisticsDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Statistics <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="statisticsDropdown">
|
|
<li>
|
|
<a href="/statistics/update"> Update List </a>
|
|
</li>
|
|
<li>
|
|
<a href="/statistics/entry"> Entry Statistics </a>
|
|
</li>
|
|
<li>
|
|
<a href="/statistics/geneMap"> Phenotype-Gene Statistics </a>
|
|
</li>
|
|
<li>
|
|
<a href="/statistics/paceGraph"> Pace of Gene Discovery Graph </a>
|
|
</li>
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimDownloadsDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Downloads <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="downloadsDropdown">
|
|
|
|
<li>
|
|
<a href="/downloads/"> Register for Downloads </a>
|
|
</li>
|
|
<li>
|
|
<a href="/api"> Register for API Access </a>
|
|
</li>
|
|
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li>
|
|
<a href="/contact?mimNumber=603851"><span class="mim-navbar-menu-font"> Contact Us </span></a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<li>
|
|
|
|
<a href="/mimmatch/">
|
|
|
|
<span class="mim-navbar-menu-font">
|
|
<span class="mim-tip-bottom" qtip_title="<strong>MIMmatch</strong>" qtip_text="MIMmatch is a way to follow OMIM entries that interest you and to find other researchers who may share interest in the same entries. <br /><br />A bonus to all MIMmatch users is the option to sign up for updates on new gene-phenotype relationships.">
|
|
MIMmatch
|
|
</span>
|
|
</span>
|
|
</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimDonateDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Donate <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="donateDropdown">
|
|
<li>
|
|
<a href="https://secure.jhu.edu/form/OMIM" target="_blank" onclick="gtag('event', 'mim_donation', {'destination': 'secure.jhu.edu'})"> Donate! </a>
|
|
</li>
|
|
<li>
|
|
<a href="/donors"> Donors </a>
|
|
</li>
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimHelpDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Help <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="helpDropdown">
|
|
<li>
|
|
<a href="/help/faq"> Frequently Asked Questions (FAQs) </a>
|
|
</li>
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/help/search"> Search Help </a>
|
|
</li>
|
|
<li>
|
|
<a href="/help/linking"> Linking Help </a>
|
|
</li>
|
|
<li>
|
|
<a href="/help/api"> API Help </a>
|
|
</li>
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/help/external"> External Links </a>
|
|
</li>
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/help/agreement"> Use Agreement </a>
|
|
</li>
|
|
<li>
|
|
<a href="/help/copyright"> Copyright </a>
|
|
</li>
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li>
|
|
<a href="#" id="mimShowTips" class="mim-tip-hint" title="Click to reveal all tips on the page. You can also hover over individual elements to reveal the tip."><span class="mim-navbar-menu-font"><span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span></span></a>
|
|
</li>
|
|
|
|
|
|
</ul>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
</nav>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimSearch" class="hidden-print">
|
|
|
|
<div class="container">
|
|
|
|
<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
|
|
|
|
<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
|
|
<input type="hidden" id="mimSearchStart" name="start" value="1" />
|
|
<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
|
|
<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
|
|
|
|
|
|
<div class="row">
|
|
|
|
<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
|
|
<div class="form-group">
|
|
<div class="input-group">
|
|
<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
|
|
<div class="input-group-btn">
|
|
<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
|
|
<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
|
|
<ul class="dropdown-menu dropdown-menu-right">
|
|
<li class="dropdown-header">
|
|
Advanced Search
|
|
</li>
|
|
<li style="margin-left: 0.5em;">
|
|
<a href="/search/advanced/entry"> OMIM </a>
|
|
</li>
|
|
<li style="margin-left: 0.5em;">
|
|
<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
|
|
</li>
|
|
<li style="margin-left: 0.5em;">
|
|
<a href="/search/advanced/geneMap"> Gene Map </a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/history"> Search History </a>
|
|
</li>
|
|
|
|
|
|
</ul>
|
|
</div>
|
|
</div>
|
|
<div class="autocomplete" id="mimEntrySearchAutocomplete"></div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="col-lg-4 col-md-4 col-sm-4 col-xs-4">
|
|
<span class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</form>
|
|
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
<!-- <div id="mimSearch"> -->
|
|
|
|
|
|
|
|
|
|
<div id="mimContent">
|
|
|
|
|
|
|
|
<div class="container hidden-print">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
|
|
<div id="mimAlertBanner">
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="row">
|
|
|
|
|
|
|
|
|
|
<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
|
|
|
|
<div id="mimFloatingTocMenu" class="small" role="navigation">
|
|
|
|
<p>
|
|
<span class="h4">*603851</span>
|
|
<br />
|
|
<strong>Table of Contents</strong>
|
|
</p>
|
|
|
|
<nav>
|
|
<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
|
|
|
|
<li role="presentation">
|
|
<a href="#title"><strong>Title</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#text"><strong>Text</strong></a>
|
|
</li>
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#cloning">Cloning and Expression</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#geneFunction">Gene Function</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#mapping">Mapping</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#molecularGenetics">Molecular Genetics</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#cytogenetics">Cytogenetics</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#animalModel">Animal Model</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
|
|
</li>
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="/allelicVariants/603851">Table View</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#references"><strong>References</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#contributors"><strong>Contributors</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#creationDate"><strong>Creation Date</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#editHistory"><strong>Edit History</strong></a>
|
|
</li>
|
|
|
|
</ul>
|
|
|
|
</nav>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimFloatingLinksMenu">
|
|
|
|
<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
|
|
<h4 class="panel-title">
|
|
<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
|
|
<div style="display: table-row">
|
|
<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
|
|
|
|
<div style="display: table-cell;">External Links</div>
|
|
</div>
|
|
</a>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
|
|
<div id="mimExternalLinksFold" class="collapse in">
|
|
|
|
<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000109132;t=ENST00000226382" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=8929" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
|
|
|
|
|
|
<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=603851" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000109132;t=ENST00000226382" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_003924" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_003924" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
|
|
|
|
|
|
<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=603851" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://hprd.org/summary?hprd_id=09157&isoform_id=09157_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.proteinatlas.org/search/PHOX2B" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/protein/1841338,4633284,5672611,12707580,16877955,116242712,119613395,1594464241,1733275701,1750927132,1750927134,1750927136,1750927138,1750927140,1750927142,2214710236" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.uniprot.org/uniprotkb/Q99453" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Gene Info</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="http://biogps.org/#goto=genereport&id=8929" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000109132;t=ENST00000226382" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=PHOX2B" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=PHOX2B" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+8929" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
|
|
|
|
|
|
|
|
<dd><a href="http://v1.marrvel.org/search/gene/PHOX2B" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
|
|
|
|
|
|
|
|
<dd><a href="https://monarchinitiative.org/NCBIGene:8929" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gene/8929" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr4&hgg_gene=ENST00000226382.4&hgg_start=41744082&hgg_end=41748725&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Clinical Resources</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:9143" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:9143" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://medlineplus.gov/genetics/gene/phox2b" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603851[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=603851[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.deciphergenomics.org/gene/PHOX2B/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000109132" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ebi.ac.uk/gwas/search?query=PHOX2B" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.gwascentral.org/search?q=PHOX2B" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PHOX2B" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=PHOX2B&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.pharmgkb.org/gene/PA33467" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Animal Models</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.alliancegenome.org/gene/HGNC:9143" 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>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://flybase.org/reports/FBgn0025334.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.mousephenotype.org/data/genes/MGI:1100882" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://v1.marrvel.org/search/gene/PHOX2B#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://www.informatics.jax.org/marker/MGI:1100882" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gene/8929/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.orthodb.org/?ncbi=8929" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00000440;class=Gene" 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'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://zfin.org/ZDB-GENE-050407-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Cellular Pathways</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://reactome.org/content/query?q=PHOX2B&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
<span>
|
|
<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.">
|
|
|
|
</span>
|
|
</span>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
|
|
|
|
<div>
|
|
|
|
<a id="title" class="mim-anchor"></a>
|
|
|
|
<div>
|
|
<a id="number" class="mim-anchor"></a>
|
|
<div class="text-right">
|
|
|
|
|
|
|
|
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
|
|
|
|
<strong>SNOMEDCT:</strong> 719972004<br />
|
|
|
|
|
|
|
|
|
|
|
|
|
|
">ICD+</a>
|
|
|
|
</div>
|
|
<div>
|
|
<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
603851
|
|
</span>
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
PAIRED-LIKE HOMEOBOX 2B; PHOX2B
|
|
|
|
</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">
|
|
PAIRED MESODERM HOMEOBOX 2B; PMX2B<br />
|
|
NEUROBLASTOMA PAIRED-TYPE HOMEOBOX GENE; NBPHOX
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PHOX2B" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PHOX2B</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/4/176?start=-3&limit=10&highlight=176">4p13</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr4:41744082-41748725&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">4:41,744,082-41,748,725</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=613013,209880,613013" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/4/176?start=-3&limit=10&highlight=176">
|
|
4p13
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Neuroblastoma, susceptibility to, 2}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613013"> 613013 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/209880"> 209880 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Neuroblastoma with Hirschsprung disease
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613013"> 613013 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<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/603851" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/603851" 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>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="text" class="mim-anchor"></a>
|
|
|
|
|
|
|
|
<h4>
|
|
|
|
<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="cloning" class="mim-anchor"></a>
|
|
<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimCloningFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#29" class="mim-tip-reference" title="Yokoyama, M., Nishi, Y., Yoshii, J., Okubo, K., Matsubara, K. <strong>Identification and cloning of neuroblastoma-specific and nerve tissue-specific genes through compiled expression profiles.</strong> DNA Res. 3: 311-320, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039501</a>] [<a href="https://doi.org/10.1093/dnares/3.5.311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9039501">Yokoyama et al. (1996)</a> identified the PHOX2B gene, which they called NBPhox for 'neuroblastoma phox,' from a 3-prime-directed cDNA library derived from the human neuroblastoma cell line CHP134. PHOX2B has an mRNA of 3,074 nucleotides and contains an open reading frame of 314 amino acids spanning nucleotides 361 to 1,302. The polyadenylation signal AATAAA is located 17 bases upstream from the site of polyadenylation. The gene encodes a protein with a homeodomain that is significantly homologous with those in various members of the paired-type homeobox genes. The amino acid sequences of the homeodomains of PHOX2B and PHOX2A (<a href="/entry/602753">602753</a>) cover 60 amino acids and are identical, but outside the homeodomain no significant sequence similarity was observed. A proline-rich domain lies between amino acids 192 and 284 of the PHOX2B protein, and a glycine-rich domain lies between amino acids 196 and 289. There are 2 alanine-rich repeats in the C terminus of the homeodomain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9039501" 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="#19" class="mim-tip-reference" title="Pattyn, A., Morin, X., Cremer, H., Goridis, C., Brunet, J.-F. <strong>Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis.</strong> Development 124: 4065-4075, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9374403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9374403</a>] [<a href="https://doi.org/10.1242/dev.124.20.4065" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9374403">Pattyn et al. (1997)</a> cloned the mouse Phox2b gene. The homeodomains of mouse Phox2a and Phox2b are identical. The N-terminal domains of mouse Phox2a and Phox2b are 57% identical, but the C-terminal domains are highly divergent. The murine Phox2b gene also contains 2 alanine stretches in the C terminus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9374403" 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>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="geneFunction" class="mim-anchor"></a>
|
|
<h4 href="#mimGeneFunctionFold" id="mimGeneFunctionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimGeneFunctionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimGeneFunctionFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#19" class="mim-tip-reference" title="Pattyn, A., Morin, X., Cremer, H., Goridis, C., Brunet, J.-F. <strong>Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis.</strong> Development 124: 4065-4075, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9374403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9374403</a>] [<a href="https://doi.org/10.1242/dev.124.20.4065" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9374403">Pattyn et al. (1997)</a> studied the expression pattern of Phox2b. In embryonic day 9 brains, 2 ventral columns of Phox2b-positive cells ran on either side of the floor plate from an abrupt rostral limit just anterior to the rhombomere1/rhombomere2 boundary into the cervical spinal cord. One day later the ventral column was still strongly labeled. Two ventral patches on both sides of the met-mesencephalic border could be identified at later stages as, respectively, the forming trochlear and oculomotor nuclei. By embryonic day 11.5, the ventral columns had disappeared, whereas the dorsal column contained many more Phox2b-positive cells. In the neonatal brain, Phox2b expression was similar to that of Phox2a. No expression was seen in the spinal cord. In the peripheral nervous system, Phox2b, like Phox2a, was expressed in 3 cranial sensory ganglia and in all ganglia of the autonomic nervous system as early as they had formed, and at least up to midgestation. Although the list of Phox2b expression sites was strikingly similar to that reported for Phox2a, <a href="#19" class="mim-tip-reference" title="Pattyn, A., Morin, X., Cremer, H., Goridis, C., Brunet, J.-F. <strong>Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis.</strong> Development 124: 4065-4075, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9374403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9374403</a>] [<a href="https://doi.org/10.1242/dev.124.20.4065" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9374403">Pattyn et al. (1997)</a> observed systematic differences in onset, persistence, and extent of expression. The expression pattern of Phox2b in Phox2a-null mice indicated that Phox2a regulates Phox2b directly or indirectly in cranial ganglia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9374403" 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="#1" class="mim-tip-reference" title="Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simmoneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S. <strong>Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.</strong> Nature Genet. 33: 459-460, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640453</a>] [<a href="https://doi.org/10.1038/ng1130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640453">Amiel et al. (2003)</a> showed that PHOX2B is expressed in both the central and the peripheral autonomic nervous system during human embryonic development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12640453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Espinosa-Medina, I., Outin, E., Picard, C. A., Chettouh, Z., Dymecki, S., Consalez, G. G., Coppola, E., Brunet, J.-F. <strong>Parasympathetic ganglia derive from Schwann cell precursors.</strong> Science 345: 87-90, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24925912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24925912</a>] [<a href="https://doi.org/10.1126/science.1253286" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24925912">Espinosa-Medina et al. (2014)</a> studied how parasympathetic ganglia form close to visceral organs as well as what their precursors are and found that many cranial nerve-associated crest cells coexpress the panautonomic determinant PHOX2B together with markers of Schwann cell precursors. Some give rise to Schwann cells after downregulation of PHOX2B. Others form parasympathetic ganglia after being guided to the site of ganglion formation by the nerves that carry preganglionic fibers, a parsimonious way of wiring the pathway. <a href="#8" class="mim-tip-reference" title="Espinosa-Medina, I., Outin, E., Picard, C. A., Chettouh, Z., Dymecki, S., Consalez, G. G., Coppola, E., Brunet, J.-F. <strong>Parasympathetic ganglia derive from Schwann cell precursors.</strong> Science 345: 87-90, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24925912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24925912</a>] [<a href="https://doi.org/10.1126/science.1253286" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24925912">Espinosa-Medina et al. (2014)</a> concluded that cranial Schwann cell precursors are the source of parasympathetic neurons during normal development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24925912" 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>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="mapping" class="mim-anchor"></a>
|
|
<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimMappingFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#1" class="mim-tip-reference" title="Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simmoneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S. <strong>Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.</strong> Nature Genet. 33: 459-460, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640453</a>] [<a href="https://doi.org/10.1038/ng1130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640453">Amiel et al. (2003)</a> stated that the PHOX2B gene maps to chromosome 4p12. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12640453" 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>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="molecularGenetics" class="mim-anchor"></a>
|
|
<h4 href="#mimMolecularGeneticsFold" id="mimMolecularGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimMolecularGeneticsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimMolecularGeneticsFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Congenital Central Hypoventilation Syndrome 1</em></strong></p><p>
|
|
Because in mice the development of reflex circuits of the autonomic nervous system is dependent on the Phox2b gene, <a href="#1" class="mim-tip-reference" title="Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simmoneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S. <strong>Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.</strong> Nature Genet. 33: 459-460, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640453</a>] [<a href="https://doi.org/10.1038/ng1130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640453">Amiel et al. (2003)</a> investigated its human ortholog, PHOX2B, in 29 individuals with congenital central hypoventilation syndrome (CCHS1; <a href="/entry/209880">209880</a>). This syndrome is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. The core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system including Hirschsprung disease and tumors of neural crest derivatives such as ganglioneuromas and neuroblastomas. <a href="#1" class="mim-tip-reference" title="Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simmoneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S. <strong>Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.</strong> Nature Genet. 33: 459-460, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640453</a>] [<a href="https://doi.org/10.1038/ng1130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640453">Amiel et al. (2003)</a> found that 18 of the 29 patients had heterozygous de novo mutations in PHOX2B. Most mutations consisted of 5-9 alanine expansions within a 20-residue polyalanine tract (<a href="#0001">603851.0001</a>) probably resulting from nonhomologous recombination. In 2 CCHS cases, a de novo cytosine insertion in a stretch of 4 cytosines (<a href="#0002">603851.0002</a>) and a deletion of 37 nucleotides (<a href="#0003">603851.0003</a>) resulted in a frameshift downstream of the homeobox, predicting a mutant protein with no known function or homology. <a href="#1" class="mim-tip-reference" title="Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simmoneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S. <strong>Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.</strong> Nature Genet. 33: 459-460, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640453</a>] [<a href="https://doi.org/10.1038/ng1130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640453">Amiel et al. (2003)</a> found 2 individuals who in addition to polyalanine expansions in PHOX2B had heterozygous variants in genes involved in the same developmental pathway; these variants were amino acid substitutions pro1039 to leu in RET (<a href="/entry/164761#0046">164761.0046</a>) and arg93 to trp in GDNF (<a href="/entry/600837#0001">600837.0001</a>), respectively. Phox2 genes control Ret expression in both sympathetic and enteric neurons in mice. Unlike the polyalanine expansions, however, these variants are neither necessary (most individuals with CCHS do not have any RET or GDNF gene variant) nor sufficient for the disease to occur (carrier parents have no phenotypic expression). <a href="#1" class="mim-tip-reference" title="Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simmoneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S. <strong>Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.</strong> Nature Genet. 33: 459-460, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640453</a>] [<a href="https://doi.org/10.1038/ng1130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640453">Amiel et al. (2003)</a> concluded that PHOX2B is a primary disease locus in CCHS. They found mutations in PHOX2B not only in isolated cases of CCHS but also in individuals with a more complex neural crest involvement including CCHS and Hirschsprung disease (Haddad syndrome) as well as early-onset neuroblastoma. They found no correlation between the size of the polyalanine tract and the complexity of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12640453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Sasaki, A., Kanai, M., Kijima, K., Akaba, K., Hashimoto, M., Hasegawa, H., Otaki, S., Koizumi, T., Kusuda, S., Ogawa, Y., Tuchiya, K., Yamamoto, W., Nakamura, T., Hayasaka, K. <strong>Molecular analysis of congenital central hypoventilation syndrome.</strong> Hum. Genet. 114: 22-26, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14566559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14566559</a>] [<a href="https://doi.org/10.1007/s00439-003-1036-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14566559">Sasaki et al. (2003)</a> studied 7 patients with isolated CCHS and 3 CCHS patients with Hirschsprung disease. In 4 patients they detected polyalanine expansions in the PHOX2B gene and in 1 patient a novel frameshift mutation in PHOX2B. They could not reject the possibility that mutations in the RET (<a href="/entry/164761">164761</a>), GDNF, PHOX2A, and HASH1 (<a href="/entry/100790">100790</a>) genes may also be involved in the pathogenesis of CCHS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14566559" 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 65 of 67 CCHS probands (97%), <a href="#28" class="mim-tip-reference" title="Weese-Mayer, D. E., Berry-Kravis, E. M., Zhou, L., Maher, B. S., Silvestri, J. M., Curran, M. E., Marazita, M. L. <strong>Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b.</strong> Am. J. Med. Genet. 123A: 267-278, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14608649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14608649</a>] [<a href="https://doi.org/10.1002/ajmg.a.20527" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14608649">Weese-Mayer et al. (2003)</a> found heterozygosity for the exon 3 polyalanine expansion mutation in PHOX2B. There was an association between repeat mutation length and severity of the CCHS/ANSD (autonomic nervous system dysregulation and/or dysfunction) phenotype. Of the 2 probands who did not carry the expansion mutation, one had a nonsense mutation in exon 3 that truncated the protein and the other had no mutation in PHOX2B but had a previously reported EDN3 frameshift point mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14608649" 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="#16" class="mim-tip-reference" title="Matera, I., Bachetti, T., Puppo, F., Di Duca, M., Morandi, F., Casiraghi, G. M., Cilio, M. R., Hennekam, R., Hofstra, R., Schober, J. G., Ravazzolo, R., Ottonello, G., Ceccherini, I. <strong>PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset central hypoventilation syndrome. (Letter)</strong> J. Med. Genet. 41: 373-380, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15121777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15121777</a>] [<a href="https://doi.org/10.1136/jmg.2003.015412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15121777">Matera et al. (2004)</a> screened the PHOX2B gene in 27 patients with CCHS, including 3 with associated Hirschsprung disease and 3 with late-onset CCHS, and identified 3 heterozygous frameshift mutations and 22 polyalanine expansions ranging from 5 to 13 residues. The authors noted that phenotype severity increased with increasing polyalanine expansion size. Polyalanine triplet expansions were also detected in the affected sibs of 2 familial cases and in 2 asymptomatic parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15121777" 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="#26" class="mim-tip-reference" title="Trochet, D., O'Brien, L. M., Gozal, D., Trang, H., Nordenskjold, A., Laudier, B., Svensson, P.-J., Uhrig, S., Cole, T., Niemann, S., Munnich, A., Gaultier, C., Lyonnet, S., Amiel, J. <strong>PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.</strong> Am. J. Hum. Genet. 76: 421-426, 2005. Note: Erratum: Am. J. Hum. Genet. 76: 715 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657873</a>] [<a href="https://doi.org/10.1086/428366" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15657873">Trochet et al. (2005)</a> reported the clinical and molecular assessments of a cohort of 188 probands with CCHS, either isolated or associated with Hirschsprung disease (the association known as Haddad syndrome) and/or tumors of the sympathetic nervous system (TSNS). A heterozygous mutation of the PHOX2B gene was identified in 174 of the 188 cases (92.6%). In 161 (92.5%) of the 174 cases with an identifiable mutation, the mutation consisted of an in-frame duplication of 15 to 39 nucleotides, leading to an expansion of +5 to +13 alanines within the 20-alanine tract of the carboxy terminal of the homeodomain of the protein. Vertical transmission of an alanine expansion (+5 and +7 alanines) from an affected parent to his or her affected child was demonstrated in 2 cases. In a third familial case, with recurrence in sibs, <a href="#26" class="mim-tip-reference" title="Trochet, D., O'Brien, L. M., Gozal, D., Trang, H., Nordenskjold, A., Laudier, B., Svensson, P.-J., Uhrig, S., Cole, T., Niemann, S., Munnich, A., Gaultier, C., Lyonnet, S., Amiel, J. <strong>PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.</strong> Am. J. Hum. Genet. 76: 421-426, 2005. Note: Erratum: Am. J. Hum. Genet. 76: 715 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657873</a>] [<a href="https://doi.org/10.1086/428366" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15657873">Trochet et al. (2005)</a> detected paternal somatic mosaicism for the mutation that was identified in the index case (+7 alanines). Somatic mosaicism was detected in 10 cases (6 fathers and 4 mothers). In all cases, the nucleotide in-frame duplication leading to an alanine expansion remained unchanged in transmission, suggesting that such polyalanine expansions are both meiotically and mitotically stable. These data argued for unequal allelic homologous recombination as the mutation-causing mechanism, as proposed by <a href="#27" class="mim-tip-reference" title="Warren, S. T. <strong>Polyalanine expansion in synpolydactyly might result from unequal crossing-over of HOXD13.</strong> Science 275: 408-409, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9005557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9005557</a>] [<a href="https://doi.org/10.1126/science.275.5298.408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9005557">Warren (1997)</a> for the alanine expansion in the HOXD13 gene (<a href="/entry/142989">142989</a>) resulting in synpolydactyly (<a href="/entry/186000">186000</a>). In 5 of 9 patients with late-onset central hypoventilation syndrome, as described by <a href="#12" class="mim-tip-reference" title="Katz, E. S., McGrath, S., Marcus, C. L. <strong>Late-onset central hypoventilation with hypothalamic dysfunction: a distinct clinical syndrome.</strong> Pediat. Pulmonol. 29: 62-68, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10613788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10613788</a>] [<a href="https://doi.org/10.1002/(sici)1099-0496(200001)29:1<62::aid-ppul10>3.0.co;2-m" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10613788">Katz et al. (2000)</a>, <a href="#26" class="mim-tip-reference" title="Trochet, D., O'Brien, L. M., Gozal, D., Trang, H., Nordenskjold, A., Laudier, B., Svensson, P.-J., Uhrig, S., Cole, T., Niemann, S., Munnich, A., Gaultier, C., Lyonnet, S., Amiel, J. <strong>PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.</strong> Am. J. Hum. Genet. 76: 421-426, 2005. Note: Erratum: Am. J. Hum. Genet. 76: 715 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657873</a>] [<a href="https://doi.org/10.1086/428366" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15657873">Trochet et al. (2005)</a> found an expansion of +5 alanines in the PHOX2B gene (<a href="#0001">603851.0001</a>). From genotype-phenotype correlations, <a href="#26" class="mim-tip-reference" title="Trochet, D., O'Brien, L. M., Gozal, D., Trang, H., Nordenskjold, A., Laudier, B., Svensson, P.-J., Uhrig, S., Cole, T., Niemann, S., Munnich, A., Gaultier, C., Lyonnet, S., Amiel, J. <strong>PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.</strong> Am. J. Hum. Genet. 76: 421-426, 2005. Note: Erratum: Am. J. Hum. Genet. 76: 715 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657873</a>] [<a href="https://doi.org/10.1086/428366" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15657873">Trochet et al. (2005)</a> came to the conclusion that patients with CCHS who develop malignant tumors of the sympathetic nervous system harbor either a missense (e.g., <a href="#0005">603851.0005</a>) or frameshift heterozygous mutation of the PHOX2B gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10613788+9005557+15657873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bachetti, T., Matera, I., Borghini, S., Di Duca, M., Ravazzolo, R., Ceccherini, I. <strong>Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome.</strong> Hum. Molec. Genet. 14: 1815-1824, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15888479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15888479</a>] [<a href="https://doi.org/10.1093/hmg/ddi188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15888479">Bachetti et al. (2005)</a> tested the transcriptional activity of wildtype and mutant PHOX2B expression constructs on the regulatory regions of 2 target genes, DBH (<a href="/entry/609312">609312</a>) and PHOX2A (ARIX; <a href="/entry/602753">602753</a>). Two sets of mutations played different roles in transcriptional regulation of these genes, showing a correlation between length of polyalanine expansions and severity of reduced transcriptional activity. In particular, although reduced transactivation due to polyalanine expansions may be caused by retention of the mutated protein in the cytoplasm or in the nuclear aggregates, frameshift mutations did not impair PHOX2B nuclear localization, suggesting a different mechanism through which frameshift mutations exert the observed effects on target promoters. Moreover, a 614delC deletion seemed to cause sequestration of the corresponding mutant PHOX2B in the nucleolar compartment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15888479" 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="#25" class="mim-tip-reference" title="Trochet, D., Hong, S. J., Lim, J. K., Brunet, J.-F., Munnich, A., Kim, K.-S., Lyonnet, S., Goridis, C., Amiel, J. <strong>Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction.</strong> Hum. Molec. Genet. 14: 3697-3708, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16249188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16249188</a>] [<a href="https://doi.org/10.1093/hmg/ddi401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16249188">Trochet et al. (2005)</a> investigated aggregate formation by proteins with polyalanine tract expansions ranging from +5 to +13 alanines using immunofluorescence of transfected cells and gel filtration of in vitro translated proteins. Transactivation of the dopamine beta-hydroxylase promoter by PHOX2B proteins with frameshift and missense mutations was abolished or severely curtailed, as was in vitro DNA binding, although the proteins localized to the nucleus. The transactivation potential of proteins with polyalanine tract expansions declined with increasing length of the polyalanine stretch, and DNA binding was affected for an expansion of +9 alanines and above. Cytoplasmic aggregation in transfected cells was only observed for the longest expansions, whereas even the short expansion mutants were prone to form multimers in vitro. <a href="#25" class="mim-tip-reference" title="Trochet, D., Hong, S. J., Lim, J. K., Brunet, J.-F., Munnich, A., Kim, K.-S., Lyonnet, S., Goridis, C., Amiel, J. <strong>Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction.</strong> Hum. Molec. Genet. 14: 3697-3708, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16249188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16249188</a>] [<a href="https://doi.org/10.1093/hmg/ddi401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16249188">Trochet et al. (2005)</a> proposed that such a tendency to protein misfolding could explain loss of transactivation for alanine expansion mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16249188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Lombardo, R. C., Porollo, A., Cnota, J. F., Hopkin, R. J. <strong>Congenital heart disease and aortic arch variants associated with mutations in PHOX2B.</strong> Genet. Med. 20: 1538-1543, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29543228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29543228</a>] [<a href="https://doi.org/10.1038/gim.2018.34" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29543228">Lombardo et al. (2018)</a> reported 6 patients with CCHS who had cardiac anomalies. Only 1 had an expansion of the polyalanine tract (<a href="#0001">603851.0001</a>), and this patient required tracheostomy with continuous mechanical ventilation and had Hirschsprung disease. One had a whole-gene deletion. Two patients had missense mutations involving the homeobox domain (R141Q, <a href="#0009">603851.0009</a>; R149L, <a href="#0010">603851.0010</a>). Two had a recurrent premature termination codon (Y78X; <a href="#0011">603851.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29543228" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Sivan, Y., Zhou, A., Jennings, L. J., Berry-Kravis, E. M., Yu, M., Zhou, L., Rand, C. M., Weese-Mayer, D. E. <strong>Congenital central hypoventilation syndrome: severe disease caused by co-occurrence of two PHOX2B variants inherited separately from asymptomatic family members.</strong> Am. J. Med. Genet. 179A: 503-506, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30672101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30672101</a>] [<a href="https://doi.org/10.1002/ajmg.a.61047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30672101">Sivan et al. (2019)</a> reported a male infant with CCHS who had compound heterozygous mutations in the PHOX2B gene: a polyalanine repeat expansion (24 alanine repeats; <a href="#0001">603851.0001</a>) and a missense mutation (G262V; <a href="#0012">603851.0012</a>). The polyalanine repeat expansion was seen in the father, paternal grandfather, and 2 out of 5 of the father's sibs, and the missense mutation was seen in the mother, maternal grandfather, and 3 out of 9 of the mother's sibs. All family members, other than the proband, were phenotypically normal. The authors concluded that this was the first reported case of compound heterozygosity for variants in the PHOX2B gene in a proband with CCHS in which neither variant alone was sufficient to cause disease in multiple family members. The authors noted the importance of PHOX2B testing in parents of all probands with CCHS to identify mosaicism in a parent, confirm allele pathogenicity, determine inheritance, and provide information for future pregnancy planning. The authors also suggested sequencing of PHOX2B if a polyalanine repeat expansion has been identified, especially when the phenotype is more severe than expected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30672101" 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 male infant with CCHS and Haddad Syndrome, <a href="#10" class="mim-tip-reference" title="Guzoglu, N., Aslan, M. K., Gunay, Y. D., Atasoy, P. Ceylaner, S., Aliefendioglu, D. <strong>A novel mutation which causes a frameshift in the PHOX2B gene causes Haddad syndrome.</strong> Clin. Dysmorph. 29: 152-154, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32073407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32073407</a>] [<a href="https://doi.org/10.1097/MCD.0000000000000317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32073407">Guzoglu et al. (2020)</a> identified a c.722_759del38 deletion in the PHOX2B gene within a polyalanine tract (see <a href="#0003">603851.0003</a>). The mutation was identified by direct gene sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32073407" 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>Susceptibility to Neuroblastoma 2</em></strong></p><p>
|
|
<a href="#24" class="mim-tip-reference" title="Trochet, D., Bourdeaut, F., Janoueix-Lerosey, I., Deville, A., de Pontual, L., Schleiermacher, G., Coze, C., Philip, N., Frebourg, T., Munnich, A., Lyonnet, S., Delattre, O., Amiel, J. <strong>Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.</strong> Am. J. Hum. Genet. 74: 761-764, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024693</a>] [<a href="https://doi.org/10.1086/383253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024693">Trochet et al. (2004)</a> noted that rare familial cases of neuroblastoma (NBLST2; <a href="/entry/613013">613013</a>) and its association with other genetically determined congenital malformations of neural crest-derived cells, namely HSCR and/or CCHS, suggested that there may be a gene or genes in which germline mutations predispose to neuroblastoma. Because of the demonstration that PHOX2B is the major disease-causing gene in isolated and syndromic CCHS, <a href="#24" class="mim-tip-reference" title="Trochet, D., Bourdeaut, F., Janoueix-Lerosey, I., Deville, A., de Pontual, L., Schleiermacher, G., Coze, C., Philip, N., Frebourg, T., Munnich, A., Lyonnet, S., Delattre, O., Amiel, J. <strong>Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.</strong> Am. J. Hum. Genet. 74: 761-764, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024693</a>] [<a href="https://doi.org/10.1086/383253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024693">Trochet et al. (2004)</a> investigated it as a candidate gene in neuroblastoma. They reported germline mutations of PHOX2B in both a familial case of neuroblastoma (<a href="#0005">603851.0005</a>) and a patient with neuroblastoma associated with HSCR (<a href="#0006">603851.0006</a>). PHOX2B was the first gene in which germline mutations were demonstrated to predispose to neuroblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15024693" 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>Associations Pending Confirmation</em></strong></p><p>
|
|
<a href="#23" class="mim-tip-reference" title="Toyota, T., Yoshitsugu, K., Ebihara, M., Yamada, K., Ohba, H., Fukasawa, M., Minabe, Y., Nakamura, K., Sekine, Y., Takei, N., Suzuki, K., Itokawa, M., Meerabux, J. M. A., Iwayama-Shigeno, Y., Tomaru, Y., Shimizu, H., Hattori, E., Mori, N., Yoshikawa, T. <strong>Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B.</strong> Hum. Molec. Genet. 13: 551-561, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14709596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14709596</a>] [<a href="https://doi.org/10.1093/hmg/ddh047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14709596">Toyota et al. (2004)</a> found that a subtype of strabismus, constant exotropia, displayed marked association with schizophrenia (see <a href="/entry/181500">181500</a>) (p = 0.00000000906). They identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of the PMX2B gene, with a modest association between these functional polymorphisms and constant exotropia in schizophrenia as compared to control samples (p = 0.029). The polymorphisms were also associated with overall schizophrenia (p = 0.012) and more specifically with schizophrenia manifesting strabismus (p = 0.004). These results suggested a possible interaction between PMX2B and other schizophrenia-precipitating factors, increasing the risk of the combined phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14709596" 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>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="cytogenetics" class="mim-anchor"></a>
|
|
<h4 href="#mimCytogeneticsFold" id="mimCytogeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimCytogeneticsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Cytogenetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimCytogeneticsFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#5" class="mim-tip-reference" title="Benailly, H. K., Lapierre, J. M., Laudier, B., Amiel, J., Attie, T., De Blois, M. C., Vekemans, M., Romana, S. P. <strong>PMX2B, a new candidate gene for Hirschsprung's disease.</strong> Clin. Genet. 64: 204-209, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12919134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12919134</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00105.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12919134">Benailly et al. (2003)</a> reported a 16-month-old girl with a syndrome encompassing developmental delay, severe hypotonia, facial dysmorphism, and short-segment Hirschsprung disease, who was found to have a de novo t(4;8)(p13;p22) translocation. A comparative genomic hybridization (CGH) study found a 5-Mb deletion at chromosome 4p12-p13 that included the PMX2B gene. Dysmorphic features included frontal bossing, prominent forehead, angioma on the forehead, very short nose with slightly anteverted nostrils, high nasal bridge, prominent philtral borders, bilateral epicanthus, and an open anterior fontanel. She had discrete rhizomelia and the anus was anteriorly placed. The authors suggested that PMX2B haploinsufficiency may predispose to Hirschsprung disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12919134" 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>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="animalModel" class="mim-anchor"></a>
|
|
<h4 href="#mimAnimalModelFold" id="mimAnimalModelToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimAnimalModelToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimAnimalModelFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#20" class="mim-tip-reference" title="Pattyn, A., Morin, X., Cremer, H., Goridis, C., Brunet, J.-F. <strong>The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives.</strong> Nature 399: 366-370, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10360575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10360575</a>] [<a href="https://doi.org/10.1038/20700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10360575">Pattyn et al. (1999)</a> generated mice deficient in Phox2b by homologous recombination. In Phox2b -/- mice, autonomic ganglia failed to form properly and degenerate, as did the 3 cranial sensory ganglia that are part of the autonomic reflex circuits. In the anlagen of the enteric nervous system in the sympathetic ganglia, Phox2b is needed for the expression of the GDNF-receptor subunit Ret (<a href="/entry/164761">164761</a>) and for maintaining Mash1 (<a href="/entry/100790">100790</a>) expression. Mutant ganglionic anlagen also failed to switch on the genes that encode dopamine-beta-hydroxylase and tyrosine hydroxylase, both needed for the biosynthesis of the neurotransmitter noradrenaline, demonstrating that Phox2b regulates the noradrenergic phenotype in vertebrates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10360575" 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>Dilp1 is a semidominant mouse mutation that causes dilated pupils when heterozygous and is lethal when homozygous. <a href="#6" class="mim-tip-reference" title="Cross, S. H., Morgan, J. E., Pattyn, A., West, K., McKie, L., Hart, A., Thuang, C., Brunet, J.-F., Jackson, I. J. <strong>Haploinsufficiency for Phox2b in mice causes dilated pupils and atrophy of the ciliary ganglion: mechanistic insights into human congenital central hypoventilation syndrome.</strong> Hum. Molec. Genet. 13: 1433-1439, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15150159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15150159</a>] [<a href="https://doi.org/10.1093/hmg/ddh156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15150159">Cross et al. (2004)</a> reported a nonsense Phox2b mutation in Dilp1 mice. Mice carrying a targeted allele of Phox2b also had dilated pupils; the 2 alleles did not complement. The ciliary ganglion was atrophic in Phox2b heterozygous mutants. Some patients with congenital central hypoventilation syndrome (CCHS; <a href="/entry/209880">209880</a>) have ocular abnormalities, including constricted rather than dilated pupils. The apparent phenotypic differences between mice carrying a loss-of-function mutation of Phox2b and CCHS patients indicates that PHOX2B mutations found in CCHS patients, all of which can produce proteins with intact DNA-binding domains, are gain-of-function mutations that alter rather than abolish protein function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15150159" 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="Dubreuil, V, Ramanantsoa, N., Trochet, D., Vaubourg, V., Amiel, J., Gallego, J., Brunet, J.-F., Goridis, C. <strong>A human mutation in Phox2b causes lack of CO2 chemosensitivity, fatal central apnea, and specific loss of parafacial neurons.</strong> Proc. Nat. Acad. Sci. 105: 1067-1072, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18198276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18198276</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18198276[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0709115105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18198276">Dubreuil et al. (2008)</a> found that mice heterozygous for the CCHS-causing expanded alanine tract in the Phox2b gene (<a href="#0001">603851.0001</a>) had irregular breathing, did not respond to an increase in CO2, and died soon after birth from central apnea. Postmortem examination showed specific loss of Phox2b-expressing glutamatergic neurons in the retrotrapezoid nucleus/parafacial region, whereas other areas thought to be involved in breathing regulation were anatomically normal. The findings demonstrated the essential role of a specific population of medullary interneurons in driving proper breathing at birth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18198276" 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>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="allelicVariants" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<span href="#mimAllelicVariantsFold" id="mimAllelicVariantsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
|
|
</span>
|
|
<strong>12 Selected Examples</a>):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimAllelicVariantsFold" class="collapse in mimTextToggleFold">
|
|
<div>
|
|
<a href="/allelicVariants/603851" class="btn btn-default" role="button"> Table View </a>
|
|
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=603851[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
|
|
|
|
</div>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0001" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CCHS WITH HIRSCHSPRUNG DISEASE, INCLUDED<br />
|
|
CENTRAL HYPOVENTILATION SYNDROME, LATE-ONSET, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PHOX2B, 15- TO 27-BP DUP, ALANINE TRACT EXPANSION, NT721
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006377 OR RCV000006378 OR RCV000006379" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006377, RCV000006378, RCV000006379" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006377...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 16 of 29 patients with congenital central hypoventilation syndrome (CCHS1; <a href="/entry/209880">209880</a>), some of whom also had Hirschsprung disease and ganglioneuroblastoma or neuroblastoma, <a href="#1" class="mim-tip-reference" title="Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simmoneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S. <strong>Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.</strong> Nature Genet. 33: 459-460, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640453</a>] [<a href="https://doi.org/10.1038/ng1130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640453">Amiel et al. (2003)</a> found a triplet expansion of 15 to 27 nucleotides (nucleotides 721-780) of the PHOX2B gene, adding 5 to 9 alanines to the 20-residue polyalanine tract. Most mutant genotypes were different, suggesting that they derived from independent mutational events. The polyalanine triplet expansion was shown to be de novo in cases where parents were available. Two of these patients also carried mutations in RET (P1039L; <a href="/entry/164761#0046">164761.0046</a>) or GDNF (<a href="#0001">603851.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12640453" 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 5 of 9 patients with late-onset central hypoventilation syndrome, <a href="#26" class="mim-tip-reference" title="Trochet, D., O'Brien, L. M., Gozal, D., Trang, H., Nordenskjold, A., Laudier, B., Svensson, P.-J., Uhrig, S., Cole, T., Niemann, S., Munnich, A., Gaultier, C., Lyonnet, S., Amiel, J. <strong>PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.</strong> Am. J. Hum. Genet. 76: 421-426, 2005. Note: Erratum: Am. J. Hum. Genet. 76: 715 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657873</a>] [<a href="https://doi.org/10.1086/428366" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15657873">Trochet et al. (2005)</a> found an expansion of 5 alanines in the PHOX2B polyalanine tract. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15657873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Antic, N. A., Malow, B. A., Lange, N., McEvoy, R. D., Olson, A. L., Turkington, P., Windisch, W., Samuels, M., Stevens, C. A., Berry-Kravis, E. M., Weese-Mayer, D. E. <strong>PHOX2B mutation-confirmed congenital central hypoventilation syndrome: presentation in adulthood.</strong> Am. J. Resp. Crit. Care Med. 174: 923-927, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16873766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16873766</a>] [<a href="https://doi.org/10.1164/rccm.200605-607CR" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16873766">Antic et al. (2006)</a> reported 5 adults with late-onset central hypoventilation syndrome who each had a heterozygous expansion of 5 alanines in the PHOX2B polyalanine tract. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16873766" 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="Arai, H., Otagiri, T., Sasaki, A., Hashimoto, T., Umetsu, K., Tokunaga, K., Hayasaka, K. <strong>De novo polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: unequal sister chromatid exchange during paternal gametogenesis.</strong> J. Hum. Genet. 52: 921-925, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17928950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17928950</a>] [<a href="https://doi.org/10.1007/s10038-007-0197-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17928950">Arai et al. (2007)</a> determined that de novo PHOX2B polyalanine expansions in 6 informative CCHS families resulted from unequal crossover or unequal sister chromatid exchange during spermatogenesis. In contrast to polyglutamine expansions, which usually result from strand slippage, <a href="#3" class="mim-tip-reference" title="Arai, H., Otagiri, T., Sasaki, A., Hashimoto, T., Umetsu, K., Tokunaga, K., Hayasaka, K. <strong>De novo polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: unequal sister chromatid exchange during paternal gametogenesis.</strong> J. Hum. Genet. 52: 921-925, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17928950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17928950</a>] [<a href="https://doi.org/10.1007/s10038-007-0197-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17928950">Arai et al. (2007)</a> suggested that polyalanine expansions probably result from misalignment due to the secondary DNA structure of imperfect trinucleotide repeats (GCA, GCG, GCC, and GCT) that encode polyalanine tracts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17928950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Sivan, Y., Zhou, A., Jennings, L. J., Berry-Kravis, E. M., Yu, M., Zhou, L., Rand, C. M., Weese-Mayer, D. E. <strong>Congenital central hypoventilation syndrome: severe disease caused by co-occurrence of two PHOX2B variants inherited separately from asymptomatic family members.</strong> Am. J. Med. Genet. 179A: 503-506, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30672101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30672101</a>] [<a href="https://doi.org/10.1002/ajmg.a.61047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30672101">Sivan et al. (2019)</a> reported a male infant with CCHS who had compound heterozygous mutations in the PHOX2B gene: a polyalanine repeat expansion (24 alanine repeats) and a c.785G-T transversion in exon 3, resulting in a gly262-to-val (G262V) substitution (<a href="#0012">603851.0012</a>). The polyalanine repeat expansion was seen in the father, paternal grandfather, and 2 out of 5 of the father's sibs, and the missense mutation was seen in the mother, maternal grandfather, and 3 out of 9 of the mother's sibs. All family members, other than the proband, were phenotypically normal. The authors concluded that this was the first reported case of compound heterozygosity for variants in the PHOX2B gene in a proband with CCHS in which neither variant alone was sufficient to cause disease in multiple family members. The authors noted the importance of PHOX2B testing in parents of all probands with CCHS to identify mosaicism in a parent, confirm allele pathogenicity, determine inheritance, and provide information for future pregnancy planning. The authors also suggested sequencing of PHOX2B if a polyalanine repeat expansion has been identified, especially when the phenotype is more severe than expected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30672101" 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>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0002" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PHOX2B, 1-BP INS, 618C
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776626 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776626;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587776626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006380 OR RCV004721243" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006380, RCV004721243" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006380...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with congenital central hypoventilation syndrome (CCHS1; <a href="/entry/209880">209880</a>), <a href="#1" class="mim-tip-reference" title="Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simmoneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S. <strong>Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.</strong> Nature Genet. 33: 459-460, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640453</a>] [<a href="https://doi.org/10.1038/ng1130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640453">Amiel et al. (2003)</a> found a de novo cytosine insertion in a stretch of 4 cytosines, 618_619insC, in the PHO2B gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12640453" 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>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0003" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PHOX2B, 37-BP DEL, NT722
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1733878065 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1733878065;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1733878065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1733878065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006381 OR RCV003151706 OR RCV003415666" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006381, RCV003151706, RCV003415666" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006381...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with congenital central hypoventilation syndrome (CCHS1; <a href="/entry/209880">209880</a>), <a href="#1" class="mim-tip-reference" title="Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simmoneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S. <strong>Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.</strong> Nature Genet. 33: 459-460, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640453</a>] [<a href="https://doi.org/10.1038/ng1130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640453">Amiel et al. (2003)</a> found a deletion of 37 nucleotides (722_759del37) in the PHOX2B gene, resulting in a frameshift downstream of the homeobox. The deletion could be considered an out-of-frame contraction of the polyalanine tract. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12640453" 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>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<a id="0004" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 REMOVED FROM DATABASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0005" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 NEUROBLASTOMA, SUSCEPTIBILITY TO, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PHOX2B, ARG100LEU
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893855 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893855;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104893855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs104893855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006382 OR RCV002227997 OR RCV002433444" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006382, RCV002227997, RCV002433444" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006382...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a familial case of neuroblastoma (<a href="/entry/613013">613013</a>), <a href="#24" class="mim-tip-reference" title="Trochet, D., Bourdeaut, F., Janoueix-Lerosey, I., Deville, A., de Pontual, L., Schleiermacher, G., Coze, C., Philip, N., Frebourg, T., Munnich, A., Lyonnet, S., Delattre, O., Amiel, J. <strong>Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.</strong> Am. J. Hum. Genet. 74: 761-764, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024693</a>] [<a href="https://doi.org/10.1086/383253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024693">Trochet et al. (2004)</a> identified a heterozygous 299G-T transversion in exon 2 of the PHOX2B gene, resulting in an arg100-to-leu (R100L) mutation in the homeodomain of the protein. The proband, a male, was the first child born to nonconsanguineous parents. A multifocal abdominal ganglioneuroma was surgically removed at the age of 10 years. His younger brother presented at age 6 years with an abdominal neuroblastoma which was surgically removed, and experienced local recurrences 18 months and 30 months later. No amplification of MYCN (<a href="/entry/164840">164840</a>) was detected. The father had a ganglioneuroma of the adrenal medulla, which was surgically removed at age 44 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15024693" 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>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0006" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 NEUROBLASTOMA WITH HIRSCHSPRUNG DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PHOX2B, ARG141GLY
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28939716 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28939716;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28939716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28939716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006383" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006383" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006383</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male patient born to nonconsanguineous parents with a combination of Hirschsprung disease (<a href="/entry/142623">142623</a>) and neuroblastoma (see <a href="/entry/613013">613013</a>), <a href="#24" class="mim-tip-reference" title="Trochet, D., Bourdeaut, F., Janoueix-Lerosey, I., Deville, A., de Pontual, L., Schleiermacher, G., Coze, C., Philip, N., Frebourg, T., Munnich, A., Lyonnet, S., Delattre, O., Amiel, J. <strong>Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.</strong> Am. J. Hum. Genet. 74: 761-764, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024693</a>] [<a href="https://doi.org/10.1086/383253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024693">Trochet et al. (2004)</a> identified heterozygosity for a 421C-G transversion in exon 2 of the PHOX2B gene, resulting in an arg141-to-gly (R141G) mutation. HSCR was diagnosed in the neonatal period and was treated surgically, with a good result. Multifocal tumors, both thoracic and abdominal, were found at age 9 months and were surgically removed. No amplification of MYCN (<a href="/entry/164840">164840</a>) was detected. The R141G mutation in this patient was inherited from the healthy mother. Several hypotheses could explain this observation: the tumor may develop in adulthood, the tumor may spontaneously regress (a well-known phenomenon for neuroblastoma), or there may be incomplete penetrance, which is higher for tumor predisposition than for HSCR and has been suspected in neuroblastoma (Maris et al. (<a href="#14" class="mim-tip-reference" title="Maris, J. M., Kyemba, S. M., Rebbeck, T. R., White, P. S., Sulman, E. P., Jensen, S. J., Allen, C., Biegel, J. A., Brodeur, G. M. <strong>Molecular genetic analysis of familial neuroblastoma.</strong> Europ. J. Cancer 33: 1923-1928, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9516825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9516825</a>] [<a href="https://doi.org/10.1016/s0959-8049(97)00265-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9516825">1997</a>, <a href="#15" class="mim-tip-reference" title="Maris, J. M., Weiss, M. J., Mosse, Y., Hii, G., Guo, C., White, P. S., Hogarty, M. D., Mirensky, T., Brodeur, G. M., Rebbeck, T. R., Urbanek, M., Shusterman, S. <strong>Evidence for a hereditary neuroblastoma predisposition locus at chromosome 16p12-13.</strong> Cancer Res. 62: 6651-6658, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12438263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12438263</a>]" pmid="12438263">2002</a>)). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15024693+12438263+9516825" 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>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0007" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 NEUROBLASTOMA WITH HIRSCHSPRUNG DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PHOX2B, 1-BP DEL, 676G
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006384 OR RCV002362567" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006384, RCV002362567" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006384...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family previously described by <a href="#15" class="mim-tip-reference" title="Maris, J. M., Weiss, M. J., Mosse, Y., Hii, G., Guo, C., White, P. S., Hogarty, M. D., Mirensky, T., Brodeur, G. M., Rebbeck, T. R., Urbanek, M., Shusterman, S. <strong>Evidence for a hereditary neuroblastoma predisposition locus at chromosome 16p12-13.</strong> Cancer Res. 62: 6651-6658, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12438263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12438263</a>]" pmid="12438263">Maris et al. (2002)</a> in which 7 members spanning 3 generations had neuroblastoma (<a href="/entry/613013">613013</a>), 2 of whom also had Hirschsprung disease (<a href="/entry/142623">142623</a>), <a href="#18" class="mim-tip-reference" title="Mosse, Y. P., Laudenslager, M., Khazi, D., Carlisle, A. J., Winter, C. L., Rappaport, E., Maris, J. M. <strong>Germline PHOX2B mutation in hereditary neuroblastoma. (Letter)</strong> Am. J. Hum. Genet. 75: 727-730, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15338462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15338462</a>] [<a href="https://doi.org/10.1086/424530" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15338462">Mosse et al. (2004)</a> identified a heterozygous 1-bp deletion in the PHOX2B gene, 676delG, resulting in a frameshift and a slightly truncated protein lacking the second polyalanine tract. The mutation segregated with neuroblastoma through all 3 generations. The family had previously been shown to cosegregate a 16p13-p12 haplotype with neuroblastoma. The proband, who was affected with neuroblastoma, Hirschsprung disease, and neurofibromatosis type I (<a href="/entry/162200">162200</a>), had previously been shown to have an inactivating mutation in the NF1 gene, 3775delT (<a href="/entry/613113#0037">613113.0037</a>), which was not present in either parent. <a href="#18" class="mim-tip-reference" title="Mosse, Y. P., Laudenslager, M., Khazi, D., Carlisle, A. J., Winter, C. L., Rappaport, E., Maris, J. M. <strong>Germline PHOX2B mutation in hereditary neuroblastoma. (Letter)</strong> Am. J. Hum. Genet. 75: 727-730, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15338462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15338462</a>] [<a href="https://doi.org/10.1086/424530" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15338462">Mosse et al. (2004)</a> concluded that the presence of 2 germline mutations in the proband, as well as evidence of linkage to 16p in the family, suggested an oligogenic mechanism for neuroblastoma initiation, as had been shown for other diseases of neural crest-derived tissues (<a href="#9" class="mim-tip-reference" title="Gabriel, S. B., Salomon, R., Pelet, A., Angrist, M., Amiel, J., Fornage, M., Attie-Bitach, T., Olson, J. M., Hofstra, R., Buys, C., Steffann, J., Munnich, A., Lyonnet, S., Chakravarti, A. <strong>Segregation at three loci explains familial and population risk in Hirschsprung disease.</strong> Nature Genet. 31: 89-93, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11953745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11953745</a>] [<a href="https://doi.org/10.1038/ng868" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11953745">Gabriel et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11953745+12438263+15338462" 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>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0008" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 NEUROBLASTOMA, SUSCEPTIBILITY TO, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PHOX2B, GLY197ASP
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893856 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893856;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104893856" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs104893856" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006385 OR RCV002354150" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006385, RCV002354150" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006385...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a family with neuroblastoma (<a href="/entry/613013">613013</a>), <a href="#17" class="mim-tip-reference" title="McConville, C., Reid, S., Baskcomb, L., Douglas, J., Rahman, N. <strong>PHOX2B analysis in non-syndromic neuroblastoma cases shows novel mutations and genotype-phenotype associations.</strong> Am. J. Med. Genet. 140A: 1297-1301, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16691592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16691592</a>] [<a href="https://doi.org/10.1002/ajmg.a.31278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16691592">McConville et al. (2006)</a> identified a constitutional heterozygous 590G-A transition in the PHOX2B gene, resulting in a gly197-to-asp (G197D) substitution in a conserved residue outside of the homeodomain. No tumor DNA was available. The index case, from whom no DNA was available, died at age 5 years with metastatic neuroblastoma and ganglioneuroblastoma. Her father and paternal grandmother, both of whom had the G197D mutation, had adult-onset ganglioneuroblastoma. Another paternal relative, from whom DNA was not available, died at age 14 years from ganglioneuroblastoma. Two unaffected sibs of the index patient's grandmother also carried the mutation, indicating incomplete penetrance. None of the family members had Hirschsprung disease (<a href="/entry/142623">142623</a>) or any features of autonomic dysfunction. The mutation was not identified in 284 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16691592" 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>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0009" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PHOX2B, ARG141GLN
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1733941453 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1733941453;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1733941453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1733941453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001078156 OR RCV002327374 OR RCV003517297" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001078156, RCV002327374, RCV003517297" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001078156...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a white female (P005) with congenital central hypoventilation syndrome (CCHS1; <a href="/entry/209880">209880</a>) and an adrenal ganglioneuroma, but no evidence of Hirschsprung disease, <a href="#13" class="mim-tip-reference" title="Lombardo, R. C., Porollo, A., Cnota, J. F., Hopkin, R. J. <strong>Congenital heart disease and aortic arch variants associated with mutations in PHOX2B.</strong> Genet. Med. 20: 1538-1543, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29543228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29543228</a>] [<a href="https://doi.org/10.1038/gim.2018.34" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29543228">Lombardo et al. (2018)</a> identified a c.422G-A transition in exon 2 of the PHOX2B gene that resulted in an arginine-to-glutamine substitution at codon 141 (R141Q) in the homeobox domain of the protein. This patient had separate origin of the left vertebral artery off the aortic arch. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29543228" 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="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 04/12/2020."None>Hamosh (2020)</a> noted that the R141Q variant was absent from the gnomAD database on April 12, 2020.</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0010" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PHOX2B, ARG149LEU
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1733899167 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1733899167;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1733899167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1733899167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001078157 OR RCV004031214" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001078157, RCV004031214" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001078157...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an African American female (P003) with central hypoventilation syndrome (CCHS1; <a href="/entry/209880">209880</a>), <a href="#13" class="mim-tip-reference" title="Lombardo, R. C., Porollo, A., Cnota, J. F., Hopkin, R. J. <strong>Congenital heart disease and aortic arch variants associated with mutations in PHOX2B.</strong> Genet. Med. 20: 1538-1543, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29543228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29543228</a>] [<a href="https://doi.org/10.1038/gim.2018.34" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29543228">Lombardo et al. (2018)</a> identified a c.446G-T transversion in exon 3 of the PHOX2B gene, resulting in an arginine-to-leucine substitution at codon 149 (R149L) in the homeobox domain of the protein. This patient also had moderate secundum atrial septal defect (ASD) and a patent ductus arteriosus (PDA) that required surgical closure at age 5 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29543228" 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="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 04/12/2020."None>Hamosh (2020)</a> noted that the A149L variant was absent from the gnomAD database on April 12, 2020.</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0011" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CCHS WITH HIRSCHSPRUNG DISEASE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PHOX2B, TYR78TER
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs73810366 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs73810366;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs73810366?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs73810366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs73810366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001078158 OR RCV001078159 OR RCV002445374" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001078158, RCV001078159, RCV002445374" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001078158...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated African American females (P008 and P018) with central hypoventilation syndrome (CCHS1; <a href="/entry/209880">209880</a>), 1 of whom had Hirschsprung disease, <a href="#13" class="mim-tip-reference" title="Lombardo, R. C., Porollo, A., Cnota, J. F., Hopkin, R. J. <strong>Congenital heart disease and aortic arch variants associated with mutations in PHOX2B.</strong> Genet. Med. 20: 1538-1543, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29543228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29543228</a>] [<a href="https://doi.org/10.1038/gim.2018.34" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29543228">Lombardo et al. (2018)</a> identified a c.234C-G transversion in exon 1 of the PHOX2B gene that resulted in a tyrosine-to-termination substitution at amino acid 78 (Y78X). Both of these patients also had congenital heart disease (CHD). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29543228" 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="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 04/12/2020."None>Hamosh (2020)</a> noted that the Y78X variant was absent from the gnomAD database on April 12, 2020.</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0012" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PHOX2B, GLY262VAL
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs768420488 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs768420488;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs768420488?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs768420488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs768420488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000526554 OR RCV000561955 OR RCV001312215 OR RCV004592580" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000526554, RCV000561955, RCV001312215, RCV004592580" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000526554...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.785G-T transversion in exon 3 of the PHOX2B gene, resulting in a gly262-to-val (G262V) substitution, that was found in compound heterozygous state in a proband with congenital central hypoventilation syndrome (CCHS1; <a href="/entry/209880">209880</a>) by <a href="#22" class="mim-tip-reference" title="Sivan, Y., Zhou, A., Jennings, L. J., Berry-Kravis, E. M., Yu, M., Zhou, L., Rand, C. M., Weese-Mayer, D. E. <strong>Congenital central hypoventilation syndrome: severe disease caused by co-occurrence of two PHOX2B variants inherited separately from asymptomatic family members.</strong> Am. J. Med. Genet. 179A: 503-506, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30672101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30672101</a>] [<a href="https://doi.org/10.1002/ajmg.a.61047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30672101">Sivan et al. (2019)</a>, see <a href="#0001">603851.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30672101" 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>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="references"class="mim-anchor"></a>
|
|
<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span class="mim-font">
|
|
<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
|
|
<ol>
|
|
|
|
<li>
|
|
<a id="1" class="mim-anchor"></a>
|
|
<a id="Amiel2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simmoneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S.
|
|
<strong>Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.</strong>
|
|
Nature Genet. 33: 459-460, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640453</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12640453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ng1130" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="2" class="mim-anchor"></a>
|
|
<a id="Antic2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Antic, N. A., Malow, B. A., Lange, N., McEvoy, R. D., Olson, A. L., Turkington, P., Windisch, W., Samuels, M., Stevens, C. A., Berry-Kravis, E. M., Weese-Mayer, D. E.
|
|
<strong>PHOX2B mutation-confirmed congenital central hypoventilation syndrome: presentation in adulthood.</strong>
|
|
Am. J. Resp. Crit. Care Med. 174: 923-927, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16873766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16873766</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16873766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1164/rccm.200605-607CR" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="3" class="mim-anchor"></a>
|
|
<a id="Arai2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Arai, H., Otagiri, T., Sasaki, A., Hashimoto, T., Umetsu, K., Tokunaga, K., Hayasaka, K.
|
|
<strong>De novo polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: unequal sister chromatid exchange during paternal gametogenesis.</strong>
|
|
J. Hum. Genet. 52: 921-925, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17928950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17928950</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17928950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/s10038-007-0197-3" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="4" class="mim-anchor"></a>
|
|
<a id="Bachetti2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Bachetti, T., Matera, I., Borghini, S., Di Duca, M., Ravazzolo, R., Ceccherini, I.
|
|
<strong>Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome.</strong>
|
|
Hum. Molec. Genet. 14: 1815-1824, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15888479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15888479</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15888479" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddi188" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="5" class="mim-anchor"></a>
|
|
<a id="Benailly2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Benailly, H. K., Lapierre, J. M., Laudier, B., Amiel, J., Attie, T., De Blois, M. C., Vekemans, M., Romana, S. P.
|
|
<strong>PMX2B, a new candidate gene for Hirschsprung's disease.</strong>
|
|
Clin. Genet. 64: 204-209, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12919134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12919134</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12919134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1034/j.1399-0004.2003.00105.x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="6" class="mim-anchor"></a>
|
|
<a id="Cross2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Cross, S. H., Morgan, J. E., Pattyn, A., West, K., McKie, L., Hart, A., Thuang, C., Brunet, J.-F., Jackson, I. J.
|
|
<strong>Haploinsufficiency for Phox2b in mice causes dilated pupils and atrophy of the ciliary ganglion: mechanistic insights into human congenital central hypoventilation syndrome.</strong>
|
|
Hum. Molec. Genet. 13: 1433-1439, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15150159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15150159</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15150159" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddh156" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="7" class="mim-anchor"></a>
|
|
<a id="Dubreuil2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Dubreuil, V, Ramanantsoa, N., Trochet, D., Vaubourg, V., Amiel, J., Gallego, J., Brunet, J.-F., Goridis, C.
|
|
<strong>A human mutation in Phox2b causes lack of CO2 chemosensitivity, fatal central apnea, and specific loss of parafacial neurons.</strong>
|
|
Proc. Nat. Acad. Sci. 105: 1067-1072, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18198276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18198276</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18198276[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=18198276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1073/pnas.0709115105" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="8" class="mim-anchor"></a>
|
|
<a id="Espinosa-Medina2014" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Espinosa-Medina, I., Outin, E., Picard, C. A., Chettouh, Z., Dymecki, S., Consalez, G. G., Coppola, E., Brunet, J.-F.
|
|
<strong>Parasympathetic ganglia derive from Schwann cell precursors.</strong>
|
|
Science 345: 87-90, 2014.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24925912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24925912</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24925912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1253286" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="9" class="mim-anchor"></a>
|
|
<a id="Gabriel2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gabriel, S. B., Salomon, R., Pelet, A., Angrist, M., Amiel, J., Fornage, M., Attie-Bitach, T., Olson, J. M., Hofstra, R., Buys, C., Steffann, J., Munnich, A., Lyonnet, S., Chakravarti, A.
|
|
<strong>Segregation at three loci explains familial and population risk in Hirschsprung disease.</strong>
|
|
Nature Genet. 31: 89-93, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11953745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11953745</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11953745" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ng868" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="10" class="mim-anchor"></a>
|
|
<a id="Guzoglu2020" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Guzoglu, N., Aslan, M. K., Gunay, Y. D., Atasoy, P. Ceylaner, S., Aliefendioglu, D.
|
|
<strong>A novel mutation which causes a frameshift in the PHOX2B gene causes Haddad syndrome.</strong>
|
|
Clin. Dysmorph. 29: 152-154, 2020.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32073407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32073407</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32073407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1097/MCD.0000000000000317" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="11" class="mim-anchor"></a>
|
|
<a id="Hamosh2020" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hamosh, A.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 04/12/2020.
|
|
|
|
|
|
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Katz2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Katz, E. S., McGrath, S., Marcus, C. L.
|
|
<strong>Late-onset central hypoventilation with hypothalamic dysfunction: a distinct clinical syndrome.</strong>
|
|
Pediat. Pulmonol. 29: 62-68, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10613788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10613788</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10613788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/(sici)1099-0496(200001)29:1<62::aid-ppul10>3.0.co;2-m" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="13" class="mim-anchor"></a>
|
|
<a id="Lombardo2018" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lombardo, R. C., Porollo, A., Cnota, J. F., Hopkin, R. J.
|
|
<strong>Congenital heart disease and aortic arch variants associated with mutations in PHOX2B.</strong>
|
|
Genet. Med. 20: 1538-1543, 2018.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29543228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29543228</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29543228" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/gim.2018.34" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="14" class="mim-anchor"></a>
|
|
<a id="Maris1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Maris, J. M., Kyemba, S. M., Rebbeck, T. R., White, P. S., Sulman, E. P., Jensen, S. J., Allen, C., Biegel, J. A., Brodeur, G. M.
|
|
<strong>Molecular genetic analysis of familial neuroblastoma.</strong>
|
|
Europ. J. Cancer 33: 1923-1928, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9516825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9516825</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9516825" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s0959-8049(97)00265-7" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="15" class="mim-anchor"></a>
|
|
<a id="Maris2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Maris, J. M., Weiss, M. J., Mosse, Y., Hii, G., Guo, C., White, P. S., Hogarty, M. D., Mirensky, T., Brodeur, G. M., Rebbeck, T. R., Urbanek, M., Shusterman, S.
|
|
<strong>Evidence for a hereditary neuroblastoma predisposition locus at chromosome 16p12-13.</strong>
|
|
Cancer Res. 62: 6651-6658, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12438263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12438263</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12438263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="16" class="mim-anchor"></a>
|
|
<a id="Matera2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Matera, I., Bachetti, T., Puppo, F., Di Duca, M., Morandi, F., Casiraghi, G. M., Cilio, M. R., Hennekam, R., Hofstra, R., Schober, J. G., Ravazzolo, R., Ottonello, G., Ceccherini, I.
|
|
<strong>PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset central hypoventilation syndrome. (Letter)</strong>
|
|
J. Med. Genet. 41: 373-380, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15121777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15121777</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15121777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1136/jmg.2003.015412" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="17" class="mim-anchor"></a>
|
|
<a id="McConville2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
McConville, C., Reid, S., Baskcomb, L., Douglas, J., Rahman, N.
|
|
<strong>PHOX2B analysis in non-syndromic neuroblastoma cases shows novel mutations and genotype-phenotype associations.</strong>
|
|
Am. J. Med. Genet. 140A: 1297-1301, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16691592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16691592</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16691592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ajmg.a.31278" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="18" class="mim-anchor"></a>
|
|
<a id="Mosse2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Mosse, Y. P., Laudenslager, M., Khazi, D., Carlisle, A. J., Winter, C. L., Rappaport, E., Maris, J. M.
|
|
<strong>Germline PHOX2B mutation in hereditary neuroblastoma. (Letter)</strong>
|
|
Am. J. Hum. Genet. 75: 727-730, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15338462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15338462</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15338462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1086/424530" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="19" class="mim-anchor"></a>
|
|
<a id="Pattyn1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Pattyn, A., Morin, X., Cremer, H., Goridis, C., Brunet, J.-F.
|
|
<strong>Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis.</strong>
|
|
Development 124: 4065-4075, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9374403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9374403</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9374403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1242/dev.124.20.4065" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="20" class="mim-anchor"></a>
|
|
<a id="Pattyn1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Pattyn, A., Morin, X., Cremer, H., Goridis, C., Brunet, J.-F.
|
|
<strong>The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives.</strong>
|
|
Nature 399: 366-370, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10360575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10360575</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10360575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/20700" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="21" class="mim-anchor"></a>
|
|
<a id="Sasaki2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sasaki, A., Kanai, M., Kijima, K., Akaba, K., Hashimoto, M., Hasegawa, H., Otaki, S., Koizumi, T., Kusuda, S., Ogawa, Y., Tuchiya, K., Yamamoto, W., Nakamura, T., Hayasaka, K.
|
|
<strong>Molecular analysis of congenital central hypoventilation syndrome.</strong>
|
|
Hum. Genet. 114: 22-26, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14566559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14566559</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14566559" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/s00439-003-1036-z" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="22" class="mim-anchor"></a>
|
|
<a id="Sivan2019" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sivan, Y., Zhou, A., Jennings, L. J., Berry-Kravis, E. M., Yu, M., Zhou, L., Rand, C. M., Weese-Mayer, D. E.
|
|
<strong>Congenital central hypoventilation syndrome: severe disease caused by co-occurrence of two PHOX2B variants inherited separately from asymptomatic family members.</strong>
|
|
Am. J. Med. Genet. 179A: 503-506, 2019.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30672101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30672101</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30672101" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ajmg.a.61047" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="23" class="mim-anchor"></a>
|
|
<a id="Toyota2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Toyota, T., Yoshitsugu, K., Ebihara, M., Yamada, K., Ohba, H., Fukasawa, M., Minabe, Y., Nakamura, K., Sekine, Y., Takei, N., Suzuki, K., Itokawa, M., Meerabux, J. M. A., Iwayama-Shigeno, Y., Tomaru, Y., Shimizu, H., Hattori, E., Mori, N., Yoshikawa, T.
|
|
<strong>Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B.</strong>
|
|
Hum. Molec. Genet. 13: 551-561, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14709596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14709596</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14709596" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddh047" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="24" class="mim-anchor"></a>
|
|
<a id="Trochet2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Trochet, D., Bourdeaut, F., Janoueix-Lerosey, I., Deville, A., de Pontual, L., Schleiermacher, G., Coze, C., Philip, N., Frebourg, T., Munnich, A., Lyonnet, S., Delattre, O., Amiel, J.
|
|
<strong>Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.</strong>
|
|
Am. J. Hum. Genet. 74: 761-764, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024693</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15024693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1086/383253" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="25" class="mim-anchor"></a>
|
|
<a id="Trochet2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Trochet, D., Hong, S. J., Lim, J. K., Brunet, J.-F., Munnich, A., Kim, K.-S., Lyonnet, S., Goridis, C., Amiel, J.
|
|
<strong>Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction.</strong>
|
|
Hum. Molec. Genet. 14: 3697-3708, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16249188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16249188</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16249188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddi401" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="26" class="mim-anchor"></a>
|
|
<a id="Trochet2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Trochet, D., O'Brien, L. M., Gozal, D., Trang, H., Nordenskjold, A., Laudier, B., Svensson, P.-J., Uhrig, S., Cole, T., Niemann, S., Munnich, A., Gaultier, C., Lyonnet, S., Amiel, J.
|
|
<strong>PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.</strong>
|
|
Am. J. Hum. Genet. 76: 421-426, 2005. Note: Erratum: Am. J. Hum. Genet. 76: 715 only, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657873</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15657873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1086/428366" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="27" class="mim-anchor"></a>
|
|
<a id="Warren1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Warren, S. T.
|
|
<strong>Polyalanine expansion in synpolydactyly might result from unequal crossing-over of HOXD13.</strong>
|
|
Science 275: 408-409, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9005557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9005557</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9005557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.275.5298.408" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="28" class="mim-anchor"></a>
|
|
<a id="Weese-Mayer2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Weese-Mayer, D. E., Berry-Kravis, E. M., Zhou, L., Maher, B. S., Silvestri, J. M., Curran, M. E., Marazita, M. L.
|
|
<strong>Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b.</strong>
|
|
Am. J. Med. Genet. 123A: 267-278, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14608649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14608649</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14608649" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ajmg.a.20527" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="29" class="mim-anchor"></a>
|
|
<a id="Yokoyama1996" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Yokoyama, M., Nishi, Y., Yoshii, J., Okubo, K., Matsubara, K.
|
|
<strong>Identification and cloning of neuroblastoma-specific and nerve tissue-specific genes through compiled expression profiles.</strong>
|
|
DNA Res. 3: 311-320, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039501</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9039501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/dnares/3.5.311" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="contributors" class="mim-anchor"></a>
|
|
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="mim-text-font">
|
|
<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Cassandra L. Kniffin - updated : 08/25/2021
|
|
</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseContributors">
|
|
<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">
|
|
<span class="mim-text-font">
|
|
Sonja A. Rasmussen - updated : 09/15/2020<br>Hilary J. Vernon - updated : 09/14/2020<br>Ada Hamosh - updated : 04/16/2020<br>Ada Hamosh - updated : 8/6/2014<br>George E. Tiller - updated : 4/23/2009<br>George E. Tiller - updated : 10/28/2008<br>Cassandra L. Kniffin - updated : 5/27/2008<br>Cassandra L. Kniffin - updated : 2/5/2008<br>Cassandra L. Kniffin - updated : 12/28/2007<br>George E. Tiller - updated : 11/28/2006<br>George E. Tiller - updated : 9/21/2006<br>Cassandra L. Kniffin - updated : 8/2/2006<br>Victor A. McKusick - updated : 2/9/2005<br>Victor A. McKusick - updated : 9/14/2004<br>Marla J. F. O'Neill - updated : 6/11/2004<br>Victor A. McKusick - updated : 4/8/2004<br>Victor A. McKusick - updated : 1/5/2004<br>Victor A. McKusick - updated : 12/9/2003<br>Victor A. McKusick - updated : 10/16/2003<br>Victor A. McKusick - updated : 3/18/2003
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="creationDate" class="mim-anchor"></a>
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Ada Hamosh : 5/26/1999
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="editHistory" class="mim-anchor"></a>
|
|
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 02/13/2024
|
|
</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseEditHistory">
|
|
<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">
|
|
<span class="mim-text-font">
|
|
carol : 02/12/2024<br>carol : 08/26/2021<br>carol : 08/25/2021<br>carol : 09/16/2020<br>carol : 09/15/2020<br>carol : 09/14/2020<br>alopez : 04/16/2020<br>carol : 11/08/2019<br>carol : 02/20/2018<br>carol : 03/27/2015<br>carol : 8/7/2014<br>alopez : 8/6/2014<br>carol : 3/19/2014<br>terry : 7/6/2012<br>joanna : 11/23/2009<br>carol : 9/21/2009<br>ckniffin : 9/18/2009<br>wwang : 6/30/2009<br>terry : 4/23/2009<br>alopez : 12/5/2008<br>carol : 11/4/2008<br>wwang : 10/28/2008<br>wwang : 5/29/2008<br>ckniffin : 5/27/2008<br>wwang : 3/6/2008<br>ckniffin : 2/5/2008<br>wwang : 1/22/2008<br>ckniffin : 12/28/2007<br>alopez : 7/6/2007<br>carol : 11/28/2006<br>alopez : 9/21/2006<br>wwang : 8/3/2006<br>ckniffin : 8/2/2006<br>alopez : 2/17/2005<br>terry : 2/9/2005<br>tkritzer : 1/20/2005<br>carol : 11/1/2004<br>tkritzer : 9/16/2004<br>terry : 9/14/2004<br>carol : 6/14/2004<br>terry : 6/11/2004<br>tkritzer : 4/26/2004<br>tkritzer : 4/15/2004<br>terry : 4/8/2004<br>terry : 3/19/2004<br>terry : 3/18/2004<br>carol : 1/13/2004<br>cwells : 1/5/2004<br>tkritzer : 12/11/2003<br>terry : 12/9/2003<br>alopez : 11/14/2003<br>cwells : 10/20/2003<br>terry : 10/16/2003<br>alopez : 4/2/2003<br>alopez : 3/18/2003<br>terry : 3/18/2003<br>alopez : 5/27/1999<br>alopez : 5/26/1999
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div class="container visible-print-block">
|
|
|
|
<div class="row">
|
|
|
|
|
|
|
|
<div class="col-md-8 col-md-offset-1">
|
|
|
|
<div>
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 603851
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
PAIRED-LIKE HOMEOBOX 2B; PHOX2B
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div >
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
PAIRED MESODERM HOMEOBOX 2B; PMX2B<br />
|
|
NEUROBLASTOMA PAIRED-TYPE HOMEOBOX GENE; NBPHOX
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: PHOX2B</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 719972004;
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 4p13
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 4:41,744,082-41,748,725 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed 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>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
4p13
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Neuroblastoma, susceptibility to, 2}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613013
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
209880
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Neuroblastoma with Hirschsprung disease
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613013
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Yokoyama et al. (1996) identified the PHOX2B gene, which they called NBPhox for 'neuroblastoma phox,' from a 3-prime-directed cDNA library derived from the human neuroblastoma cell line CHP134. PHOX2B has an mRNA of 3,074 nucleotides and contains an open reading frame of 314 amino acids spanning nucleotides 361 to 1,302. The polyadenylation signal AATAAA is located 17 bases upstream from the site of polyadenylation. The gene encodes a protein with a homeodomain that is significantly homologous with those in various members of the paired-type homeobox genes. The amino acid sequences of the homeodomains of PHOX2B and PHOX2A (602753) cover 60 amino acids and are identical, but outside the homeodomain no significant sequence similarity was observed. A proline-rich domain lies between amino acids 192 and 284 of the PHOX2B protein, and a glycine-rich domain lies between amino acids 196 and 289. There are 2 alanine-rich repeats in the C terminus of the homeodomain. </p><p>Pattyn et al. (1997) cloned the mouse Phox2b gene. The homeodomains of mouse Phox2a and Phox2b are identical. The N-terminal domains of mouse Phox2a and Phox2b are 57% identical, but the C-terminal domains are highly divergent. The murine Phox2b gene also contains 2 alanine stretches in the C terminus. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Pattyn et al. (1997) studied the expression pattern of Phox2b. In embryonic day 9 brains, 2 ventral columns of Phox2b-positive cells ran on either side of the floor plate from an abrupt rostral limit just anterior to the rhombomere1/rhombomere2 boundary into the cervical spinal cord. One day later the ventral column was still strongly labeled. Two ventral patches on both sides of the met-mesencephalic border could be identified at later stages as, respectively, the forming trochlear and oculomotor nuclei. By embryonic day 11.5, the ventral columns had disappeared, whereas the dorsal column contained many more Phox2b-positive cells. In the neonatal brain, Phox2b expression was similar to that of Phox2a. No expression was seen in the spinal cord. In the peripheral nervous system, Phox2b, like Phox2a, was expressed in 3 cranial sensory ganglia and in all ganglia of the autonomic nervous system as early as they had formed, and at least up to midgestation. Although the list of Phox2b expression sites was strikingly similar to that reported for Phox2a, Pattyn et al. (1997) observed systematic differences in onset, persistence, and extent of expression. The expression pattern of Phox2b in Phox2a-null mice indicated that Phox2a regulates Phox2b directly or indirectly in cranial ganglia. </p><p>Amiel et al. (2003) showed that PHOX2B is expressed in both the central and the peripheral autonomic nervous system during human embryonic development. </p><p>Espinosa-Medina et al. (2014) studied how parasympathetic ganglia form close to visceral organs as well as what their precursors are and found that many cranial nerve-associated crest cells coexpress the panautonomic determinant PHOX2B together with markers of Schwann cell precursors. Some give rise to Schwann cells after downregulation of PHOX2B. Others form parasympathetic ganglia after being guided to the site of ganglion formation by the nerves that carry preganglionic fibers, a parsimonious way of wiring the pathway. Espinosa-Medina et al. (2014) concluded that cranial Schwann cell precursors are the source of parasympathetic neurons during normal development. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Amiel et al. (2003) stated that the PHOX2B gene maps to chromosome 4p12. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Congenital Central Hypoventilation Syndrome 1</em></strong></p><p>
|
|
Because in mice the development of reflex circuits of the autonomic nervous system is dependent on the Phox2b gene, Amiel et al. (2003) investigated its human ortholog, PHOX2B, in 29 individuals with congenital central hypoventilation syndrome (CCHS1; 209880). This syndrome is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. The core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system including Hirschsprung disease and tumors of neural crest derivatives such as ganglioneuromas and neuroblastomas. Amiel et al. (2003) found that 18 of the 29 patients had heterozygous de novo mutations in PHOX2B. Most mutations consisted of 5-9 alanine expansions within a 20-residue polyalanine tract (603851.0001) probably resulting from nonhomologous recombination. In 2 CCHS cases, a de novo cytosine insertion in a stretch of 4 cytosines (603851.0002) and a deletion of 37 nucleotides (603851.0003) resulted in a frameshift downstream of the homeobox, predicting a mutant protein with no known function or homology. Amiel et al. (2003) found 2 individuals who in addition to polyalanine expansions in PHOX2B had heterozygous variants in genes involved in the same developmental pathway; these variants were amino acid substitutions pro1039 to leu in RET (164761.0046) and arg93 to trp in GDNF (600837.0001), respectively. Phox2 genes control Ret expression in both sympathetic and enteric neurons in mice. Unlike the polyalanine expansions, however, these variants are neither necessary (most individuals with CCHS do not have any RET or GDNF gene variant) nor sufficient for the disease to occur (carrier parents have no phenotypic expression). Amiel et al. (2003) concluded that PHOX2B is a primary disease locus in CCHS. They found mutations in PHOX2B not only in isolated cases of CCHS but also in individuals with a more complex neural crest involvement including CCHS and Hirschsprung disease (Haddad syndrome) as well as early-onset neuroblastoma. They found no correlation between the size of the polyalanine tract and the complexity of the disease. </p><p>Sasaki et al. (2003) studied 7 patients with isolated CCHS and 3 CCHS patients with Hirschsprung disease. In 4 patients they detected polyalanine expansions in the PHOX2B gene and in 1 patient a novel frameshift mutation in PHOX2B. They could not reject the possibility that mutations in the RET (164761), GDNF, PHOX2A, and HASH1 (100790) genes may also be involved in the pathogenesis of CCHS. </p><p>In 65 of 67 CCHS probands (97%), Weese-Mayer et al. (2003) found heterozygosity for the exon 3 polyalanine expansion mutation in PHOX2B. There was an association between repeat mutation length and severity of the CCHS/ANSD (autonomic nervous system dysregulation and/or dysfunction) phenotype. Of the 2 probands who did not carry the expansion mutation, one had a nonsense mutation in exon 3 that truncated the protein and the other had no mutation in PHOX2B but had a previously reported EDN3 frameshift point mutation. </p><p>Matera et al. (2004) screened the PHOX2B gene in 27 patients with CCHS, including 3 with associated Hirschsprung disease and 3 with late-onset CCHS, and identified 3 heterozygous frameshift mutations and 22 polyalanine expansions ranging from 5 to 13 residues. The authors noted that phenotype severity increased with increasing polyalanine expansion size. Polyalanine triplet expansions were also detected in the affected sibs of 2 familial cases and in 2 asymptomatic parents. </p><p>Trochet et al. (2005) reported the clinical and molecular assessments of a cohort of 188 probands with CCHS, either isolated or associated with Hirschsprung disease (the association known as Haddad syndrome) and/or tumors of the sympathetic nervous system (TSNS). A heterozygous mutation of the PHOX2B gene was identified in 174 of the 188 cases (92.6%). In 161 (92.5%) of the 174 cases with an identifiable mutation, the mutation consisted of an in-frame duplication of 15 to 39 nucleotides, leading to an expansion of +5 to +13 alanines within the 20-alanine tract of the carboxy terminal of the homeodomain of the protein. Vertical transmission of an alanine expansion (+5 and +7 alanines) from an affected parent to his or her affected child was demonstrated in 2 cases. In a third familial case, with recurrence in sibs, Trochet et al. (2005) detected paternal somatic mosaicism for the mutation that was identified in the index case (+7 alanines). Somatic mosaicism was detected in 10 cases (6 fathers and 4 mothers). In all cases, the nucleotide in-frame duplication leading to an alanine expansion remained unchanged in transmission, suggesting that such polyalanine expansions are both meiotically and mitotically stable. These data argued for unequal allelic homologous recombination as the mutation-causing mechanism, as proposed by Warren (1997) for the alanine expansion in the HOXD13 gene (142989) resulting in synpolydactyly (186000). In 5 of 9 patients with late-onset central hypoventilation syndrome, as described by Katz et al. (2000), Trochet et al. (2005) found an expansion of +5 alanines in the PHOX2B gene (603851.0001). From genotype-phenotype correlations, Trochet et al. (2005) came to the conclusion that patients with CCHS who develop malignant tumors of the sympathetic nervous system harbor either a missense (e.g., 603851.0005) or frameshift heterozygous mutation of the PHOX2B gene. </p><p>Bachetti et al. (2005) tested the transcriptional activity of wildtype and mutant PHOX2B expression constructs on the regulatory regions of 2 target genes, DBH (609312) and PHOX2A (ARIX; 602753). Two sets of mutations played different roles in transcriptional regulation of these genes, showing a correlation between length of polyalanine expansions and severity of reduced transcriptional activity. In particular, although reduced transactivation due to polyalanine expansions may be caused by retention of the mutated protein in the cytoplasm or in the nuclear aggregates, frameshift mutations did not impair PHOX2B nuclear localization, suggesting a different mechanism through which frameshift mutations exert the observed effects on target promoters. Moreover, a 614delC deletion seemed to cause sequestration of the corresponding mutant PHOX2B in the nucleolar compartment. </p><p>Trochet et al. (2005) investigated aggregate formation by proteins with polyalanine tract expansions ranging from +5 to +13 alanines using immunofluorescence of transfected cells and gel filtration of in vitro translated proteins. Transactivation of the dopamine beta-hydroxylase promoter by PHOX2B proteins with frameshift and missense mutations was abolished or severely curtailed, as was in vitro DNA binding, although the proteins localized to the nucleus. The transactivation potential of proteins with polyalanine tract expansions declined with increasing length of the polyalanine stretch, and DNA binding was affected for an expansion of +9 alanines and above. Cytoplasmic aggregation in transfected cells was only observed for the longest expansions, whereas even the short expansion mutants were prone to form multimers in vitro. Trochet et al. (2005) proposed that such a tendency to protein misfolding could explain loss of transactivation for alanine expansion mutations. </p><p>Lombardo et al. (2018) reported 6 patients with CCHS who had cardiac anomalies. Only 1 had an expansion of the polyalanine tract (603851.0001), and this patient required tracheostomy with continuous mechanical ventilation and had Hirschsprung disease. One had a whole-gene deletion. Two patients had missense mutations involving the homeobox domain (R141Q, 603851.0009; R149L, 603851.0010). Two had a recurrent premature termination codon (Y78X; 603851.0011). </p><p>Sivan et al. (2019) reported a male infant with CCHS who had compound heterozygous mutations in the PHOX2B gene: a polyalanine repeat expansion (24 alanine repeats; 603851.0001) and a missense mutation (G262V; 603851.0012). The polyalanine repeat expansion was seen in the father, paternal grandfather, and 2 out of 5 of the father's sibs, and the missense mutation was seen in the mother, maternal grandfather, and 3 out of 9 of the mother's sibs. All family members, other than the proband, were phenotypically normal. The authors concluded that this was the first reported case of compound heterozygosity for variants in the PHOX2B gene in a proband with CCHS in which neither variant alone was sufficient to cause disease in multiple family members. The authors noted the importance of PHOX2B testing in parents of all probands with CCHS to identify mosaicism in a parent, confirm allele pathogenicity, determine inheritance, and provide information for future pregnancy planning. The authors also suggested sequencing of PHOX2B if a polyalanine repeat expansion has been identified, especially when the phenotype is more severe than expected. </p><p>In a male infant with CCHS and Haddad Syndrome, Guzoglu et al. (2020) identified a c.722_759del38 deletion in the PHOX2B gene within a polyalanine tract (see 603851.0003). The mutation was identified by direct gene sequencing. </p><p><strong><em>Susceptibility to Neuroblastoma 2</em></strong></p><p>
|
|
Trochet et al. (2004) noted that rare familial cases of neuroblastoma (NBLST2; 613013) and its association with other genetically determined congenital malformations of neural crest-derived cells, namely HSCR and/or CCHS, suggested that there may be a gene or genes in which germline mutations predispose to neuroblastoma. Because of the demonstration that PHOX2B is the major disease-causing gene in isolated and syndromic CCHS, Trochet et al. (2004) investigated it as a candidate gene in neuroblastoma. They reported germline mutations of PHOX2B in both a familial case of neuroblastoma (603851.0005) and a patient with neuroblastoma associated with HSCR (603851.0006). PHOX2B was the first gene in which germline mutations were demonstrated to predispose to neuroblastoma. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
|
|
Toyota et al. (2004) found that a subtype of strabismus, constant exotropia, displayed marked association with schizophrenia (see 181500) (p = 0.00000000906). They identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of the PMX2B gene, with a modest association between these functional polymorphisms and constant exotropia in schizophrenia as compared to control samples (p = 0.029). The polymorphisms were also associated with overall schizophrenia (p = 0.012) and more specifically with schizophrenia manifesting strabismus (p = 0.004). These results suggested a possible interaction between PMX2B and other schizophrenia-precipitating factors, increasing the risk of the combined phenotypes. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cytogenetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Benailly et al. (2003) reported a 16-month-old girl with a syndrome encompassing developmental delay, severe hypotonia, facial dysmorphism, and short-segment Hirschsprung disease, who was found to have a de novo t(4;8)(p13;p22) translocation. A comparative genomic hybridization (CGH) study found a 5-Mb deletion at chromosome 4p12-p13 that included the PMX2B gene. Dysmorphic features included frontal bossing, prominent forehead, angioma on the forehead, very short nose with slightly anteverted nostrils, high nasal bridge, prominent philtral borders, bilateral epicanthus, and an open anterior fontanel. She had discrete rhizomelia and the anus was anteriorly placed. The authors suggested that PMX2B haploinsufficiency may predispose to Hirschsprung disease. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Pattyn et al. (1999) generated mice deficient in Phox2b by homologous recombination. In Phox2b -/- mice, autonomic ganglia failed to form properly and degenerate, as did the 3 cranial sensory ganglia that are part of the autonomic reflex circuits. In the anlagen of the enteric nervous system in the sympathetic ganglia, Phox2b is needed for the expression of the GDNF-receptor subunit Ret (164761) and for maintaining Mash1 (100790) expression. Mutant ganglionic anlagen also failed to switch on the genes that encode dopamine-beta-hydroxylase and tyrosine hydroxylase, both needed for the biosynthesis of the neurotransmitter noradrenaline, demonstrating that Phox2b regulates the noradrenergic phenotype in vertebrates. </p><p>Dilp1 is a semidominant mouse mutation that causes dilated pupils when heterozygous and is lethal when homozygous. Cross et al. (2004) reported a nonsense Phox2b mutation in Dilp1 mice. Mice carrying a targeted allele of Phox2b also had dilated pupils; the 2 alleles did not complement. The ciliary ganglion was atrophic in Phox2b heterozygous mutants. Some patients with congenital central hypoventilation syndrome (CCHS; 209880) have ocular abnormalities, including constricted rather than dilated pupils. The apparent phenotypic differences between mice carrying a loss-of-function mutation of Phox2b and CCHS patients indicates that PHOX2B mutations found in CCHS patients, all of which can produce proteins with intact DNA-binding domains, are gain-of-function mutations that alter rather than abolish protein function. </p><p>Dubreuil et al. (2008) found that mice heterozygous for the CCHS-causing expanded alanine tract in the Phox2b gene (603851.0001) had irregular breathing, did not respond to an increase in CO2, and died soon after birth from central apnea. Postmortem examination showed specific loss of Phox2b-expressing glutamatergic neurons in the retrotrapezoid nucleus/parafacial region, whereas other areas thought to be involved in breathing regulation were anatomically normal. The findings demonstrated the essential role of a specific population of medullary interneurons in driving proper breathing at birth. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>12 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CCHS WITH HIRSCHSPRUNG DISEASE, INCLUDED<br />
|
|
CENTRAL HYPOVENTILATION SYNDROME, LATE-ONSET, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PHOX2B, 15- TO 27-BP DUP, ALANINE TRACT EXPANSION, NT721
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000006377, RCV000006378, RCV000006379
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 16 of 29 patients with congenital central hypoventilation syndrome (CCHS1; 209880), some of whom also had Hirschsprung disease and ganglioneuroblastoma or neuroblastoma, Amiel et al. (2003) found a triplet expansion of 15 to 27 nucleotides (nucleotides 721-780) of the PHOX2B gene, adding 5 to 9 alanines to the 20-residue polyalanine tract. Most mutant genotypes were different, suggesting that they derived from independent mutational events. The polyalanine triplet expansion was shown to be de novo in cases where parents were available. Two of these patients also carried mutations in RET (P1039L; 164761.0046) or GDNF (603851.0001). </p><p>In 5 of 9 patients with late-onset central hypoventilation syndrome, Trochet et al. (2005) found an expansion of 5 alanines in the PHOX2B polyalanine tract. </p><p>Antic et al. (2006) reported 5 adults with late-onset central hypoventilation syndrome who each had a heterozygous expansion of 5 alanines in the PHOX2B polyalanine tract. </p><p>Arai et al. (2007) determined that de novo PHOX2B polyalanine expansions in 6 informative CCHS families resulted from unequal crossover or unequal sister chromatid exchange during spermatogenesis. In contrast to polyglutamine expansions, which usually result from strand slippage, Arai et al. (2007) suggested that polyalanine expansions probably result from misalignment due to the secondary DNA structure of imperfect trinucleotide repeats (GCA, GCG, GCC, and GCT) that encode polyalanine tracts. </p><p>Sivan et al. (2019) reported a male infant with CCHS who had compound heterozygous mutations in the PHOX2B gene: a polyalanine repeat expansion (24 alanine repeats) and a c.785G-T transversion in exon 3, resulting in a gly262-to-val (G262V) substitution (603851.0012). The polyalanine repeat expansion was seen in the father, paternal grandfather, and 2 out of 5 of the father's sibs, and the missense mutation was seen in the mother, maternal grandfather, and 3 out of 9 of the mother's sibs. All family members, other than the proband, were phenotypically normal. The authors concluded that this was the first reported case of compound heterozygosity for variants in the PHOX2B gene in a proband with CCHS in which neither variant alone was sufficient to cause disease in multiple family members. The authors noted the importance of PHOX2B testing in parents of all probands with CCHS to identify mosaicism in a parent, confirm allele pathogenicity, determine inheritance, and provide information for future pregnancy planning. The authors also suggested sequencing of PHOX2B if a polyalanine repeat expansion has been identified, especially when the phenotype is more severe than expected. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PHOX2B, 1-BP INS, 618C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776626,
|
|
|
|
|
|
|
|
ClinVar: RCV000006380, RCV004721243
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with congenital central hypoventilation syndrome (CCHS1; 209880), Amiel et al. (2003) found a de novo cytosine insertion in a stretch of 4 cytosines, 618_619insC, in the PHO2B gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PHOX2B, 37-BP DEL, NT722
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1733878065,
|
|
|
|
|
|
|
|
ClinVar: RCV000006381, RCV003151706, RCV003415666
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with congenital central hypoventilation syndrome (CCHS1; 209880), Amiel et al. (2003) found a deletion of 37 nucleotides (722_759del37) in the PHOX2B gene, resulting in a frameshift downstream of the homeobox. The deletion could be considered an out-of-frame contraction of the polyalanine tract. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 REMOVED FROM DATABASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 NEUROBLASTOMA, SUSCEPTIBILITY TO, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PHOX2B, ARG100LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104893855,
|
|
|
|
|
|
|
|
ClinVar: RCV000006382, RCV002227997, RCV002433444
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a familial case of neuroblastoma (613013), Trochet et al. (2004) identified a heterozygous 299G-T transversion in exon 2 of the PHOX2B gene, resulting in an arg100-to-leu (R100L) mutation in the homeodomain of the protein. The proband, a male, was the first child born to nonconsanguineous parents. A multifocal abdominal ganglioneuroma was surgically removed at the age of 10 years. His younger brother presented at age 6 years with an abdominal neuroblastoma which was surgically removed, and experienced local recurrences 18 months and 30 months later. No amplification of MYCN (164840) was detected. The father had a ganglioneuroma of the adrenal medulla, which was surgically removed at age 44 years. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 NEUROBLASTOMA WITH HIRSCHSPRUNG DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PHOX2B, ARG141GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28939716,
|
|
|
|
|
|
|
|
ClinVar: RCV000006383
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male patient born to nonconsanguineous parents with a combination of Hirschsprung disease (142623) and neuroblastoma (see 613013), Trochet et al. (2004) identified heterozygosity for a 421C-G transversion in exon 2 of the PHOX2B gene, resulting in an arg141-to-gly (R141G) mutation. HSCR was diagnosed in the neonatal period and was treated surgically, with a good result. Multifocal tumors, both thoracic and abdominal, were found at age 9 months and were surgically removed. No amplification of MYCN (164840) was detected. The R141G mutation in this patient was inherited from the healthy mother. Several hypotheses could explain this observation: the tumor may develop in adulthood, the tumor may spontaneously regress (a well-known phenomenon for neuroblastoma), or there may be incomplete penetrance, which is higher for tumor predisposition than for HSCR and has been suspected in neuroblastoma (Maris et al. (1997, 2002)). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 NEUROBLASTOMA WITH HIRSCHSPRUNG DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PHOX2B, 1-BP DEL, 676G
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000006384, RCV002362567
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family previously described by Maris et al. (2002) in which 7 members spanning 3 generations had neuroblastoma (613013), 2 of whom also had Hirschsprung disease (142623), Mosse et al. (2004) identified a heterozygous 1-bp deletion in the PHOX2B gene, 676delG, resulting in a frameshift and a slightly truncated protein lacking the second polyalanine tract. The mutation segregated with neuroblastoma through all 3 generations. The family had previously been shown to cosegregate a 16p13-p12 haplotype with neuroblastoma. The proband, who was affected with neuroblastoma, Hirschsprung disease, and neurofibromatosis type I (162200), had previously been shown to have an inactivating mutation in the NF1 gene, 3775delT (613113.0037), which was not present in either parent. Mosse et al. (2004) concluded that the presence of 2 germline mutations in the proband, as well as evidence of linkage to 16p in the family, suggested an oligogenic mechanism for neuroblastoma initiation, as had been shown for other diseases of neural crest-derived tissues (Gabriel et al., 2002). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 NEUROBLASTOMA, SUSCEPTIBILITY TO, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PHOX2B, GLY197ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104893856,
|
|
|
|
|
|
|
|
ClinVar: RCV000006385, RCV002354150
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a family with neuroblastoma (613013), McConville et al. (2006) identified a constitutional heterozygous 590G-A transition in the PHOX2B gene, resulting in a gly197-to-asp (G197D) substitution in a conserved residue outside of the homeodomain. No tumor DNA was available. The index case, from whom no DNA was available, died at age 5 years with metastatic neuroblastoma and ganglioneuroblastoma. Her father and paternal grandmother, both of whom had the G197D mutation, had adult-onset ganglioneuroblastoma. Another paternal relative, from whom DNA was not available, died at age 14 years from ganglioneuroblastoma. Two unaffected sibs of the index patient's grandmother also carried the mutation, indicating incomplete penetrance. None of the family members had Hirschsprung disease (142623) or any features of autonomic dysfunction. The mutation was not identified in 284 controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PHOX2B, ARG141GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1733941453,
|
|
|
|
|
|
|
|
ClinVar: RCV001078156, RCV002327374, RCV003517297
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a white female (P005) with congenital central hypoventilation syndrome (CCHS1; 209880) and an adrenal ganglioneuroma, but no evidence of Hirschsprung disease, Lombardo et al. (2018) identified a c.422G-A transition in exon 2 of the PHOX2B gene that resulted in an arginine-to-glutamine substitution at codon 141 (R141Q) in the homeobox domain of the protein. This patient had separate origin of the left vertebral artery off the aortic arch. </p><p>Hamosh (2020) noted that the R141Q variant was absent from the gnomAD database on April 12, 2020.</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PHOX2B, ARG149LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1733899167,
|
|
|
|
|
|
|
|
ClinVar: RCV001078157, RCV004031214
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an African American female (P003) with central hypoventilation syndrome (CCHS1; 209880), Lombardo et al. (2018) identified a c.446G-T transversion in exon 3 of the PHOX2B gene, resulting in an arginine-to-leucine substitution at codon 149 (R149L) in the homeobox domain of the protein. This patient also had moderate secundum atrial septal defect (ASD) and a patent ductus arteriosus (PDA) that required surgical closure at age 5 years. </p><p>Hamosh (2020) noted that the A149L variant was absent from the gnomAD database on April 12, 2020.</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CCHS WITH HIRSCHSPRUNG DISEASE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PHOX2B, TYR78TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs73810366,
|
|
|
|
|
|
gnomAD: rs73810366,
|
|
|
|
|
|
ClinVar: RCV001078158, RCV001078159, RCV002445374
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated African American females (P008 and P018) with central hypoventilation syndrome (CCHS1; 209880), 1 of whom had Hirschsprung disease, Lombardo et al. (2018) identified a c.234C-G transversion in exon 1 of the PHOX2B gene that resulted in a tyrosine-to-termination substitution at amino acid 78 (Y78X). Both of these patients also had congenital heart disease (CHD). </p><p>Hamosh (2020) noted that the Y78X variant was absent from the gnomAD database on April 12, 2020.</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PHOX2B, GLY262VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs768420488,
|
|
|
|
|
|
gnomAD: rs768420488,
|
|
|
|
|
|
ClinVar: RCV000526554, RCV000561955, RCV001312215, RCV004592580
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.785G-T transversion in exon 3 of the PHOX2B gene, resulting in a gly262-to-val (G262V) substitution, that was found in compound heterozygous state in a proband with congenital central hypoventilation syndrome (CCHS1; 209880) by Sivan et al. (2019), see 603851.0001. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simmoneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S.
|
|
<strong>Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.</strong>
|
|
Nature Genet. 33: 459-460, 2003.
|
|
|
|
|
|
[PubMed: 12640453]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng1130]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Antic, N. A., Malow, B. A., Lange, N., McEvoy, R. D., Olson, A. L., Turkington, P., Windisch, W., Samuels, M., Stevens, C. A., Berry-Kravis, E. M., Weese-Mayer, D. E.
|
|
<strong>PHOX2B mutation-confirmed congenital central hypoventilation syndrome: presentation in adulthood.</strong>
|
|
Am. J. Resp. Crit. Care Med. 174: 923-927, 2006.
|
|
|
|
|
|
[PubMed: 16873766]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1164/rccm.200605-607CR]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Arai, H., Otagiri, T., Sasaki, A., Hashimoto, T., Umetsu, K., Tokunaga, K., Hayasaka, K.
|
|
<strong>De novo polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: unequal sister chromatid exchange during paternal gametogenesis.</strong>
|
|
J. Hum. Genet. 52: 921-925, 2007.
|
|
|
|
|
|
[PubMed: 17928950]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s10038-007-0197-3]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bachetti, T., Matera, I., Borghini, S., Di Duca, M., Ravazzolo, R., Ceccherini, I.
|
|
<strong>Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome.</strong>
|
|
Hum. Molec. Genet. 14: 1815-1824, 2005.
|
|
|
|
|
|
[PubMed: 15888479]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddi188]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Benailly, H. K., Lapierre, J. M., Laudier, B., Amiel, J., Attie, T., De Blois, M. C., Vekemans, M., Romana, S. P.
|
|
<strong>PMX2B, a new candidate gene for Hirschsprung's disease.</strong>
|
|
Clin. Genet. 64: 204-209, 2003.
|
|
|
|
|
|
[PubMed: 12919134]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1034/j.1399-0004.2003.00105.x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Cross, S. H., Morgan, J. E., Pattyn, A., West, K., McKie, L., Hart, A., Thuang, C., Brunet, J.-F., Jackson, I. J.
|
|
<strong>Haploinsufficiency for Phox2b in mice causes dilated pupils and atrophy of the ciliary ganglion: mechanistic insights into human congenital central hypoventilation syndrome.</strong>
|
|
Hum. Molec. Genet. 13: 1433-1439, 2004.
|
|
|
|
|
|
[PubMed: 15150159]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddh156]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dubreuil, V, Ramanantsoa, N., Trochet, D., Vaubourg, V., Amiel, J., Gallego, J., Brunet, J.-F., Goridis, C.
|
|
<strong>A human mutation in Phox2b causes lack of CO2 chemosensitivity, fatal central apnea, and specific loss of parafacial neurons.</strong>
|
|
Proc. Nat. Acad. Sci. 105: 1067-1072, 2008.
|
|
|
|
|
|
[PubMed: 18198276]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0709115105]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Espinosa-Medina, I., Outin, E., Picard, C. A., Chettouh, Z., Dymecki, S., Consalez, G. G., Coppola, E., Brunet, J.-F.
|
|
<strong>Parasympathetic ganglia derive from Schwann cell precursors.</strong>
|
|
Science 345: 87-90, 2014.
|
|
|
|
|
|
[PubMed: 24925912]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1253286]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gabriel, S. B., Salomon, R., Pelet, A., Angrist, M., Amiel, J., Fornage, M., Attie-Bitach, T., Olson, J. M., Hofstra, R., Buys, C., Steffann, J., Munnich, A., Lyonnet, S., Chakravarti, A.
|
|
<strong>Segregation at three loci explains familial and population risk in Hirschsprung disease.</strong>
|
|
Nature Genet. 31: 89-93, 2002.
|
|
|
|
|
|
[PubMed: 11953745]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng868]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Guzoglu, N., Aslan, M. K., Gunay, Y. D., Atasoy, P. Ceylaner, S., Aliefendioglu, D.
|
|
<strong>A novel mutation which causes a frameshift in the PHOX2B gene causes Haddad syndrome.</strong>
|
|
Clin. Dysmorph. 29: 152-154, 2020.
|
|
|
|
|
|
[PubMed: 32073407]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1097/MCD.0000000000000317]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hamosh, A.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 04/12/2020.
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Katz, E. S., McGrath, S., Marcus, C. L.
|
|
<strong>Late-onset central hypoventilation with hypothalamic dysfunction: a distinct clinical syndrome.</strong>
|
|
Pediat. Pulmonol. 29: 62-68, 2000.
|
|
|
|
|
|
[PubMed: 10613788]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/(sici)1099-0496(200001)29:1<62::aid-ppul10>3.0.co;2-m]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lombardo, R. C., Porollo, A., Cnota, J. F., Hopkin, R. J.
|
|
<strong>Congenital heart disease and aortic arch variants associated with mutations in PHOX2B.</strong>
|
|
Genet. Med. 20: 1538-1543, 2018.
|
|
|
|
|
|
[PubMed: 29543228]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/gim.2018.34]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Maris, J. M., Kyemba, S. M., Rebbeck, T. R., White, P. S., Sulman, E. P., Jensen, S. J., Allen, C., Biegel, J. A., Brodeur, G. M.
|
|
<strong>Molecular genetic analysis of familial neuroblastoma.</strong>
|
|
Europ. J. Cancer 33: 1923-1928, 1997.
|
|
|
|
|
|
[PubMed: 9516825]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0959-8049(97)00265-7]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Maris, J. M., Weiss, M. J., Mosse, Y., Hii, G., Guo, C., White, P. S., Hogarty, M. D., Mirensky, T., Brodeur, G. M., Rebbeck, T. R., Urbanek, M., Shusterman, S.
|
|
<strong>Evidence for a hereditary neuroblastoma predisposition locus at chromosome 16p12-13.</strong>
|
|
Cancer Res. 62: 6651-6658, 2002.
|
|
|
|
|
|
[PubMed: 12438263]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Matera, I., Bachetti, T., Puppo, F., Di Duca, M., Morandi, F., Casiraghi, G. M., Cilio, M. R., Hennekam, R., Hofstra, R., Schober, J. G., Ravazzolo, R., Ottonello, G., Ceccherini, I.
|
|
<strong>PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset central hypoventilation syndrome. (Letter)</strong>
|
|
J. Med. Genet. 41: 373-380, 2004.
|
|
|
|
|
|
[PubMed: 15121777]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.2003.015412]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
McConville, C., Reid, S., Baskcomb, L., Douglas, J., Rahman, N.
|
|
<strong>PHOX2B analysis in non-syndromic neuroblastoma cases shows novel mutations and genotype-phenotype associations.</strong>
|
|
Am. J. Med. Genet. 140A: 1297-1301, 2006.
|
|
|
|
|
|
[PubMed: 16691592]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.31278]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Mosse, Y. P., Laudenslager, M., Khazi, D., Carlisle, A. J., Winter, C. L., Rappaport, E., Maris, J. M.
|
|
<strong>Germline PHOX2B mutation in hereditary neuroblastoma. (Letter)</strong>
|
|
Am. J. Hum. Genet. 75: 727-730, 2004.
|
|
|
|
|
|
[PubMed: 15338462]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1086/424530]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Pattyn, A., Morin, X., Cremer, H., Goridis, C., Brunet, J.-F.
|
|
<strong>Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis.</strong>
|
|
Development 124: 4065-4075, 1997.
|
|
|
|
|
|
[PubMed: 9374403]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1242/dev.124.20.4065]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Pattyn, A., Morin, X., Cremer, H., Goridis, C., Brunet, J.-F.
|
|
<strong>The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives.</strong>
|
|
Nature 399: 366-370, 1999.
|
|
|
|
|
|
[PubMed: 10360575]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/20700]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sasaki, A., Kanai, M., Kijima, K., Akaba, K., Hashimoto, M., Hasegawa, H., Otaki, S., Koizumi, T., Kusuda, S., Ogawa, Y., Tuchiya, K., Yamamoto, W., Nakamura, T., Hayasaka, K.
|
|
<strong>Molecular analysis of congenital central hypoventilation syndrome.</strong>
|
|
Hum. Genet. 114: 22-26, 2003.
|
|
|
|
|
|
[PubMed: 14566559]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s00439-003-1036-z]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sivan, Y., Zhou, A., Jennings, L. J., Berry-Kravis, E. M., Yu, M., Zhou, L., Rand, C. M., Weese-Mayer, D. E.
|
|
<strong>Congenital central hypoventilation syndrome: severe disease caused by co-occurrence of two PHOX2B variants inherited separately from asymptomatic family members.</strong>
|
|
Am. J. Med. Genet. 179A: 503-506, 2019.
|
|
|
|
|
|
[PubMed: 30672101]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.61047]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Toyota, T., Yoshitsugu, K., Ebihara, M., Yamada, K., Ohba, H., Fukasawa, M., Minabe, Y., Nakamura, K., Sekine, Y., Takei, N., Suzuki, K., Itokawa, M., Meerabux, J. M. A., Iwayama-Shigeno, Y., Tomaru, Y., Shimizu, H., Hattori, E., Mori, N., Yoshikawa, T.
|
|
<strong>Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B.</strong>
|
|
Hum. Molec. Genet. 13: 551-561, 2004.
|
|
|
|
|
|
[PubMed: 14709596]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddh047]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Trochet, D., Bourdeaut, F., Janoueix-Lerosey, I., Deville, A., de Pontual, L., Schleiermacher, G., Coze, C., Philip, N., Frebourg, T., Munnich, A., Lyonnet, S., Delattre, O., Amiel, J.
|
|
<strong>Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.</strong>
|
|
Am. J. Hum. Genet. 74: 761-764, 2004.
|
|
|
|
|
|
[PubMed: 15024693]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1086/383253]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Trochet, D., Hong, S. J., Lim, J. K., Brunet, J.-F., Munnich, A., Kim, K.-S., Lyonnet, S., Goridis, C., Amiel, J.
|
|
<strong>Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction.</strong>
|
|
Hum. Molec. Genet. 14: 3697-3708, 2005.
|
|
|
|
|
|
[PubMed: 16249188]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddi401]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Trochet, D., O'Brien, L. M., Gozal, D., Trang, H., Nordenskjold, A., Laudier, B., Svensson, P.-J., Uhrig, S., Cole, T., Niemann, S., Munnich, A., Gaultier, C., Lyonnet, S., Amiel, J.
|
|
<strong>PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.</strong>
|
|
Am. J. Hum. Genet. 76: 421-426, 2005. Note: Erratum: Am. J. Hum. Genet. 76: 715 only, 2005.
|
|
|
|
|
|
[PubMed: 15657873]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1086/428366]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Warren, S. T.
|
|
<strong>Polyalanine expansion in synpolydactyly might result from unequal crossing-over of HOXD13.</strong>
|
|
Science 275: 408-409, 1997.
|
|
|
|
|
|
[PubMed: 9005557]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.275.5298.408]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Weese-Mayer, D. E., Berry-Kravis, E. M., Zhou, L., Maher, B. S., Silvestri, J. M., Curran, M. E., Marazita, M. L.
|
|
<strong>Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b.</strong>
|
|
Am. J. Med. Genet. 123A: 267-278, 2003.
|
|
|
|
|
|
[PubMed: 14608649]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.20527]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Yokoyama, M., Nishi, Y., Yoshii, J., Okubo, K., Matsubara, K.
|
|
<strong>Identification and cloning of neuroblastoma-specific and nerve tissue-specific genes through compiled expression profiles.</strong>
|
|
DNA Res. 3: 311-320, 1996.
|
|
|
|
|
|
[PubMed: 9039501]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/dnares/3.5.311]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Contributors:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Cassandra L. Kniffin - updated : 08/25/2021<br>Sonja A. Rasmussen - updated : 09/15/2020<br>Hilary J. Vernon - updated : 09/14/2020<br>Ada Hamosh - updated : 04/16/2020<br>Ada Hamosh - updated : 8/6/2014<br>George E. Tiller - updated : 4/23/2009<br>George E. Tiller - updated : 10/28/2008<br>Cassandra L. Kniffin - updated : 5/27/2008<br>Cassandra L. Kniffin - updated : 2/5/2008<br>Cassandra L. Kniffin - updated : 12/28/2007<br>George E. Tiller - updated : 11/28/2006<br>George E. Tiller - updated : 9/21/2006<br>Cassandra L. Kniffin - updated : 8/2/2006<br>Victor A. McKusick - updated : 2/9/2005<br>Victor A. McKusick - updated : 9/14/2004<br>Marla J. F. O'Neill - updated : 6/11/2004<br>Victor A. McKusick - updated : 4/8/2004<br>Victor A. McKusick - updated : 1/5/2004<br>Victor A. McKusick - updated : 12/9/2003<br>Victor A. McKusick - updated : 10/16/2003<br>Victor A. McKusick - updated : 3/18/2003
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Ada Hamosh : 5/26/1999
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Edit History:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 02/13/2024<br>carol : 02/12/2024<br>carol : 08/26/2021<br>carol : 08/25/2021<br>carol : 09/16/2020<br>carol : 09/15/2020<br>carol : 09/14/2020<br>alopez : 04/16/2020<br>carol : 11/08/2019<br>carol : 02/20/2018<br>carol : 03/27/2015<br>carol : 8/7/2014<br>alopez : 8/6/2014<br>carol : 3/19/2014<br>terry : 7/6/2012<br>joanna : 11/23/2009<br>carol : 9/21/2009<br>ckniffin : 9/18/2009<br>wwang : 6/30/2009<br>terry : 4/23/2009<br>alopez : 12/5/2008<br>carol : 11/4/2008<br>wwang : 10/28/2008<br>wwang : 5/29/2008<br>ckniffin : 5/27/2008<br>wwang : 3/6/2008<br>ckniffin : 2/5/2008<br>wwang : 1/22/2008<br>ckniffin : 12/28/2007<br>alopez : 7/6/2007<br>carol : 11/28/2006<br>alopez : 9/21/2006<br>wwang : 8/3/2006<br>ckniffin : 8/2/2006<br>alopez : 2/17/2005<br>terry : 2/9/2005<br>tkritzer : 1/20/2005<br>carol : 11/1/2004<br>tkritzer : 9/16/2004<br>terry : 9/14/2004<br>carol : 6/14/2004<br>terry : 6/11/2004<br>tkritzer : 4/26/2004<br>tkritzer : 4/15/2004<br>terry : 4/8/2004<br>terry : 3/19/2004<br>terry : 3/18/2004<br>carol : 1/13/2004<br>cwells : 1/5/2004<br>tkritzer : 12/11/2003<br>terry : 12/9/2003<br>alopez : 11/14/2003<br>cwells : 10/20/2003<br>terry : 10/16/2003<br>alopez : 4/2/2003<br>alopez : 3/18/2003<br>terry : 3/18/2003<br>alopez : 5/27/1999<br>alopez : 5/26/1999
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div id="mimFooter">
|
|
|
|
|
|
<div class="container ">
|
|
<div class="row">
|
|
<br />
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="hidden-print mim-footer">
|
|
<div class="container">
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
<div class="row text-center small">
|
|
NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
|
|
and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
|
|
medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
|
|
<br />
|
|
OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
|
|
<br />
|
|
Copyright<sup>®</sup> 1966-2025 Johns Hopkins University.
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="visible-print-block mim-footer" style="position: relative;">
|
|
<div class="container">
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
<div class="row text-center small">
|
|
NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
|
|
and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
|
|
medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
|
|
<br />
|
|
OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
|
|
<br />
|
|
Copyright<sup>®</sup> 1966-2025 Johns Hopkins University.
|
|
<br />
|
|
Printed: March 5, 2025
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="modal fade" id="mimDonationPopupModal" tabindex="-1" role="dialog" aria-labelledby="mimDonationPopupModalTitle">
|
|
<div class="modal-dialog" role="document">
|
|
<div class="modal-content">
|
|
<div class="modal-header">
|
|
<button type="button" id="mimDonationPopupCancel" class="close" data-dismiss="modal" aria-label="Close"><span aria-hidden="true">×</span></button>
|
|
<h4 class="modal-title" id="mimDonationPopupModalTitle">
|
|
OMIM Donation:
|
|
</h4>
|
|
</div>
|
|
<div class="modal-body">
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
Dear OMIM User,
|
|
</p>
|
|
</div>
|
|
</div>
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
To ensure long-term funding for the OMIM project, we have diversified
|
|
our revenue stream. We are determined to keep this website freely
|
|
accessible. Unfortunately, it is not free to produce. Expert curators
|
|
review the literature and organize it to facilitate your work. Over 90%
|
|
of the OMIM's operating expenses go to salary support for MD and PhD
|
|
science writers and biocurators. Please join your colleagues by making a
|
|
donation now and again in the future. Donations are an important
|
|
component of our efforts to ensure long-term funding to provide you the
|
|
information that you need at your fingertips.
|
|
</p>
|
|
</div>
|
|
</div>
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
Thank you in advance for your generous support, <br />
|
|
Ada Hamosh, MD, MPH <br />
|
|
Scientific Director, OMIM <br />
|
|
</p>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div class="modal-footer">
|
|
<button type="button" id="mimDonationPopupDonate" class="btn btn-success btn-block" data-dismiss="modal"> Donate To OMIM! </button>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
</body>
|
|
|
|
</html>
|
|
|
|
|