649 lines
No EOL
156 KiB
HTML
649 lines
No EOL
156 KiB
HTML
<?xml version="1.0" encoding="utf-8"?>
|
||
<!DOCTYPE html PUBLIC "-//W3C//DTD XHTML 1.0 Transitional//EN" "http://www.w3.org/TR/xhtml1/DTD/xhtml1-transitional.dtd">
|
||
<html xmlns="http://www.w3.org/1999/xhtml" xml:lang="en" lang="en">
|
||
|
||
<head><meta http-equiv="Content-Type" content="text/html; charset=utf-8" />
|
||
<!-- AppResources meta begin -->
|
||
<meta name="paf-app-resources" content="" />
|
||
<script type="text/javascript">var ncbi_startTime = new Date();</script>
|
||
|
||
<!-- AppResources meta end -->
|
||
|
||
<!-- TemplateResources meta begin -->
|
||
<meta name="paf_template" content="" />
|
||
|
||
<!-- TemplateResources meta end -->
|
||
|
||
<!-- Logger begin -->
|
||
<meta name="ncbi_db" content="books" /><meta name="ncbi_pdid" content="book-part" /><meta name="ncbi_acc" content="NBK1728" /><meta name="ncbi_domain" content="gene" /><meta name="ncbi_report" content="record" /><meta name="ncbi_type" content="fulltext" /><meta name="ncbi_objectid" content="" /><meta name="ncbi_pcid" content="/NBK1728/" /><meta name="ncbi_pagename" content="FREM1 Autosomal Recessive Disorders - GeneReviews® - NCBI Bookshelf" /><meta name="ncbi_bookparttype" content="chapter" /><meta name="ncbi_app" content="bookshelf" />
|
||
<!-- Logger end -->
|
||
|
||
<title>FREM1 Autosomal Recessive Disorders - GeneReviews® - NCBI Bookshelf</title>
|
||
|
||
<!-- AppResources external_resources begin -->
|
||
<link rel="stylesheet" href="/core/jig/1.15.2/css/jig.min.css" /><script type="text/javascript" src="/core/jig/1.15.2/js/jig.min.js"></script>
|
||
|
||
<!-- AppResources external_resources end -->
|
||
|
||
<!-- Page meta begin -->
|
||
<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="FREM1 Autosomal Recessive Disorders" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2019/05/09" /><meta name="citation_author" content="Chumei Li" /><meta name="citation_author" content="Anne Slavotinek" /><meta name="citation_pmid" content="20301721" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1728/" /><meta name="citation_keywords" content="Manitoba Oculotrichoanal (MOTA) Syndrome" /><meta name="citation_keywords" content="Bifid Nose With or Without Anorectal and Renal Anomalies (BNAR Syndrome)" /><meta name="citation_keywords" content="FREM1 Congenital Anomalies of Kidney and Urinary Tract (CAKUT)" /><meta name="citation_keywords" content="FRAS1-related extracellular matrix protein 1" /><meta name="citation_keywords" content="FREM1" /><meta name="citation_keywords" content="FREM1 Autosomal Recessive Disorders" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="FREM1 Autosomal Recessive Disorders" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Chumei Li" /><meta name="DC.Contributor" content="Anne Slavotinek" /><meta name="DC.Date" content="2019/05/09" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1728/" /><meta name="description" content="FREM1 autosomal recessive disorders include Manitoba oculotrichoanal (MOTA) syndrome, bifid nose with or without anorectal and renal anomalies (BNAR syndrome), and isolated congenital anomalies of kidney and urinary tract (CAKUT)." /><meta name="og:title" content="FREM1 Autosomal Recessive Disorders" /><meta name="og:type" content="book" /><meta name="og:description" content="FREM1 autosomal recessive disorders include Manitoba oculotrichoanal (MOTA) syndrome, bifid nose with or without anorectal and renal anomalies (BNAR syndrome), and isolated congenital anomalies of kidney and urinary tract (CAKUT)." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK1728/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/gene/mota/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK1728/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script><meta name="book-collection" content="NONE" />
|
||
|
||
<!-- Page meta end -->
|
||
<link rel="shortcut icon" href="//www.ncbi.nlm.nih.gov/favicon.ico" /><meta name="ncbi_phid" content="CE8EA6EB7D2A20110000000000EB00BA.m_13" />
|
||
<meta name='referrer' content='origin-when-cross-origin'/><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3852956/3985586/3808861/4121862/3974050/3917732/251717/4216701/14534/45193/4113719/3849091/3984811/3751656/4033350/3840896/3577051/3852958/4008682/4207974/4206132/4062871/12930/3964959/3854974/36029/4128070/9685/3549676/3609192/3609193/3609213/3395586.css" /><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3411343/3882866.css" media="print" /></head>
|
||
<body class="book-part">
|
||
<div class="grid">
|
||
<div class="col twelve_col nomargin shadow">
|
||
<!-- System messages like service outage or JS required; this is handled by the TemplateResources portlet -->
|
||
<div class="sysmessages">
|
||
<noscript>
|
||
<p class="nojs">
|
||
<strong>Warning:</strong>
|
||
The NCBI web site requires JavaScript to function.
|
||
<a href="/guide/browsers/#enablejs" title="Learn how to enable JavaScript" target="_blank">more...</a>
|
||
</p>
|
||
</noscript>
|
||
</div>
|
||
<!--/.sysmessage-->
|
||
<div class="wrap">
|
||
<div class="page">
|
||
<div class="top">
|
||
<div id="universal_header">
|
||
<section class="usa-banner">
|
||
<div class="usa-accordion">
|
||
<header class="usa-banner-header">
|
||
<div class="usa-grid usa-banner-inner">
|
||
<img src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/favicons/favicon-57.png" alt="U.S. flag" />
|
||
<p>An official website of the United States government</p>
|
||
<button class="non-usa-accordion-button usa-banner-button" aria-expanded="false" aria-controls="gov-banner-top" type="button">
|
||
<span class="usa-banner-button-text">Here's how you know</span>
|
||
</button>
|
||
</div>
|
||
</header>
|
||
<div class="usa-banner-content usa-grid usa-accordion-content" id="gov-banner-top" aria-hidden="true">
|
||
<div class="usa-banner-guidance-gov usa-width-one-half">
|
||
<img class="usa-banner-icon usa-media_block-img" src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/icon-dot-gov.svg" alt="Dot gov" />
|
||
<div class="usa-media_block-body">
|
||
<p>
|
||
<strong>The .gov means it's official.</strong>
|
||
<br />
|
||
Federal government websites often end in .gov or .mil. Before
|
||
sharing sensitive information, make sure you're on a federal
|
||
government site.
|
||
</p>
|
||
</div>
|
||
</div>
|
||
<div class="usa-banner-guidance-ssl usa-width-one-half">
|
||
<img class="usa-banner-icon usa-media_block-img" src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/icon-https.svg" alt="Https" />
|
||
<div class="usa-media_block-body">
|
||
<p>
|
||
<strong>The site is secure.</strong>
|
||
<br />
|
||
The <strong>https://</strong> ensures that you are connecting to the
|
||
official website and that any information you provide is encrypted
|
||
and transmitted securely.
|
||
</p>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
</section>
|
||
<div class="usa-overlay"></div>
|
||
<header class="ncbi-header" role="banner" data-section="Header">
|
||
|
||
<div class="usa-grid">
|
||
<div class="usa-width-one-whole">
|
||
|
||
<div class="ncbi-header__logo">
|
||
<a href="/" class="logo" aria-label="NCBI Logo" data-ga-action="click_image" data-ga-label="NIH NLM Logo">
|
||
<img src="https://www.ncbi.nlm.nih.gov/coreutils/nwds/img/logos/AgencyLogo.svg" alt="NIH NLM Logo" />
|
||
</a>
|
||
</div>
|
||
|
||
<div class="ncbi-header__account">
|
||
<a id="account_login" href="https://account.ncbi.nlm.nih.gov" class="usa-button header-button" style="display:none" data-ga-action="open_menu" data-ga-label="account_menu">Log in</a>
|
||
<button id="account_info" class="header-button" style="display:none" aria-controls="account_popup" type="button">
|
||
<span class="fa fa-user" aria-hidden="true">
|
||
<svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 24 24" width="20px" height="20px">
|
||
<g style="fill: #fff">
|
||
<ellipse cx="12" cy="8" rx="5" ry="6"></ellipse>
|
||
<path d="M21.8,19.1c-0.9-1.8-2.6-3.3-4.8-4.2c-0.6-0.2-1.3-0.2-1.8,0.1c-1,0.6-2,0.9-3.2,0.9s-2.2-0.3-3.2-0.9 C8.3,14.8,7.6,14.7,7,15c-2.2,0.9-3.9,2.4-4.8,4.2C1.5,20.5,2.6,22,4.1,22h15.8C21.4,22,22.5,20.5,21.8,19.1z"></path>
|
||
</g>
|
||
</svg>
|
||
</span>
|
||
<span class="username desktop-only" aria-hidden="true" id="uname_short"></span>
|
||
<span class="sr-only">Show account info</span>
|
||
</button>
|
||
</div>
|
||
|
||
<div class="ncbi-popup-anchor">
|
||
<div class="ncbi-popup account-popup" id="account_popup" aria-hidden="true">
|
||
<div class="ncbi-popup-head">
|
||
<button class="ncbi-close-button" data-ga-action="close_menu" data-ga-label="account_menu" type="button">
|
||
<span class="fa fa-times">
|
||
<svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 48 48" width="24px" height="24px">
|
||
<path d="M38 12.83l-2.83-2.83-11.17 11.17-11.17-11.17-2.83 2.83 11.17 11.17-11.17 11.17 2.83 2.83 11.17-11.17 11.17 11.17 2.83-2.83-11.17-11.17z"></path>
|
||
</svg>
|
||
</span>
|
||
<span class="usa-sr-only">Close</span></button>
|
||
<h4>Account</h4>
|
||
</div>
|
||
<div class="account-user-info">
|
||
Logged in as:<br />
|
||
<b><span class="username" id="uname_long">username</span></b>
|
||
</div>
|
||
<div class="account-links">
|
||
<ul class="usa-unstyled-list">
|
||
<li><a id="account_myncbi" href="/myncbi/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_myncbi">Dashboard</a></li>
|
||
<li><a id="account_pubs" href="/myncbi/collections/bibliography/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_pubs">Publications</a></li>
|
||
<li><a id="account_settings" href="/account/settings/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_settings">Account settings</a></li>
|
||
<li><a id="account_logout" href="/account/signout/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_logout">Log out</a></li>
|
||
</ul>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
</div>
|
||
</div>
|
||
</header>
|
||
<div role="navigation" aria-label="access keys">
|
||
<a id="nws_header_accesskey_0" href="https://www.ncbi.nlm.nih.gov/guide/browsers/#ncbi_accesskeys" class="usa-sr-only" accesskey="0" tabindex="-1">Access keys</a>
|
||
<a id="nws_header_accesskey_1" href="https://www.ncbi.nlm.nih.gov" class="usa-sr-only" accesskey="1" tabindex="-1">NCBI Homepage</a>
|
||
<a id="nws_header_accesskey_2" href="/myncbi/" class="set-base-url usa-sr-only" accesskey="2" tabindex="-1">MyNCBI Homepage</a>
|
||
<a id="nws_header_accesskey_3" href="#maincontent" class="usa-sr-only" accesskey="3" tabindex="-1">Main Content</a>
|
||
<a id="nws_header_accesskey_4" href="#" class="usa-sr-only" accesskey="4" tabindex="-1">Main Navigation</a>
|
||
</div>
|
||
<section data-section="Alerts">
|
||
<div class="ncbi-alerts-placeholder"></div>
|
||
</section>
|
||
</div>
|
||
<div class="header">
|
||
<div class="res_logo"><h1 class="res_name"><a href="/books/" title="Bookshelf home">Bookshelf</a></h1><h2 class="res_tagline"></h2></div>
|
||
<div class="search"><form method="get" action="/books/"><div class="search_form"><label for="database" class="offscreen_noflow">Search database</label><select id="database"><optgroup label="Recent"><option value="books" selected="selected" data-ac_dict="bookshelf-search">Books</option><option value="pubmed">PubMed</option><option value="clinvar">ClinVar</option><option value="medgen" class="last">MedGen</option></optgroup><optgroup label="All"><option value="gquery">All Databases</option><option value="assembly">Assembly</option><option value="biocollections">Biocollections</option><option value="bioproject">BioProject</option><option value="biosample">BioSample</option><option value="books" data-ac_dict="bookshelf-search">Books</option><option value="clinvar">ClinVar</option><option value="cdd">Conserved Domains</option><option value="gap">dbGaP</option><option value="dbvar">dbVar</option><option value="gene">Gene</option><option value="genome">Genome</option><option value="gds">GEO DataSets</option><option value="geoprofiles">GEO Profiles</option><option value="gtr">GTR</option><option value="ipg">Identical Protein Groups</option><option value="medgen">MedGen</option><option value="mesh">MeSH</option><option value="nlmcatalog">NLM Catalog</option><option value="nuccore">Nucleotide</option><option value="omim">OMIM</option><option value="pmc">PMC</option><option value="protein">Protein</option><option value="proteinclusters">Protein Clusters</option><option value="protfam">Protein Family Models</option><option value="pcassay">PubChem BioAssay</option><option value="pccompound">PubChem Compound</option><option value="pcsubstance">PubChem Substance</option><option value="pubmed">PubMed</option><option value="snp">SNP</option><option value="sra">SRA</option><option value="structure">Structure</option><option value="taxonomy">Taxonomy</option><option value="toolkit">ToolKit</option><option value="toolkitall">ToolKitAll</option><option value="toolkitbookgh">ToolKitBookgh</option></optgroup></select><div class="nowrap"><label for="term" class="offscreen_noflow" accesskey="/">Search term</label><div class="nowrap"><input type="text" name="term" id="term" title="Search Books. Use up and down arrows to choose an item from the autocomplete." value="" class="jig-ncbiclearbutton jig-ncbiautocomplete" data-jigconfig="dictionary:'bookshelf-search',disableUrl:'NcbiSearchBarAutoComplCtrl'" autocomplete="off" data-sbconfig="ds:'no',pjs:'no',afs:'no'" /></div><button id="search" type="submit" class="button_search nowrap" cmd="go">Search</button></div></div></form><ul class="searchlinks inline_list"><li>
|
||
<a href="/books/browse/">Browse Titles</a>
|
||
</li><li>
|
||
<a href="/books/advanced/">Advanced</a>
|
||
</li><li class="help">
|
||
<a href="/books/NBK3833/">Help</a>
|
||
</li><li class="disclaimer">
|
||
<a target="_blank" data-ga-category="literature_resources" data-ga-action="link_click" data-ga-label="disclaimer_link" href="https://www.ncbi.nlm.nih.gov/books/about/disclaimer/">Disclaimer</a>
|
||
</li></ul></div>
|
||
</div>
|
||
|
||
|
||
|
||
<!--<component id="Page" label="headcontent"/>-->
|
||
|
||
</div>
|
||
<div class="content">
|
||
<!-- site messages -->
|
||
<!-- Custom content 1 -->
|
||
<div class="col1">
|
||
|
||
</div>
|
||
|
||
<div class="container">
|
||
<div id="maincontent" class="content eight_col col">
|
||
<!-- Custom content in the left column above book nav -->
|
||
<div class="col2">
|
||
|
||
</div>
|
||
|
||
<!-- Book content -->
|
||
|
||
|
||
<!-- Custom content between navigation and content -->
|
||
<div class="col3">
|
||
|
||
</div>
|
||
|
||
<div class="document">
|
||
<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK1728_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1728_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/foxp2-sl-dis/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/xl-nystag/" title="Next page in this title">Next ></a></div></div></div></div></div>
|
||
<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK1728_"><span class="title" itemprop="name"><i>FREM1</i> Autosomal Recessive Disorders</span></h1><p class="contrib-group"><span itemprop="author">Chumei Li</span>, MD, PhD, FRCPC, FCCMG and <span itemprop="author">Anne Slavotinek</span>, MBBS, PhD.</p><a data-jig="ncbitoggler" href="#__NBK1728_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1728_ai__"><div class="contrib half_rhythm"><span itemprop="author">Chumei Li</span>, MD, PhD, FRCPC, FCCMG<div class="affiliation small">Director, Clinical Genetics Program<br />McMaster Children's Hospital<br />Department of Pediatrics<br />McMaster University<br />Hamilton, Ontario, Canada<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.liamtoh@iliemuhc" class="oemail">moc.liamtoh@iliemuhc</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Anne Slavotinek</span>, MBBS, PhD<div class="affiliation small">Department of Pediatrics<br />Division of Genetics<br />University of California, San Francisco<br />San Francisco, California<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.fscu@kenitovals.enna" class="oemail">ude.fscu@kenitovals.enna</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">July 9, 2008</span>; Last Update: <span itemprop="dateModified">May 9, 2019</span>.</p><p><em>Estimated reading time: 18 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="mota.Summary" itemprop="description"><h2 id="_mota_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorders include Manitoba oculotrichoanal (MOTA) syndrome, <i>b</i>ifid <i>n</i>ose with or without <i>a</i>norectal and <i>r</i>enal anomalies (BNAR syndrome), and <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> <i>c</i>ongenital <i>a</i>nomalies of <i>k</i>idney and <i>u</i>rinary <i>t</i>ract (CAKUT).</p><ul><li class="half_rhythm"><div>MOTA syndrome is characterized by an aberrant hairline (unilateral or bilateral wedge-shaped extension of the anterior hairline from the temple region to the ipsilateral eye) and anomalies of the eyes (widely spaced eyes, anophthalmia/microphthalmia and/or cryptophthalmos, colobomas of the upper eyelid, and corneopalpebral synechiae), nose (bifid or broad nasal tip), abdominal wall (omphalocele or umbilical hernia), and anus (stenosis and/or anterior displacement of the anal opening). The manifestations and degree of severity vary even among affected members of the same family. Growth and psychomotor development are normal.</div></li><li class="half_rhythm"><div>BNAR syndrome is characterized by a bifid or wide nasal tip, anorectal anomalies, and renal malformations (e.g., renal agenesis, renal dysplasia). Typically the eye manifestations of MOTA syndrome are absent.</div></li><li class="half_rhythm"><div><i>FREM1</i>-CAKUT was identified in one individual with bilateral vesicoureteral reflux (VUR) and a second individual with VUR and renal hypodysplasia.</div></li></ul></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of a <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorder is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> by identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>FREM1</i> on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p>
|
||
<i>Treatment of manifestations:</i>
|
||
</p><ul><li class="half_rhythm"><div>Intensive ocular lubrication to avoid exposure keratopathy before surgery is performed; release of synechiae between the eyelid and cornea; surgical intervention and/or prostheses for anophthalmia/microphthalmia and cryptophthalmos if warranted; supportive care for those with visual impairment</div></li><li class="half_rhythm"><div>Rhinoplasty for notched ala nasi or bifid nose</div></li><li class="half_rhythm"><div>Surgical closure of omphalocele; surgical or conservative management of umbilical hernia</div></li><li class="half_rhythm"><div>Dilation for anal stenosis</div></li><li class="half_rhythm"><div>Supportive treatment to preserve renal functions and electrolyte balance; dialysis and transplant if indicated in individuals with renal failure</div></li><li class="half_rhythm"><div>Psychosocial support</div></li></ul></div><div><h4 class="inline">Genetic counseling.</h4><p>MOTA, BNAR syndrome, and <i>FREM1</i>-CAKUT are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner. At conception, each full sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier. Once the <i>FREM1</i> pathogenic variants have been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p></div></div><div id="mota.GeneReview_Scope"><h2 id="_mota_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><div id="mota.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1728/table/mota.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mota.Tc_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_mota.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>FREM1</i> Autosomal Recessive Disorders: Included Phenotypes <sup>1, 2</sup></th></tr></thead><tbody><tr><td headers="hd_h_mota.Tc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Manitoba oculotrichoanal (MOTA) syndrome</div></li><li class="half_rhythm"><div>Bifid nose with or without anorectal and renal anomalies (BNAR syndrome)</div></li><li class="half_rhythm"><div><i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> anomalies of kidney and urinary tract (CAKUT)</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="mota.TF.c.1"><p class="no_margin">For other genetic causes of these phenotypes, see <a href="#mota.Differential_Diagnosis">Differential Diagnosis</a>.</p></div></dd><dt>2. </dt><dd><div id="mota.TF.c.2"><p class="no_margin">Nonsyndromic metopic craniosynostosis (OMIM <a href="https://omim.org/entry/614485" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">614485</a>) due to <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic variants in <i>FREM1</i> is not included in the scope of this chapter (see <a href="#mota.Genetically_Related_Allelic_Disorde">Genetically Related Disorders</a>).</p></div></dd></dl></div></div></div><div id="mota.Suggestive_Findings"><h3>Suggestive Findings</h3><p>A <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorder <b>should be suspected</b> in an individual with features of Manitoba oculotrichoanal (MOTA) syndrome, <i>b</i>ifid <i>n</i>ose with or without <i>a</i>norectal and <i>r</i>enal anomalies (BNAR syndrome), and <i>c</i>ongenital <i>a</i>nomalies of <i>k</i>idney and <i>u</i>rinary <i>t</i>ract (CAKUT).</p><p>
|
||
<b>MOTA syndrome</b>
|
||
</p><ul><li class="half_rhythm"><div>Widely spaced eyes</div></li><li class="half_rhythm"><div>Aberrant anterior hairline extending to the ipsilateral eye (unilateral or bilateral); often wedge-shaped, but may also resemble a thin stripe or appear tongue-shaped</div></li><li class="half_rhythm"><div>Ocular abnormalities including ipsilateral colobomas of the upper eyelid (sometimes referred to as a Tessier number 10 cleft by surgeons), corneopalpebral synechiae (i.e., adhesions between the eyelids and the cornea), and microphthalmia/anophthalmia and/or cryptophthalmos. Corneal clouding was described in one individual. The upper eyelid colobomas and cryptophthalmos are part of a spectrum of anomalies ranging from colobomas of the lid to eyelid coloboma plus corneopalpebral synechiae (also known as abortive cryptophthalmos) to complete cryptophthalmos [<a class="bk_pop" href="#mota.REF.nouby.2002.373">Nouby 2002</a>]. Anomalies may be unilateral or bilateral; the severity may differ between the two eyes.</div></li><li class="half_rhythm"><div>Absent or interrupted eyebrow ipsilateral to the eye defect</div></li><li class="half_rhythm"><div>A bifid nose, a notch at the nasal tip, or a broad nose</div></li><li class="half_rhythm"><div>Anal stenosis and/or anteriorly placed anus</div></li><li class="half_rhythm"><div>Omphalocele or umbilical hernia</div></li><li class="half_rhythm"><div>Family history consistent with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> inheritance</div></li><li class="half_rhythm"><div>Ethnic origin of aboriginal Oji-Cree</div></li></ul><p>
|
||
<b><i>B</i>ifid <i>n</i>ose with or without <i>a</i>norectal and <i>r</i>enal anomalies (BNAR syndrome)</b>
|
||
</p><ul><li class="half_rhythm"><div>Median nose cleft or notch, or wide bulbous nasal tip</div></li><li class="half_rhythm"><div>Anorectal anomalies (e.g., anal stenosis, anteriorly placed anus)</div></li><li class="half_rhythm"><div>Renal malformations (e.g., renal agenesis, renal dysplasia)</div></li><li class="half_rhythm"><div>Eye manifestations of MOTA syndrome typically absent</div></li></ul><p><b><i>FREM1</i>
|
||
<i>c</i>ongenital <i>a</i>nomalies of <i>k</i>idney and <i>u</i>rinary <i>t</i>ract (CAKUT).</b> Renal malformations (e.g., vesicoureteral reflux, renal hypodysplasia) [<a class="bk_pop" href="#mota.REF.kohl.2014.1917">Kohl et al 2014</a>]</p></div><div id="mota.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of a <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorder <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> by identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variants in <i>FREM1</i> on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK1728/table/mota.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobmotaTmoleculargenetictestingusedin">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [<a class="bk_pop" href="#mota.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>FREM1</i> variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> (or of one known <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and one <i>FREM1</i> variant of uncertain significance) does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b><a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing</b> (single-gene testing, <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>) and <b>comprehensive</b>
|
||
<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/chromosomal-microarray/">chromosomal microarray</a> analysis, <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/exome-array/">exome array</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>) depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p><p>Gene-targeted testing requires that the clinician determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing does not. Because the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorders is broad, individuals with the distinctive findings described in <a href="#mota.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#mota.Option_1">Option 1</a>), whereas those in whom the diagnosis of a <i>FREM1</i> autosomal recessive disorder has not been considered are more likely to be diagnosed using genomic testing (see <a href="#mota.Option_2">Option 2</a>).</p><div id="mota.Option_1"><h4>Option 1</h4><p>When the phenotypic and laboratory findings suggest the diagnosis of a <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorder, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> approaches can include <b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b> or use of a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b>.</p><ul><li class="half_rhythm"><div class="half_rhythm">
|
||
<b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b>
|
||
</div><ul><li class="half_rhythm"><div>In individuals with <b>Oji-Cree ancestry</b>, <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> to detect intragenic deletions or duplications of <i>FREM1</i> may be considered first. If only one or no <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is found, <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> of <i>FREM1</i> can be performed.</div></li><li class="half_rhythm"><div>In individuals of <b>other ethnicities</b>, <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> of <i>FREM1</i> that detects small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants can be performed first. If only one or no <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is found, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> of <i>FREM1</i> can be performed.</div></li></ul></li><li class="half_rhythm"><div class="half_rhythm"><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>FREM1</i> and other genes of interest (see <a href="#mota.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see <a href="/books/NBK1728/table/mota.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobmotaTmoleculargenetictestingusedin">Table 1</a>).</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul></div><div id="mota.Option_2"><h4>Option 2</h4><p>When the diagnosis of a <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorder is not considered because an individual has an atypical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>, <b>comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (which does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>[s] are likely involved) is the best option. <b>Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible.</p><p>If <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a> is not diagnostic, <b><a class="def" href="/books/n/gene/glossary/def-item/exome-array/">exome array</a></b> (when clinically available) may be considered to detect (multi)<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications that cannot be detected by <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="mota.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>FREM1</i> Autosomal Recessive Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1728/table/mota.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mota.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_mota.T.molecular_genetic_testing_used_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_mota.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_mota.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_mota.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>FREM1</i>
|
||
</td><td headers="hd_h_mota.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_mota.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~80%-90% <sup>4</sup></td></tr><tr><td headers="hd_h_mota.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>5</sup></td><td headers="hd_h_mota.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7 persons <sup>6</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="mota.TF.1.1"><p class="no_margin">See <a href="/books/NBK1728/#mota.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="mota.TF.1.2"><p class="no_margin">See <a href="#mota.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="mota.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="mota.TF.1.4"><p class="no_margin"><a class="bk_pop" href="#mota.REF.alazami.2009.414">Alazami et al [2009]</a>, <a class="bk_pop" href="#mota.REF.slavotinek.2011.375">Slavotinek et al [2011]</a>, <a class="bk_pop" href="#mota.REF.nathanson.2013.473">Nathanson et al [2013]</a></p></div></dd><dt>5. </dt><dd><div id="mota.TF.1.5"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd><dt>6. </dt><dd><div id="mota.TF.1.6"><p class="no_margin">A <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> of exons 8 to 23 (<a href="/books/NBK1728/table/mota.T.notable_frem1_pathogenic_variants/?report=objectonly" target="object" rid-ob="figobmotaTnotablefrem1pathogenicvariants">c.824+627_c.3840-1311del</a>) was identified in six individuals of Oji-Cree ancestry [<a class="bk_pop" href="#mota.REF.slavotinek.2011.375">Slavotinek et al 2011</a>]. An upstream deletion in <a class="def" href="/books/n/gene/glossary/def-item/compound-heterozygous/">compound heterozygous</a> form in an individual with <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> diaphragmatic hernia was reported by <a class="bk_pop" href="#mota.REF.beck.2013.1026">Beck et al [2013]</a>.</p></div></dd></dl></div></div></div></div></div></div><div id="mota.Clinical_Characteristics"><h2 id="_mota_Clinical_Characteristics_">Clinical Characteristics</h2><div id="mota.Clinical_Description"><h3>Clinical Description</h3><div id="mota.Manitoba_Oculotrichoanal_MOTA_Syndr"><h4>Manitoba Oculotrichoanal (MOTA) Syndrome</h4><p><b>Ocular abnormalities</b> include ipsilateral colobomas of the upper eyelid (sometimes referred to as a Tessier number 10 cleft by surgeons), corneopalpebral synechiae (i.e., adhesions between the eyelids and the cornea, also known as abortive cryptophthalmos), and microphthalmia/anophthalmia and/or cryptophthalmos. Anomalies may be unilateral or bilateral; the severity may differ between the two eyes.</p><p>Visual impairment may result directly from the ocular malformations or indirectly from exposure keratopathy. The long-term visual outcome depends on the severity of the ocular malformations and is poor for individuals with bilateral complete cryptophthalmos. In those with milder ocular malformations, such as upper eyelid colobomas, vision is typically intact.</p><p>Corneal clouding was described in one individual.</p><p><b>Anal anomalies</b> include anal stenosis and/or anteriorly placed anus. No associated anomalies of the sacrum, vertebrae, or tethered cord have been reported. No affected individuals have had refractory constipation, fecal incontinence, or procedure-related stenosis or fistula.</p><p><b>Characteristic facial features</b> include widely spaced eyes; an aberrant anterior hairline extending to the ipsilateral eye (unilateral or bilateral) that is often wedge-shaped but may also resemble a thin stripe or appear tongue-shaped; ipsilateral absent or interrupted eyebrow; and a broad nose or notched or bifid nasal tip.</p><p><b>Omphalocele or umbilical hernia</b> has been reported in approximately one third of affected individuals. Conservative management or surgical intervention for omphalocele or umbilical hernia is usually well tolerated and outcomes are excellent. Long-term intestinal complications have not been described.</p><p><b>Other.</b> Additional findings have been reported: renal pelviectasis, renal dysplasia, hydrometrocolpos and vaginal atresia, cutaneous syndactyly, and additional <a class="def" href="/books/n/gene/glossary/def-item/dysmorphic/">dysmorphic</a> features (e.g., high forehead with a frontal upsweep of hair, dysplastic ears, maxillary hypoplasia, underdeveloped ala nasi, short philtrum, thin upper lip, and relative microstomia) [<a class="bk_pop" href="#mota.REF.slavotinek.2011.375">Slavotinek et al 2011</a>, <a class="bk_pop" href="#mota.REF.mitter.2012.136">Mitter et al 2012</a>, <a class="bk_pop" href="#mota.REF.nathanson.2013.473">Nathanson et al 2013</a>].</p><p><b>Growth and development.</b> Individuals with MOTA syndrome assessed at various ages appear generally healthy with age-appropriate growth and cognition. Motor, social, and speech and language skills are typically normal, although development may be influenced by the presence of severe eye defects that lead to visual impairment.</p><p>The manifestations and degree of severity vary even among affected members of the same family.</p></div><div id="mota.Bifid_Nose_with_or_without_Anorecta"><h4><i>B</i>ifid <i>N</i>ose with or without <i>A</i>norectal and <i>R</i>enal Anomalies (BNAR) Syndrome</h4><p>BNAR syndrome was described by <a class="bk_pop" href="#mota.REF.algazali.2002.33">Al-Gazali et al [2002]</a> and <a class="bk_pop" href="#mota.REF.alazami.2009.414">Alazami et al [2009]</a> in ten individuals from three <a class="def" href="/books/n/gene/glossary/def-item/consanguineous/">consanguineous</a> families of Egyptian, Afghani, and Pakistani origin.</p><ul><li class="half_rhythm"><div><b>Craniofacial features.</b> Broad and/or bifid nose (100%), widely spaced eyes, short and thick oral frenula</div></li><li class="half_rhythm"><div><b>Renal malformations</b> (e.g., bilateral renal agenesis, unilateral renal agenesis) in 6/9 individuals evaluated</div></li><li class="half_rhythm"><div><b>Anorectal malformations</b> (e.g., anteriorly placed anus, anal stenosis) in 2/9 individuals evaluated</div></li><li class="half_rhythm"><div><b>Airway malformations</b> in 2/8 individuals evaluated</div></li></ul></div><div id="mota.FREM1_Congenital_Anomalies_of_Kidne"><h4><i>FREM1</i>
|
||
<i>C</i>ongenital <i>A</i>nomalies of <i>K</i>idney and <i>U</i>rinary <i>T</i>ract (CAKUT)</h4><p><i>FREM1</i>-CAKUT <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> has been reported in an individual with bilateral vesicoureteral reflux (VUR) grade III and in another individual with right-sided VUR grade V in conjunction with right-sided renal hypodysplasia [<a class="bk_pop" href="#mota.REF.kohl.2014.1917">Kohl et al 2014</a>].</p></div><div id="mota.Other_Phenotypes"><h4>Other Phenotypes</h4><p>The following other phenotypes have been reported in individuals with <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <i>FREM1</i> pathogenic variants:</p><ul><li class="half_rhythm"><div>One individual with <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> diaphragmatic hernia [<a class="bk_pop" href="#mota.REF.beck.2013.1026">Beck et al 2013</a>]</div></li><li class="half_rhythm"><div>One fetus with severe hydrocephalus and shortened limbs associated with novel <i>FREM1</i> pathogenic variants [<a class="bk_pop" href="#mota.REF.yang.2017.262">Yang et al 2017</a>]</div></li></ul></div></div><div id="mota.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>Genotype-<a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> correlations have not been possible to date given the rarity of the condition and limited number of pathogenic variants described.</p></div><div id="mota.Prevalence"><h3>Prevalence</h3><p>The prevalence of <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorders are unknown. To date, the authors are aware of 27 published individuals with MOTA syndrome.</p><p>Based on the number of individuals identified to date in the aboriginal Oji-Cree community of the Island Lake region of northern Manitoba, Canada, which had a population of 4,685 in 1996 and 2,020 in 2001 [First Nation <a class="bk_pop" href="#mota.REF.profiles.2004">Profiles 2004</a>], the incidence of MOTA syndrome in that population is estimated at 2:1,000-6:1,000 births; however, this may be an underestimate in this population, as a few presumably affected individuals have also been identified through family histories of affected individuals, and some milder cases may not have come to medical attention. All affected individuals from the Island Lake region identified to date are presumed to be related.</p></div></div><div id="mota.Genetically_Related_Allelic_Disorde"><h2 id="_mota_Genetically_Related_Allelic_Disorde_">Genetically Related (Allelic) Disorders</h2><p>Heterozygous <i>FREM1</i> pathogenic variants have been reported in individuals with nonsyndromic metopic craniosynostosis (OMIM <a href="https://omim.org/entry/614485" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">614485</a>) [<a class="bk_pop" href="#mota.REF.vissers.2011.e1002278">Vissers et al 2011</a>].</p><p>Larger deletions of <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> 9p22.3 encompassing part or all of the <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> have been reported in individuals with metopic craniosynostosis [<a class="bk_pop" href="#mota.REF.swinkels.2008.1430">Swinkels et al 2008</a>]. Additional clinical features associated with 9p22.3 <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> may include developmental delay, short stature, and <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> cardiac defect (e.g., pulmonary stenosis, ventricular septal defect).</p></div><div id="mota.Differential_Diagnosis"><h2 id="_mota_Differential_Diagnosis_">Differential Diagnosis</h2><p>The following disorders should be considered in the differential diagnosis of Manitoba oculotrichoanal (MOTA) syndrome and <i>b</i>ifid <i>n</i>ose with or without <i>a</i>norectal and <i>r</i>enal anomalies (BNAR) syndrome (<a href="/books/NBK1728/table/mota.T.disorders_to_consider_in_the_diff/?report=objectonly" target="object" rid-ob="figobmotaTdisorderstoconsiderinthediff">Table 2</a>).</p><div id="mota.T.disorders_to_consider_in_the_diff" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Disorders to Consider in the Differential Diagnosis of MOTA Syndrome and BNAR Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1728/table/mota.T.disorders_to_consider_in_the_diff/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mota.T.disorders_to_consider_in_the_diff_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_1" style="text-align:left;vertical-align:middle;">DiffDx Disorder</th><th id="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_2" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Clinical Features of DiffDx Disorder</th></tr><tr><th headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4" id="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/MOTA &/or BNAR syndrome</th><th headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4" id="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from MOTA & BNAR syndromes</th></tr></thead><tbody><tr><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fraser syndrome<br />(OMIM <a href="https://omim.org/phenotypicSeries/PS219000" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS219000</a>)</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>FRAS1</i>
|
||
<br />
|
||
<i>REM2</i>
|
||
<br />
|
||
<i>GRIP1</i>
|
||
</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Anophthalmia/microphthalmia, cryptophthalmos, eyelid colobomas, widely spaced eyes</div></li><li class="half_rhythm"><div>Wedge-shaped lateral anterior hairline</div></li><li class="half_rhythm"><div>Bifid nasal tip / notched ala nasi</div></li><li class="half_rhythm"><div>Anal stenosis or imperforate anus <sup>1</sup></div></li></ul>
|
||
</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cognitive impairment</div></li><li class="half_rhythm"><div>Often early mortality</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frontonasal dysplasia (FND) (OMIM <a href="https://omim.org/phenotypicSeries/PS136760" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS136760</a>)</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>ALX1</i>
|
||
<br />
|
||
<i>ALX3</i>
|
||
<br />
|
||
<i>ALX4</i>
|
||
</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Widely spaced eyes</div></li><li class="half_rhythm"><div>Broad forehead</div></li><li class="half_rhythm"><div>Widow's peak</div></li><li class="half_rhythm"><div>Range from notched ala nasi to bifid nose <sup>2</sup></div></li></ul>
|
||
</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cranium bifidum <sup>3</sup></div></li><li class="half_rhythm"><div>Absence of omphalocele & anorectal abnormalities</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Craniofrontonasal dysplasia (CFND)<br />(OMIM <a href="https://omim.org/entry/304110" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">304110</a>)</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>EFNB1</i>
|
||
</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In females w/CFND: <sup>4</sup>
|
||
<ul><li class="half_rhythm"><div>Widely spaced eyes</div></li><li class="half_rhythm"><div>Broad nasal bridge, bifid nasal tip</div></li></ul>
|
||
</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Craniosynostosis</div></li><li class="half_rhythm"><div>Cranium bifidum</div></li><li class="half_rhythm"><div>Absence of omphalocele & anorectal abnormalities</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Oculoauriculofrontonasal syndrome<br />(OMIM <a href="https://omim.org/entry/601452" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">601452</a>)</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Upper eyelid colobomas, widely spaced eyes</div></li><li class="half_rhythm"><div>Notched ala nasi or bifid nose</div></li><li class="half_rhythm"><div>Normal intelligence</div></li></ul>
|
||
</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hemifacial microsomia</div></li><li class="half_rhythm"><div>Ear malformations, preauricular tags</div></li><li class="half_rhythm"><div>Epibulbar dermoids</div></li><li class="half_rhythm"><div>Abnormalities of the frontal bone</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">FG syndrome type 1<br />(See <a href="/books/n/gene/fg/"><i>MED12</i>-Related Disorders</a>.)</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>MED12</i>
|
||
</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In a male infant:
|
||
<ul><li class="half_rhythm"><div>Widely spaced eyes</div></li><li class="half_rhythm"><div>Anteriorly placed anus, anal stenosis</div></li></ul>
|
||
</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Often, additional findings such as:
|
||
<ul><li class="half_rhythm"><div>Thumb anomalies</div></li><li class="half_rhythm"><div>Vertebral abnormalities</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/tbs/">Townes-Brocks syndrome</a>
|
||
</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>SALL1</i>
|
||
</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Anteriorly placed anus, anal stenosis</td></tr><tr><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">VACTERL<br />(OMIM <a href="https://omim.org/entry/192350" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">192350</a>)</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown</td></tr><tr><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/donnai/">Donnai-Barrow syndrome</a>
|
||
</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>LRP2</i>
|
||
</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Widely spaced eyes</div></li><li class="half_rhythm"><div>Omphalocele</div></li></ul>
|
||
</td><td headers="hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_mota.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Agenesis of the corpus callosum</div></li><li class="half_rhythm"><div>Sensorineural hearing loss</div></li><li class="half_rhythm"><div>Diaphragmatic hernia</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; DiffDx = differential diagnosis; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; VACTERL = <i>v</i>ertebral abnormalities, <i>a</i>nal abnormalities, <i>c</i>ardiac defects, <i>t</i>racheo<i>e</i>sophageal fistula, <i>r</i>enal and/or <i>r</i>adial ray abnormalities, and <i>l</i>imb anomalies; XL = <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a></p></div></dd><dt>1. </dt><dd><div id="mota.TF.2.1"><p class="no_margin"><a class="bk_pop" href="#mota.REF.slavotinek.2002.623">Slavotinek & Tifft [2002]</a>, <a class="bk_pop" href="#mota.REF.mcgregor.2003.203">McGregor et al [2003]</a>, <a class="bk_pop" href="#mota.REF.vrontou.2003.209">Vrontou et al [2003]</a></p></div></dd><dt>2. </dt><dd><div id="mota.TF.2.2"><p class="no_margin">
|
||
<a class="bk_pop" href="#mota.REF.jones.2006">Jones [2006]</a>
|
||
</p></div></dd><dt>3. </dt><dd><div id="mota.TF.2.3"><p class="no_margin">Cranium bifidum is a midline defect of the frontal bone detected on skull x-rays.</p></div></dd><dt>4. </dt><dd><div id="mota.TF.2.4"><p class="no_margin">CFND is inherited in a unique <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a> manner that paradoxically shows greater severity in <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> females than in <a class="def" href="/books/n/gene/glossary/def-item/hemizygous/">hemizygous</a> males. Typically, females have FND, craniofacial asymmetry, craniosynostosis, a bifid nasal tip, and grooved nails; they may also have skeletal abnormalities. In contrast, males typically show only widely spaced eyes [<a class="bk_pop" href="#mota.REF.twigg.2004.8652">Twigg et al 2004</a>, <a class="bk_pop" href="#mota.REF.wieland.2004.1209">Wieland et al 2004</a>].</p></div></dd></dl></div></div></div><p><b><i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> anomalies of kidney and urinary tract (CAKUT).</b> Isolated CAKUT has been associated with more than 20 genes to date and may be inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>, <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>, or <a class="def" href="/books/n/gene/glossary/def-item/multifactorial/">multifactorial</a> manner [<a class="bk_pop" href="#mota.REF.nicolaou.2015.720">Nicolaou et al 2015</a>]. The genetic etiology in most individuals with <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> CAKUT is unknown [<a class="bk_pop" href="#mota.REF.kohl.2014.1917">Kohl et al 2014</a>].</p></div><div id="mota.Management"><h2 id="_mota_Management_">Management</h2><div id="mota.Evaluations_Following_Initial_Diagn"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with a <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorder, the evaluations summarized in <a href="/books/NBK1728/table/mota.T.recommended_evaluations_following/?report=objectonly" target="object" rid-ob="figobmotaTrecommendedevaluationsfollowing">Table 3</a>, <a href="/books/NBK1728/table/mota.T.recommended_evaluations_following_1/?report=objectonly" target="object" rid-ob="figobmotaTrecommendedevaluationsfollowing1">Table 4</a>, or <a href="/books/NBK1728/table/mota.T.recommended_evaluations_following_2/?report=objectonly" target="object" rid-ob="figobmotaTrecommendedevaluationsfollowing2">Table 5</a> (depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>) are recommended if they have not already been performed as part of the evaluation that led to the diagnosis:</p><div id="mota.T.recommended_evaluations_following" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with MOTA Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1728/table/mota.T.recommended_evaluations_following/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mota.T.recommended_evaluations_following_lrgtbl__"><table><thead><tr><th id="hd_h_mota.T.recommended_evaluations_following_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_mota.T.recommended_evaluations_following_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_mota.T.recommended_evaluations_following_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Ocular</b>
|
||
</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic eval</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For coloboma &/or keratopathy</td></tr><tr><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal</b>
|
||
</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to surgeon</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For omphalocele, umbilical hernia, &/or anal anomalies if present</td></tr><tr><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>ENT</b>
|
||
</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval for bifid nose / notched ala nasi</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to plastic surgeon as needed</td></tr><tr><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Other</b>
|
||
</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div></div><div id="mota.T.recommended_evaluations_following_1" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with BNAR Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1728/table/mota.T.recommended_evaluations_following_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mota.T.recommended_evaluations_following_1_lrgtbl__"><table><thead><tr><th id="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Renal</b>
|
||
</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Renal imaging & renal functional analysis</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal</b>
|
||
</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to surgeon</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For omphalocele, umbilical hernia, &/or anal anomalies if present</td></tr><tr><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Respiratory</b>
|
||
</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>ENT eval for bifid or notched nose</div></li><li class="half_rhythm"><div>Eval of the airway</div></li></ul>
|
||
</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to plastic surgeon as needed</td></tr><tr><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Other</b>
|
||
</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td><td headers="hd_h_mota.T.recommended_evaluations_following_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div></div><div id="mota.T.recommended_evaluations_following_2" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with <i>FREM1</i>-CAKUT</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1728/table/mota.T.recommended_evaluations_following_2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mota.T.recommended_evaluations_following_2_lrgtbl__"><table><thead><tr><th id="hd_h_mota.T.recommended_evaluations_following_2_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_mota.T.recommended_evaluations_following_2_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th></tr></thead><tbody><tr><td headers="hd_h_mota.T.recommended_evaluations_following_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genitourinary</b>
|
||
</td><td headers="hd_h_mota.T.recommended_evaluations_following_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical exam, imaging & surgical eval</td></tr><tr><td headers="hd_h_mota.T.recommended_evaluations_following_2_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Other</b>
|
||
</td><td headers="hd_h_mota.T.recommended_evaluations_following_2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td></tr></tbody></table></div></div></div><div id="mota.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Treatment of <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorders consists primarily of surgical intervention with procedures tailored to the specific needs of the individual. A multidisciplinary team comprising a clinical geneticist, general surgeon, ophthalmologist, otolaryngologist, plastic surgeon, and social worker is preferred for optimal management.</p><div id="mota.T.treatment_of_manifestations_in_in" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with <i>FREM1</i> Autosomal Recessive Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1728/table/mota.T.treatment_of_manifestations_in_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mota.T.treatment_of_manifestations_in_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/<br />Concern</th><th id="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Colobomas of upper eyelids & synechiae</b>
|
||
</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Managed conservatively w/intensive ocular lubrication</div></li><li class="half_rhythm"><div>Surgical release of synechiae</div></li></ul>
|
||
</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To avoid exposure keratopathy before surgery is performed</td></tr><tr><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Anophthalmia/microphthalmia & cryptophthalmos</b>
|
||
</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May warrant surgical intervention & insertion of prostheses</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To facilitate development of ocular region <sup>1</sup></td></tr><tr><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Visual impairment (e.g., refractive errors)</b>
|
||
</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per ophthalmologist</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May be assoc w/colobomas & corneopalpebral synechiae</td></tr><tr><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Notched ala nasi or bifid nose</b>
|
||
</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rhinoplasty</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May be performed for cosmetic purposes</td></tr><tr><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Omphalocele & umbilical hernia</b>
|
||
</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May be managed conservatively or surgically</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To date, all persons w/a <i>FREM1</i> AR disorder managed surgically have tolerated the procedure w/out complications.</td></tr><tr><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Anal stenosis</b>
|
||
</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Serial dilations</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Anteriorly placed anus</b>
|
||
</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Managed conservatively or w/surgical intervention</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As determined on an individual basis</td></tr><tr><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Renal malformations</b>
|
||
</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Supportive treatment to preserve renal function & electrolyte balance</div></li><li class="half_rhythm"><div>Surgical correction when indicated</div></li></ul>
|
||
</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dialysis & transplant may be indicated in persons w/renal failure.</td></tr><tr><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Psychosocial stressors</b>
|
||
</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Psychosocial support</td><td headers="hd_h_mota.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May be indicated for parents & affected child</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a></p></div></dd><dt>1. </dt><dd><div id="mota.TF.6.1"><p class="no_margin">
|
||
<a class="bk_pop" href="#mota.REF.seah.2002.190">Seah et al [2002]</a>
|
||
</p></div></dd></dl></div></div></div></div><div id="mota.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#mota.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="mota.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="mota.Genetic_Counseling"><h2 id="_mota_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="mota.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Manitoba oculotrichoanal (MOTA) syndrome, <i>b</i>ifid <i>n</i>ose with or without <i>a</i>norectal and <i>r</i>enal anomalies (BNAR syndrome), and <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> anomalies of kidney and urinary tract (CAKUT) are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> manner.</p></div><div id="mota.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>The parents of an affected child are obligate heterozygotes (i.e., carriers of one <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>).</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are not affected with MOTA, BNAR, or <i>FREM1</i>-CAKUT. To date, <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parents of individuals with MOTA, BNAR, or <i>FREM1</i>-CAKUT have not been reported to have <i>FREM1</i> trigonocephaly (see <a href="#mota.Genetically_Related_Allelic_Disorde">Genetically Related Disorders</a>).</div></li></ul><p>
|
||
<b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a>, and a 25% chance of being unaffected and not a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are not affected with MOTA, BNAR, or <i>FREM1</i>-CAKUT. To date, <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> sibs of individuals with MOTA, BNAR, or <i>FREM1</i>-CAKUT have not been reported to have <i>FREM1</i> trigonocephaly (see <a href="#mota.Genetically_Related_Allelic_Disorde">Genetically Related Disorders</a>).</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The offspring of an individual with a <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorder are obligate heterozygotes (carriers) for a <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p><p><b>Other family members.</b> Each sib of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents is at a 50% risk of being a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> of a <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p></div><div id="mota.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>FREM1</i> pathogenic variants in the family.</p></div><div id="mota.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk, clarification of <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> status, and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bk_pop" href="#mota.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="mota.Prenatal_Testing_and_Preimplantatio"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p><b>Molecular genetic testing.</b> Once the <i>FREM1</i> pathogenic variants have been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p><p><b>Pregnancies at high a priori risk.</b> Ultrasound examination may be diagnostic of Manitoba oculotrichoanal (MOTA) syndrome if findings such as omphalocele, cryptophthalmos, anophthalmia/microphthalmia, widely spaced eyes, and/or a wide nose are detected. However, mild findings may be difficult to detect on prenatal imaging.</p><p><b>Pregnancies at low a priori risk.</b> Chromosome analysis and possibly DNA-based testing for other specific disorders with findings similar to MOTA syndrome should be considered when omphalocele and craniofacial features associated with MOTA syndrome are identified on fetal ultrasound examination in a pregnancy not known to be at risk for MOTA syndrome.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="mota.Resources"><h2 id="_mota_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>Children's Craniofacial Association</b>
|
||
</div><div><b>Phone:</b> 800-535-3643</div><div><b>Email:</b> contactCCA@ccakids.com</div><div>
|
||
<a href="https://ccakids.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ccakids.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Face Equality International</b>
|
||
</div><div>United Kingdom</div><div>
|
||
<a href="https://faceequalityinternational.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">faceequalityinternational.org</a>
|
||
</div></li></ul>
|
||
</div><div id="mota.Molecular_Genetics"><h2 id="_mota_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="mota.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>FREM1 Autosomal Recessive Disorders : Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1728/table/mota.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mota.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_mota.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_mota.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_mota.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_mota.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_mota.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_mota.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_mota.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/158326" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>FREM1</i>
|
||
</a>
|
||
</td><td headers="hd_b_mota.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=158326" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">9p22<wbr style="display:inline-block"></wbr>.3</a>
|
||
</td><td headers="hd_b_mota.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q5H8C1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FRAS1-related extracellular matrix protein 1</a>
|
||
</td><td headers="hd_b_mota.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://databases.lovd.nl/shared/genes/FREM1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FREM1 database</a>
|
||
</td><td headers="hd_b_mota.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=FREM1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FREM1</a>
|
||
</td><td headers="hd_b_mota.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=FREM1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FREM1</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="mota.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="mota.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for FREM1 Autosomal Recessive Disorders (<a href="/omim/248450,608944,608980" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1728/table/mota.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mota.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/248450" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">248450</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MANITOBA OCULOTRICHOANAL SYNDROME; MOTA</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/608944" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">608944</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">FRAS1-RELATED EXTRACELLULAR MATRIX PROTEIN 1; FREM1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/608980" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">608980</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">BIFID NOSE WITH OR WITHOUT ANORECTAL AND RENAL ANOMALIES; BNAR</td></tr></tbody></table></div></div><div id="mota.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>The FREM1 protein is a member of the FRAS1/FREM family of extracellular matrix proteins that are located in the sublamina densa of epithelial basement membranes during embryogenesis [<a class="bk_pop" href="#mota.REF.pavlakis.2011.487">Pavlakis et al 2011</a>]. FREM1 forms a ternary complex with FRAS1, FREM2, and FREM3, which have similar functional domains and structures [<a class="bk_pop" href="#mota.REF.pavlakis.2011.487">Pavlakis et al 2011</a>]. The ternary complex is critical for maintenance of epithelial-mesenchymal cohesion during embryonic development in mammals [<a class="bk_pop" href="#mota.REF.pavlakis.2011.487">Pavlakis et al 2011</a>]. <i>FREM1</i> pathogenic variants in humans are predicted to disturb the interactions with the proteins in this complex, although the levels of FRAS1 and FREM2 are not decreased [<a class="bk_pop" href="#mota.REF.vissers.2011.e1002278">Vissers et al 2011</a>]. Loss or disruption of the ternary complex is thought to reduce epithelial-mesenchymal adhesion during development, with subsequent generation of the characteristic clinical findings associated with Fraser syndrome and the <i>FREM1</i> <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorders [<a class="bk_pop" href="#mota.REF.chaconcamacho.2017.190">Chacon-Camacho et al 2017</a>].</p><p><b>Mechanism of disease causation.</b> All pathogenic variants reported to date in <i>FREM1</i> are hypothesized to result in loss of function.</p><div id="mota.T.notable_frem1_pathogenic_variants" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Notable <i>FREM1</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1728/table/mota.T.notable_frem1_pathogenic_variants/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__mota.T.notable_frem1_pathogenic_variants_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change<br />(Alias <sup>1</sup>)</th><th id="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_1" rowspan="6" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_144966.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_144966<wbr style="display:inline-block"></wbr>.5</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_659403.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_659403<wbr style="display:inline-block"></wbr>.4</a>
|
||
</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.824+627_3840-1311del<br />(IVS7+631_IVS23-1311 del; del8-23 <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a>)</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.385_1327del</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Common <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> assoc w/MOTA in Oji-Cree [<a class="bk_pop" href="#mota.REF.slavotinek.2011.375">Slavotinek et al 2011</a>]</td></tr><tr><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.3971T>G</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu1324Arg</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_4" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Observed in 1 person w/MOTA & features of Fraser syndrome [<a class="bk_pop" href="#mota.REF.mitter.2012.136">Mitter et al 2012</a>]</td></tr><tr><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.4629delC</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Phe1544SerfsTer62</td></tr><tr><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.2721delG</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Val908SerfsTer17</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_4" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Observed <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> in persons w/BNAR [<a class="bk_pop" href="#mota.REF.alazami.2009.414">Alazami et al 2009</a>]</td></tr><tr><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1945C>T</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg649Trp</td></tr><tr><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.4318G>A</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly1440Ser</td></tr><tr><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_144966.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_144966<wbr style="display:inline-block"></wbr>.5</a>
|
||
</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.5334+1G>A/~86-kb <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> upstream <i>FREM1</i></td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">--</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Complex <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> assoc w/<a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> CDH [<a class="bk_pop" href="#mota.REF.beck.2013.1026">Beck et al 2013</a>]</td></tr><tr><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_144966.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_144966<wbr style="display:inline-block"></wbr>.5</a>
|
||
<br />
|
||
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_659403.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_659403<wbr style="display:inline-block"></wbr>.4</a>
|
||
</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.4879G>T</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ala1627Ser</td><td headers="hd_h_mota.T.notable_frem1_pathogenic_variants_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Observed in persons w/CAKUT [<a class="bk_pop" href="#mota.REF.kohl.2014.1917">Kohl et al 2014</a>]</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd><dt>1. </dt><dd><div id="mota.TF.7.1"><p class="no_margin">Variant designation that does not conform to current naming conventions</p></div></dd></dl></div></div></div></div></div><div id="mota.Chapter_Notes"><h2 id="_mota_Chapter_Notes_">Chapter Notes</h2><div id="mota.Author_History"><h3>Author History</h3><p>Albert E Chudley, MD, FRCPC, FCCMG; University of Manitoba (2011-2019)<br />Chumei Li, MD, PhD, FRCPC, FCCMG (2008-present)<br />Anne Slavotinek, MBBS, PhD (2011-present)</p></div><div id="mota.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>9 May 2019 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>13 October 2011 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>9 July 2008 (me) Review posted live</div></li><li class="half_rhythm"><div>16 May 2008 (cl) Original submission</div></li></ul></div></div><div id="mota.References"><h2 id="_mota_References_">References</h2><div id="mota.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="mota.REF.alazami.2009.414">Alazami AM, Shaheen R, Alzahrani F, Snape K, Saggar A, Brinkmann B, Bavi P, Al-Gazali LI, Alkuraya FS. FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome. <span><span class="ref-journal">Am J Hum Genet. </span>2009;<span class="ref-vol">85</span>:414–8.</span> [<a href="/pmc/articles/PMC2771533/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2771533</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19732862" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19732862</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.algazali.2002.33">Al-Gazali LI, Bakir M, Hamud OA, Gerami S. An autosomal recessive syndrome of nasal anomalies associated with renal and anorectal malformations. <span><span class="ref-journal">Clin Dysmorphol. </span>2002;<span class="ref-vol">11</span>:33–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11822703" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11822703</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.beck.2013.1026">Beck TF, Veenma D, Shchelochkov OA, Yu Z, Kim BJ, Zaveri HP, van Bever Y, Choi S, Douben H, Bertin TK, Patel PI, Lee B, Tibboel D, de Klein A, Stockton DW, Justice MJ, Scott DA. Deficiency of FRAS1-related extracellular matrix 1 (FREM1) causes congenital diaphragmatic hernia in humans and mice. <span><span class="ref-journal">Hum Mol Genet. </span>2013;<span class="ref-vol">22</span>:1026–38.</span> [<a href="/pmc/articles/PMC3561915/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3561915</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23221805" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23221805</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.chaconcamacho.2017.190">Chacon-Camacho OF, Zenker M, Schanze D, Ledesma-Gil J, Zenteno JC. Novel FREM1 mutations in a patient with MOTA syndrome: clinical findings, mutation update and review of FREM1-related disorders literature. <span><span class="ref-journal">Eur J Med Genet. </span>2017;<span class="ref-vol">60</span>:190–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28111185" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28111185</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.profiles.2004">First Nation Profiles. Indigenous and Northern Affairs Canada <a href="https://www.canada.ca/en/indigenous-northern-affairs.html" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">website</a>. 2004. Accessed 5-23-23.</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.huang.2022.389">Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. <span><span class="ref-journal">J Community Genet. </span>2022;<span class="ref-vol">13</span>:389–97.</span> [<a href="/pmc/articles/PMC9314484/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9314484</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35834113" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35834113</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.jones.2006">Jones KL. Frontonasal dysplasia sequence. In: <em>Smith’s Recognizable Patterns of Human Malformation</em>. 6 ed. Philadelphia, PA: Elsevier Saunders; 2006:1268-9.</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.kohl.2014.1917">Kohl S, Hwang DY, Dworschak GC, Hilger AC, Saisawat P, Vivante A, Stajic N, Bogdanovic R, Reutter HM, Kehinde EO, Tasic V, Hildebrandt F. Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. <span><span class="ref-journal">J Am Soc Nephrol. </span>2014;<span class="ref-vol">25</span>:1917–22.</span> [<a href="/pmc/articles/PMC4147986/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4147986</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24700879" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24700879</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.mcgregor.2003.203">McGregor L, Makela V, Darling SM, Vrontou S, Chalepakis G, Roberts C, Smart N, Rutland P, Prescott N, Hopkins J, Bentley E, Shaw A, Roberts E, Mueller R, Jadeja S, Philip N, Nelson J, Francannet C, Perez AA, Megarband A, Kerr B, Wainwright B, Woolf AS, Winter RM, Scambler PJ. Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. <span><span class="ref-journal">Nat Genet. </span>2003;<span class="ref-vol">34</span>:203–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12766769" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12766769</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.mitter.2012.136">Mitter D, Schanze D, Sterker I, Müller D, Till H, Zenker M. MOTA syndrome: molecular genetic confirmation of the diagnosis in a newborn with previously unreported clinical features. <span><span class="ref-journal">Mol Syndromol. </span>2012;<span class="ref-vol">3</span>:136–9.</span> [<a href="/pmc/articles/PMC3473350/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3473350</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23112756" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23112756</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.nathanson.2013.473">Nathanson J, Swarr DT, Singer A, Liu M, Chinn A, Jones W, Hurst J, Khalek N, Zackai E, Slavotinek A. Novel FREM1 mutations expand the phenotypic spectrum associated with Manitoba-oculo-tricho-anal (MOTA) syndrome and bifid nose renal agenesis anorectal malformations (BNAR) syndrome. <span><span class="ref-journal">Am J Med Genet A. </span>2013;<span class="ref-vol">161A</span>:473–8.</span> [<a href="/pmc/articles/PMC3581754/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3581754</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23401257" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23401257</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.nicolaou.2015.720">Nicolaou N, Renkema KY, Bongers EM, Giles RH, Knoers NV. Genetic, environmental, and epigenetic factors involved in CAKUT. <span><span class="ref-journal">Nat Rev Nephrol. </span>2015;<span class="ref-vol">11</span>:720–31.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/26281895" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26281895</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.nouby.2002.373">Nouby G. Congenital upper eyelid coloboma and cryptophthalmos. <span><span class="ref-journal">Ophthal Plast Reconstr Surg. </span>2002;<span class="ref-vol">18</span>:373–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12352825" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12352825</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.pavlakis.2011.487">Pavlakis E, Chiotaki R, Chalepakis G. The role of Fras1/Frem proteins in the structure and function of the basement membrane. <span><span class="ref-journal">Int J Biochem Cell Biol. </span>2011;<span class="ref-vol">43</span>:487–95.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21182980" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21182980</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.richards.2015.405">Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. <span><span class="ref-journal">Genet Med. </span>2015;<span class="ref-vol">17</span>:405–24.</span> [<a href="/pmc/articles/PMC4544753/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4544753</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25741868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25741868</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.seah.2002.190">Seah LL, Choo CT, Fong KS. Congenital upper lid colobomas: management and visual outcome. <span><span class="ref-journal">Ophthal Plast Reconstr Surg. </span>2002;<span class="ref-vol">18</span>:190–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12021649" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12021649</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.slavotinek.2011.375">Slavotinek AM, Baranzini SE, Schanze D, Labelle-Dumais C, Short KM, Chao R, Yahyavi M, Bijlsma EK, Chu C, Musone S, Wheatley A, Kwok PY, Marles S, Fryns JP, Maga AM, Hassan MG, Gould DB, Madireddy L, Li C, Cox TC, Smyth I, Chudley AE, Zenker M. Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1. <span><span class="ref-journal">J Med Genet. </span>2011;<span class="ref-vol">48</span>:375–82.</span> [<a href="/pmc/articles/PMC4294942/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4294942</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21507892" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21507892</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.slavotinek.2002.623">Slavotinek AM, Tifft CJ. Fraser syndrome and cryptophthalmos: review of the diagnostic criteria and evidence for phenotypic modules in complex malformation syndromes. <span><span class="ref-journal">J Med Genet. </span>2002;<span class="ref-vol">39</span>:623–33.</span> [<a href="/pmc/articles/PMC1735240/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1735240</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12205104" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12205104</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.swinkels.2008.1430">Swinkels ME, Simons A, Smeets DF, Vissers LE, Veltman JA, Pfundt R, de Vries BB, Faas BH, Schrander-Stumpel CT, McCann E, Sweeney E, May P, Draaisma JM, Knoers NV, van Kessel AG, van Ravenswaaij-Arts CM. Clinical and cytogenetic characterization of 13 Dutch patients with deletion 9p syndrome: delineation of the critical region for a consensus phenotype. <span><span class="ref-journal">Am J Med Genet A. </span>2008;<span class="ref-vol">146A</span>:1430–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18452192" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18452192</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.twigg.2004.8652">Twigg SRF, Kan R, Babbs C, Bochukova EG, Robertson SP, Wall SA, Morriss-Kay GM, Wilkie AOM. Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause craniofrontonasal syndrome. <span><span class="ref-journal">Proc Nat Acad Sci. </span>2004;<span class="ref-vol">101</span>:8652–7.</span> [<a href="/pmc/articles/PMC423250/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC423250</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15166289" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15166289</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.vissers.2011.e1002278">Vissers LE, Cox TC, Maga AM, Short KM, Wiradjaja F, Janssen IM, Jehee F, Bertola D, Liu J, Yagnik G, Sekiguchi K, Kiyozumi D, van Bokhoven H, Marcelis C, Cunningham ML, Anderson PJ, Boyadjiev SA, Passos-Bueno MR, Veltman JA, Smyth I, Buckley MF, Roscioli T. Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. <span><span class="ref-journal">PLoS Genet. </span>2011;<span class="ref-vol">7</span>:e1002278. </span> [<a href="/pmc/articles/PMC3169541/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3169541</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21931569" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21931569</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.vrontou.2003.209">Vrontou S, Petrou P, Meyer BI, Galanopoulos VK, Imai K, Yanagi M, Chowdhury K, Scambler PJ, Chalepakis G. Fras1 deficiency results in cryptophthalmos, renal agenesis and blebbed phenotype in mice. <span><span class="ref-journal">Nat Genet. </span>2003;<span class="ref-vol">34</span>:209–14.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12766770" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12766770</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.wieland.2004.1209">Wieland I, Jakubiczka S, Muschke P, Cohen M, Thiele H, Gerlach KL, Adams RH, Wieacker P. Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome. <span><span class="ref-journal">Am J Hum Genet. </span>2004;<span class="ref-vol">74</span>:1209–15.</span> [<a href="/pmc/articles/PMC1182084/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1182084</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15124102" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15124102</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="mota.REF.yang.2017.262">Yang YD, Huang LY, Yan JM, Han J, Zhang Y, Li DZ. Novel FREM1 mutations are associated with severe hydrocephalus and shortened limbs in a prenatal case. <span><span class="ref-journal">Eur J Obstet Gynecol Reprod Biol. </span>2017;<span class="ref-vol">215</span>:262–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28622873" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28622873</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
|
||
<div class="post-content"><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
|
||
a registered trademark of the University of Washington, Seattle. All rights
|
||
reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
|
||
hereby granted to reproduce, distribute, and translate copies of content materials for
|
||
noncommercial research purposes only, provided that (i) credit for source (<a href="http://www.genereviews.org/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">http://www.genereviews.org/</a>) and copyright (© 1993-2025 University of
|
||
Washington) are included with each copy; (ii) a link to the original material is provided
|
||
whenever the material is published elsewhere on the Web; and (iii) reproducers,
|
||
distributors, and/or translators comply with the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
|
||
Disclaimer</a>. No further modifications are allowed. For clarity, excerpts
|
||
of GeneReviews chapters for use in lab reports and clinic notes are a permitted
|
||
use.</p><p class="small">For more information, see the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
|
||
Disclaimer</a>.</p><p class="small">For questions regarding permissions or whether a specified use is allowed,
|
||
contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div><div class="small"><span class="label">Bookshelf ID: NBK1728</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/20301721" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">20301721</a></span></div><div style="margin-top:2em" class="bk_noprnt"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/foxp2-sl-dis/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/xl-nystag/" title="Next page in this title">Next ></a></div></div></div></div>
|
||
|
||
</div>
|
||
|
||
<!-- Custom content below content -->
|
||
<div class="col4">
|
||
|
||
</div>
|
||
|
||
|
||
<!-- Book content -->
|
||
|
||
<!-- Custom contetnt below bottom nav -->
|
||
<div class="col5">
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div id="rightcolumn" class="four_col col last">
|
||
<!-- Custom content above discovery portlets -->
|
||
<div class="col6">
|
||
<div id="ncbi_share_book"><a href="#" class="ncbi_share" data-ncbi_share_config="popup:false,shorten:true" ref="id=NBK1728&db=books">Share</a></div>
|
||
|
||
</div>
|
||
<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK1728/?report=reader">PubReader</a></li><li><a href="/books/NBK1728/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK1728" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK1728" style="display:none" title="Cite this Page"><div class="bk_tt">Li C, Slavotinek A. FREM1 Autosomal Recessive Disorders. 2008 Jul 9 [Updated 2019 May 9]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK1728/pdf/Bookshelf_NBK1728.pdf">PDF version of this page</a> (495K)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this GeneReview</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#mota.Summary" ref="log$=inpage&link_id=inpage">Summary</a></li><li><a href="#mota.GeneReview_Scope" ref="log$=inpage&link_id=inpage"><i>GeneReview</i> Scope</a></li><li><a href="#mota.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#mota.Genetically_Related_Allelic_Disorde" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#mota.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#mota.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#mota.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#mota.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#mota.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#mota.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li><li><a href="#mota.References" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/ca/84/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download GeneReviews data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>GeneReviews Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/gene/advanced/"><i>GeneReviews</i> Advanced Search</a></li><li><a href="/books/n/gene/glossary/"><i>GeneReviews</i> Glossary</a></li><li><a href="/books/n/gene/resource_mats/">Resource Materials</a> <span class="bk_hlight1">NEW FEATURE</span></li><li><a href="/books/n/gene/updates/">New in <i>GeneReviews</i></a></li><li><a href="/books/n/gene/authors/">Author List</a></li><li><a href="/books/n/gene/prospective_authors/">For Current/Prospective Authors</a></li><li><a href="/books/n/gene/GRpersonnel/"><i>GeneReviews</i> Personnel</a></li><li><a href="/books/n/gene/howto_linkin/">Download/Link to <i>GeneReviews</i></a></li><li><a href="/books/n/gene/contact_us/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Tests in GTR by Gene</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
|
||
<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=158326[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">FREM1</a>
|
||
</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=medgen&DbFrom=books&Cmd=Link&LinkName=books_medgen&IdsFromResult=1469556" ref="log$=recordlinks">MedGen</a><div class="brieflinkpop offscreen_noflow">Related information in MedGen</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=omim&DbFrom=books&Cmd=Link&LinkName=books_omim&IdsFromResult=1469556" ref="log$=recordlinks">OMIM</a><div class="brieflinkpop offscreen_noflow">Related OMIM records</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=1469556" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=1469556" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=gene&DbFrom=books&Cmd=Link&LinkName=books_gene&IdsFromResult=1469556" ref="log$=recordlinks">Gene</a><div class="brieflinkpop offscreen_noflow">Locus Links</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301736" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FLNB Disorders.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> FLNB Disorders.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Robertson S. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301599" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Beta-Thalassemia.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Beta-Thalassemia.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Langer AL. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301781" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Thrombocytopenia Absent Radius Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Thrombocytopenia Absent Radius Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Petit F, Boussion S. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301765" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Von Willebrand Disease.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Von Willebrand Disease.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Johnsen J. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301656" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Adenosine Deaminase Deficiency.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Hershfield M, Tarrant T. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=20301721" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=20301721" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67d2abd9f4a390645e37d748">FREM1 Autosomal Recessive Disorders - GeneReviews®</a><div class="ralinkpop offscreen_noflow">FREM1 Autosomal Recessive Disorders - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=2" href="/portal/utils/pageresolver.fcgi?recordid=67d2abd6f4a390645e37c3b1">FOXP2 forkhead box P2 [Homo sapiens]</a><div class="ralinkpop offscreen_noflow">FOXP2 forkhead box P2 [Homo sapiens]<div class="brieflinkpopdesc">Gene ID:93986</div></div><div class="tertiary">Gene</div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=3" href="/portal/utils/pageresolver.fcgi?recordid=67d2abd5f4a390645e37b274">FOXP2-Related Speech and Language Disorder - GeneReviews®</a><div class="ralinkpop offscreen_noflow">FOXP2-Related Speech and Language Disorder - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=4" href="/portal/utils/pageresolver.fcgi?recordid=67d2abd2f4a390645e37ab43">FOXP1 Syndrome - GeneReviews®</a><div class="ralinkpop offscreen_noflow">FOXP1 Syndrome - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=5" href="/portal/utils/pageresolver.fcgi?recordid=67d2abd0b15b832ebc1a799d">FOXG1 Syndrome - GeneReviews®</a><div class="ralinkpop offscreen_noflow">FOXG1 Syndrome - GeneReviews®<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li></ul><p class="HTOn">Your browsing activity is empty.</p><p class="HTOff">Activity recording is turned off.</p><p id="turnOn" class="HTOff"><a href="javascript:historyDisplayState('HTOn')">Turn recording back on</a></p><a class="seemore" href="/sites/myncbi/recentactivity">See more...</a></div></div></div>
|
||
|
||
<!-- Custom content below discovery portlets -->
|
||
<div class="col7">
|
||
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<!-- Custom content after all -->
|
||
<div class="col8">
|
||
|
||
</div>
|
||
<div class="col9">
|
||
|
||
</div>
|
||
|
||
<script type="text/javascript" src="/corehtml/pmc/js/jquery.scrollTo-1.4.2.js"></script>
|
||
<script type="text/javascript">
|
||
(function($){
|
||
$('.skiplink').each(function(i, item){
|
||
var href = $($(item).attr('href'));
|
||
href.attr('tabindex', '-1').addClass('skiptarget'); // ensure the target can receive focus
|
||
$(item).on('click', function(event){
|
||
event.preventDefault();
|
||
$.scrollTo(href, 0, {
|
||
onAfter: function(){
|
||
href.focus();
|
||
}
|
||
});
|
||
});
|
||
});
|
||
})(jQuery);
|
||
</script>
|
||
</div>
|
||
<div class="bottom">
|
||
|
||
<div id="NCBIFooter_dynamic">
|
||
<!--<component id="Breadcrumbs" label="breadcrumbs"/>
|
||
<component id="Breadcrumbs" label="helpdesk"/>-->
|
||
|
||
</div>
|
||
|
||
<div class="footer" id="footer">
|
||
<section class="icon-section">
|
||
<div id="icon-section-header" class="icon-section_header">Follow NCBI</div>
|
||
<div class="grid-container container">
|
||
<div class="icon-section_container">
|
||
<a class="footer-icon" id="footer_twitter" href="https://twitter.com/ncbi" aria-label="Twitter"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<defs>
|
||
<style>
|
||
.cls-11 {
|
||
fill: #737373;
|
||
}
|
||
</style>
|
||
</defs>
|
||
<title>Twitter</title>
|
||
<path class="cls-11" d="M250.11,105.48c-7,3.14-13,3.25-19.27.14,8.12-4.86,8.49-8.27,11.43-17.46a78.8,78.8,0,0,1-25,9.55,39.35,39.35,0,0,0-67,35.85,111.6,111.6,0,0,1-81-41.08A39.37,39.37,0,0,0,81.47,145a39.08,39.08,0,0,1-17.8-4.92c0,.17,0,.33,0,.5a39.32,39.32,0,0,0,31.53,38.54,39.26,39.26,0,0,1-17.75.68,39.37,39.37,0,0,0,36.72,27.3A79.07,79.07,0,0,1,56,223.34,111.31,111.31,0,0,0,116.22,241c72.3,0,111.83-59.9,111.83-111.84,0-1.71,0-3.4-.1-5.09C235.62,118.54,244.84,113.37,250.11,105.48Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_facebook" href="https://www.facebook.com/ncbi.nlm" aria-label="Facebook"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<title>Facebook</title>
|
||
<path class="cls-11" d="M210.5,115.12H171.74V97.82c0-8.14,5.39-10,9.19-10h27.14V52l-39.32-.12c-35.66,0-42.42,26.68-42.42,43.77v19.48H99.09v36.32h27.24v109h45.41v-109h35Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_linkedin" href="https://www.linkedin.com/company/ncbinlm" aria-label="LinkedIn"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<title>LinkedIn</title>
|
||
<path class="cls-11" d="M101.64,243.37H57.79v-114h43.85Zm-22-131.54h-.26c-13.25,0-21.82-10.36-21.82-21.76,0-11.65,8.84-21.15,22.33-21.15S101.7,78.72,102,90.38C102,101.77,93.4,111.83,79.63,111.83Zm100.93,52.61A17.54,17.54,0,0,0,163,182v61.39H119.18s.51-105.23,0-114H163v13a54.33,54.33,0,0,1,34.54-12.66c26,0,44.39,18.8,44.39,55.29v58.35H198.1V182A17.54,17.54,0,0,0,180.56,164.44Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_github" href="https://github.com/ncbi" aria-label="GitHub"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<defs>
|
||
<style>
|
||
.cls-11,
|
||
.cls-12 {
|
||
fill: #737373;
|
||
}
|
||
|
||
.cls-11 {
|
||
fill-rule: evenodd;
|
||
}
|
||
</style>
|
||
</defs>
|
||
<title>GitHub</title>
|
||
<path class="cls-11" d="M151.36,47.28a105.76,105.76,0,0,0-33.43,206.1c5.28,1,7.22-2.3,7.22-5.09,0-2.52-.09-10.85-.14-19.69-29.42,6.4-35.63-12.48-35.63-12.48-4.81-12.22-11.74-15.47-11.74-15.47-9.59-6.56.73-6.43.73-6.43,10.61.75,16.21,10.9,16.21,10.9,9.43,16.17,24.73,11.49,30.77,8.79,1-6.83,3.69-11.5,6.71-14.14C108.57,197.1,83.88,188,83.88,147.51a40.92,40.92,0,0,1,10.9-28.39c-1.1-2.66-4.72-13.42,1-28,0,0,8.88-2.84,29.09,10.84a100.26,100.26,0,0,1,53,0C198,88.3,206.9,91.14,206.9,91.14c5.76,14.56,2.14,25.32,1,28a40.87,40.87,0,0,1,10.89,28.39c0,40.62-24.74,49.56-48.29,52.18,3.79,3.28,7.17,9.71,7.17,19.58,0,14.15-.12,25.54-.12,29,0,2.82,1.9,6.11,7.26,5.07A105.76,105.76,0,0,0,151.36,47.28Z">
|
||
</path>
|
||
<path class="cls-12" d="M85.66,199.12c-.23.52-1.06.68-1.81.32s-1.2-1.06-.95-1.59,1.06-.69,1.82-.33,1.21,1.07.94,1.6Zm-1.3-1">
|
||
</path>
|
||
<path class="cls-12" d="M90,203.89c-.51.47-1.49.25-2.16-.49a1.61,1.61,0,0,1-.31-2.19c.52-.47,1.47-.25,2.17.49s.82,1.72.3,2.19Zm-1-1.08">
|
||
</path>
|
||
<path class="cls-12" d="M94.12,210c-.65.46-1.71,0-2.37-.91s-.64-2.07,0-2.52,1.7,0,2.36.89.65,2.08,0,2.54Zm0,0"></path>
|
||
<path class="cls-12" d="M99.83,215.87c-.58.64-1.82.47-2.72-.41s-1.18-2.06-.6-2.7,1.83-.46,2.74.41,1.2,2.07.58,2.7Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M107.71,219.29c-.26.82-1.45,1.2-2.64.85s-2-1.34-1.74-2.17,1.44-1.23,2.65-.85,2,1.32,1.73,2.17Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M116.36,219.92c0,.87-1,1.59-2.24,1.61s-2.29-.68-2.3-1.54,1-1.59,2.26-1.61,2.28.67,2.28,1.54Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M124.42,218.55c.15.85-.73,1.72-2,1.95s-2.37-.3-2.52-1.14.73-1.75,2-2,2.37.29,2.53,1.16Zm0,0"></path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_blog" href="https://ncbiinsights.ncbi.nlm.nih.gov/" aria-label="Blog">
|
||
<svg xmlns="http://www.w3.org/2000/svg" id="Layer_1" data-name="Layer 1" viewBox="0 0 40 40">
|
||
<defs><style>.cls-1{fill:#737373;}</style></defs>
|
||
<title>NCBI Insights Blog</title>
|
||
<path class="cls-1" d="M14,30a4,4,0,1,1-4-4,4,4,0,0,1,4,4Zm11,3A19,19,0,0,0,7.05,15a1,1,0,0,0-1,1v3a1,1,0,0,0,.93,1A14,14,0,0,1,20,33.07,1,1,0,0,0,21,34h3a1,1,0,0,0,1-1Zm9,0A28,28,0,0,0,7,6,1,1,0,0,0,6,7v3a1,1,0,0,0,1,1A23,23,0,0,1,29,33a1,1,0,0,0,1,1h3A1,1,0,0,0,34,33Z"></path>
|
||
</svg>
|
||
</a>
|
||
</div>
|
||
</div>
|
||
</section>
|
||
|
||
<section class="container-fluid bg-primary">
|
||
<div class="container pt-5">
|
||
<div class="row mt-3">
|
||
<div class="col-lg-3 col-12">
|
||
<p><a class="text-white" href="https://www.nlm.nih.gov/socialmedia/index.html">Connect with NLM</a></p>
|
||
<ul class="list-inline social_media">
|
||
<li class="list-inline-item"><a href="https://twitter.com/NLM_NIH" aria-label="Twitter" target="_blank" rel="noopener noreferrer"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<style type="text/css">
|
||
.st20 {
|
||
fill: #FFFFFF;
|
||
}
|
||
|
||
.st30 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
</style>
|
||
<title>Twitter</title>
|
||
<g>
|
||
<g>
|
||
<g>
|
||
<path class="st20" d="M192.9,88.1c-5,2.2-9.2,2.3-13.6,0.1c5.7-3.4,6-5.8,8.1-12.3c-5.4,3.2-11.4,5.5-17.6,6.7 c-10.5-11.2-28.1-11.7-39.2-1.2c-7.2,6.8-10.2,16.9-8,26.5c-22.3-1.1-43.1-11.7-57.2-29C58,91.6,61.8,107.9,74,116 c-4.4-0.1-8.7-1.3-12.6-3.4c0,0.1,0,0.2,0,0.4c0,13.2,9.3,24.6,22.3,27.2c-4.1,1.1-8.4,1.3-12.5,0.5c3.6,11.3,14,19,25.9,19.3 c-11.6,9.1-26.4,13.2-41.1,11.5c12.7,8.1,27.4,12.5,42.5,12.5c51,0,78.9-42.2,78.9-78.9c0-1.2,0-2.4-0.1-3.6 C182.7,97.4,189.2,93.7,192.9,88.1z"></path>
|
||
</g>
|
||
</g>
|
||
<circle class="st30" cx="124.4" cy="128.8" r="108.2"></circle>
|
||
</g>
|
||
</svg></a></li>
|
||
<li class="list-inline-item"><a href="https://www.facebook.com/nationallibraryofmedicine" aria-label="Facebook" rel="noopener noreferrer" target="_blank">
|
||
<svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<style type="text/css">
|
||
.st10 {
|
||
fill: #FFFFFF;
|
||
}
|
||
|
||
.st110 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
</style>
|
||
<title>Facebook</title>
|
||
<g>
|
||
<g>
|
||
<path class="st10" d="M159,99.1h-24V88.4c0-5,3.3-6.2,5.7-6.2h16.8V60l-24.4-0.1c-22.1,0-26.2,16.5-26.2,27.1v12.1H90v22.5h16.9 v67.5H135v-67.5h21.7L159,99.1z"></path>
|
||
</g>
|
||
</g>
|
||
<circle class="st110" cx="123.6" cy="123.2" r="108.2"></circle>
|
||
</svg>
|
||
</a></li>
|
||
<li class="list-inline-item"><a href="https://www.youtube.com/user/NLMNIH" aria-label="Youtube" target="_blank" rel="noopener noreferrer"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<title>Youtube</title>
|
||
<style type="text/css">
|
||
.st4 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
|
||
.st5 {
|
||
fill: #FFFFFF;
|
||
}
|
||
</style>
|
||
<circle class="st4" cx="124.2" cy="123.4" r="108.2"></circle>
|
||
<g transform="translate(0,-952.36218)">
|
||
<path class="st5" d="M88.4,1037.4c-10.4,0-18.7,8.3-18.7,18.7v40.1c0,10.4,8.3,18.7,18.7,18.7h72.1c10.4,0,18.7-8.3,18.7-18.7 v-40.1c0-10.4-8.3-18.7-18.7-18.7H88.4z M115.2,1058.8l29.4,17.4l-29.4,17.4V1058.8z"></path>
|
||
</g>
|
||
</svg></a></li>
|
||
</ul>
|
||
</div>
|
||
<div class="col-lg-3 col-12">
|
||
<p class="address_footer text-white">National Library of Medicine<br />
|
||
<a href="https://www.google.com/maps/place/8600+Rockville+Pike,+Bethesda,+MD+20894/@38.9959508,-77.101021,17z/data=!3m1!4b1!4m5!3m4!1s0x89b7c95e25765ddb:0x19156f88b27635b8!8m2!3d38.9959508!4d-77.0988323" class="text-white" target="_blank" rel="noopener noreferrer">8600 Rockville Pike<br />
|
||
Bethesda, MD 20894</a></p>
|
||
</div>
|
||
<div class="col-lg-3 col-12 centered-lg">
|
||
<p><a href="https://www.nlm.nih.gov/web_policies.html" class="text-white">Web Policies</a><br />
|
||
<a href="https://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/freedom-information-act-office" class="text-white">FOIA</a><br />
|
||
<a href="https://www.hhs.gov/vulnerability-disclosure-policy/index.html" class="text-white" id="vdp">HHS Vulnerability Disclosure</a></p>
|
||
</div>
|
||
<div class="col-lg-3 col-12 centered-lg">
|
||
<p><a class="supportLink text-white" href="https://support.nlm.nih.gov/">Help</a><br />
|
||
<a href="https://www.nlm.nih.gov/accessibility.html" class="text-white">Accessibility</a><br />
|
||
<a href="https://www.nlm.nih.gov/careers/careers.html" class="text-white">Careers</a></p>
|
||
</div>
|
||
</div>
|
||
<div class="row">
|
||
<div class="col-lg-12 centered-lg">
|
||
<nav class="bottom-links">
|
||
<ul class="mt-3">
|
||
<li>
|
||
<a class="text-white" href="//www.nlm.nih.gov/">NLM</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.nih.gov/">NIH</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.hhs.gov/">HHS</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.usa.gov/">USA.gov</a>
|
||
</li>
|
||
</ul>
|
||
</nav>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
</section>
|
||
<script type="text/javascript" src="/portal/portal3rc.fcgi/rlib/js/InstrumentOmnitureBaseJS/InstrumentNCBIConfigJS/InstrumentNCBIBaseJS/InstrumentPageStarterJS.js?v=1"> </script>
|
||
<script type="text/javascript" src="/portal/portal3rc.fcgi/static/js/hfjs2.js"> </script>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
<!--/.page-->
|
||
</div>
|
||
<!--/.wrap-->
|
||
</div><!-- /.twelve_col -->
|
||
</div>
|
||
<!-- /.grid -->
|
||
|
||
<span class="PAFAppResources"></span>
|
||
|
||
<!-- BESelector tab -->
|
||
|
||
|
||
|
||
<noscript><img alt="statistics" src="/stat?jsdisabled=true&ncbi_db=books&ncbi_pdid=book-part&ncbi_acc=NBK1728&ncbi_domain=gene&ncbi_report=record&ncbi_type=fulltext&ncbi_objectid=&ncbi_pcid=/NBK1728/&ncbi_pagename=FREM1 Autosomal Recessive Disorders - GeneReviews® - NCBI Bookshelf&ncbi_bookparttype=chapter&ncbi_app=bookshelf" /></noscript>
|
||
|
||
|
||
<!-- usually for JS scripts at page bottom -->
|
||
<!--<component id="PageFixtures" label="styles"></component>-->
|
||
|
||
|
||
<!-- CE8B5AF87C7FFCB1_0191SID /projects/books/PBooks@9.11 portal107 v4.1.r689238 Tue, Oct 22 2024 16:10:51 -->
|
||
<span id="portal-csrf-token" style="display:none" data-token="CE8B5AF87C7FFCB1_0191SID"></span>
|
||
|
||
<script type="text/javascript" src="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/js/3879255/4121861/3501987/4008961/3893018/3821238/4062932/4209313/4212053/4076480/3921943/3400083/3426610.js" snapshot="books"></script></body>
|
||
</html> |