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</label>
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
</div>
<div class="action-panel-control-wrap">
<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="tGs11LzF4JT0i2VOq3DBkLpFlRCBdgI4Ktc6EB21EkGuct1E3mgDOTVjTVkN6Rgo">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="tGs11LzF4JT0i2VOq3DBkLpFlRCBdgI4Ktc6EB21EkGuct1E3mgDOTVjTVkN6Rgo">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="tGs11LzF4JT0i2VOq3DBkLpFlRCBdgI4Ktc6EB21EkGuct1E3mgDOTVjTVkN6Rgo">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="tGs11LzF4JT0i2VOq3DBkLpFlRCBdgI4Ktc6EB21EkGuct1E3mgDOTVjTVkN6Rgo">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="tGs11LzF4JT0i2VOq3DBkLpFlRCBdgI4Ktc6EB21EkGuct1E3mgDOTVjTVkN6Rgo">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="28886345">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(17)30329-4"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3048&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=28886345&amp;db=pubmed&amp;nlmid=0370475"
title="See full text options at Elsevier Science"
data-ga-category="full_text"
data-ga-action="Elsevier Science"
data-ga-label="28886345"
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--linkinghub.elsevier.com-ihub-images-celloa.png" alt="Elsevier Science full text link"><span class="text">
Elsevier Science
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/28886345/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=28886345&amp;db=pubmed&amp;nlmid=0370475"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="28886345"
><span class="text">
Free PMC article
</span></a>
</div>
</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/28886345/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/28886345/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="28886345" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F28886345%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="tGs11LzF4JT0i2VOq3DBkLpFlRCBdgI4Ktc6EB21EkGuct1E3mgDOTVjTVkN6Rgo"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
id="collections-action-dialog-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="collections_button"
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<h1 class="heading-title">
RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes
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><sup class="key">2</sup> Division of Developmental Biology &amp; Medicine, Faculty of Biology, Medicine and Health, University of Manchester M13 9PL, UK; Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, 13200 Kepala Batas, Penang, Malaysia.</li>
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><sup class="key">3</sup> Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27701, USA.</li>
<li data-affiliation-id="full-view-affiliation-4"
id="full-view-affiliation-4"
><sup class="key">4</sup> Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.</li>
<li data-affiliation-id="full-view-affiliation-5"
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><sup class="key">5</sup> Greenwood Genetic Center, Greenwood, SC 29646, USA.</li>
<li data-affiliation-id="full-view-affiliation-6"
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><sup class="key">6</sup> Manchester Centre for Genomic Medicine, St. Mary&#x27;s Hospital, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK.</li>
<li data-affiliation-id="full-view-affiliation-7"
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><sup class="key">7</sup> South East of Scotland Clinical Genetic Service, Western General Hospital, Edinburgh EH4 2XU, UK.</li>
<li data-affiliation-id="full-view-affiliation-8"
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><sup class="key">8</sup> Department of Clinical Genetics, Erasmus Medical Center, 3000 CA Rotterdam, the Netherlands.</li>
<li data-affiliation-id="full-view-affiliation-9"
id="full-view-affiliation-9"
><sup class="key">9</sup> Department of Clinical Genetics, Guy&#x27;s and St Thomas&#x27; Hospital, London SE1 7EH, UK.</li>
<li data-affiliation-id="full-view-affiliation-10"
id="full-view-affiliation-10"
><sup class="key">10</sup> The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.</li>
<li data-affiliation-id="full-view-affiliation-11"
id="full-view-affiliation-11"
><sup class="key">11</sup> Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.</li>
<li data-affiliation-id="full-view-affiliation-12"
id="full-view-affiliation-12"
><sup class="key">12</sup> Division of Developmental Biology &amp; Medicine, Faculty of Biology, Medicine and Health, University of Manchester M13 9PL, UK.</li>
<li data-affiliation-id="full-view-affiliation-13"
id="full-view-affiliation-13"
><sup class="key">13</sup> Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology &amp; Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands. Electronic address: han.brunner@radboudumc.nl.</li>
<li data-affiliation-id="full-view-affiliation-14"
id="full-view-affiliation-14"
><sup class="key">14</sup> Manchester Centre for Genomic Medicine, St. Mary&#x27;s Hospital, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK. Electronic address: siddharth.banka@manchester.ac.uk.</li>
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RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes
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<span class="authors-list-item "><span class="full-name">Margot R F Reijnders</span><span class="citation-separator">&nbsp;et al.</span></span>
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<span class="authors-list-item "><a class="full-name"
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data-ga-label="Margot R F Reijnders">Margot R F Reijnders</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands." href="#short-view-affiliation-1" ref="linksrc=author_aff">
1
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Nurhuda M Ansor">Nurhuda M Ansor</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Division of Developmental Biology &amp; Medicine, Faculty of Biology, Medicine and Health, University of Manchester M13 9PL, UK; Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, 13200 Kepala Batas, Penang, Malaysia." href="#short-view-affiliation-2" ref="linksrc=author_aff">
2
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Kousi+M&amp;cauthor_id=28886345"
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data-ga-label="Maria Kousi">Maria Kousi</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27701, USA." href="#short-view-affiliation-3" ref="linksrc=author_aff">
3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Wyatt W Yue">Wyatt W Yue</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK." href="#short-view-affiliation-4" ref="linksrc=author_aff">
4
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Perciliz L Tan">Perciliz L Tan</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27701, USA." href="#short-view-affiliation-3" ref="linksrc=author_aff">
3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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5
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Clayton-Smith+J&amp;cauthor_id=28886345"
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data-ga-label="Jill Clayton-Smith">Jill Clayton-Smith</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Manchester Centre for Genomic Medicine, St. Mary&#x27;s Hospital, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK." href="#short-view-affiliation-6" ref="linksrc=author_aff">
6
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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5
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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5
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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7
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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8
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Carlo Marcelis">Carlo Marcelis</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands." href="#short-view-affiliation-1" ref="linksrc=author_aff">
1
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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9
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Rolph Pfundt">Rolph Pfundt</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands." href="#short-view-affiliation-1" ref="linksrc=author_aff">
1
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Maian Roifman">Maian Roifman</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada." href="#short-view-affiliation-10" ref="linksrc=author_aff">
10
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Ronald Cohn">Ronald Cohn</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada." href="#short-view-affiliation-11" ref="linksrc=author_aff">
11
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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10
</a></sup><span class="semicolon">;&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Tom H Millard">Tom H Millard</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Division of Developmental Biology &amp; Medicine, Faculty of Biology, Medicine and Health, University of Manchester M13 9PL, UK." href="#short-view-affiliation-12" ref="linksrc=author_aff">
12
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Nicholas Katsanis">Nicholas Katsanis</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27701, USA." href="#short-view-affiliation-3" ref="linksrc=author_aff">
3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Brunner+HG&amp;cauthor_id=28886345"
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data-ga-label="Han G Brunner">Han G Brunner</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology &amp; Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands. Electronic address: han.brunner@radboudumc.nl." href="#short-view-affiliation-13" ref="linksrc=author_aff">
13
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Banka+S&amp;cauthor_id=28886345"
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data-ga-label="Siddharth Banka">Siddharth Banka</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Manchester Centre for Genomic Medicine, St. Mary&#x27;s Hospital, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK. Electronic address: siddharth.banka@manchester.ac.uk." href="#short-view-affiliation-14" ref="linksrc=author_aff">
14
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Affiliations
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<li data-affiliation-id="short-view-affiliation-1"
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><sup class="key">1</sup> Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.</li>
<li data-affiliation-id="short-view-affiliation-2"
id="short-view-affiliation-2"
><sup class="key">2</sup> Division of Developmental Biology &amp; Medicine, Faculty of Biology, Medicine and Health, University of Manchester M13 9PL, UK; Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, 13200 Kepala Batas, Penang, Malaysia.</li>
<li data-affiliation-id="short-view-affiliation-3"
id="short-view-affiliation-3"
><sup class="key">3</sup> Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27701, USA.</li>
<li data-affiliation-id="short-view-affiliation-4"
id="short-view-affiliation-4"
><sup class="key">4</sup> Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.</li>
<li data-affiliation-id="short-view-affiliation-5"
id="short-view-affiliation-5"
><sup class="key">5</sup> Greenwood Genetic Center, Greenwood, SC 29646, USA.</li>
<li data-affiliation-id="short-view-affiliation-6"
id="short-view-affiliation-6"
><sup class="key">6</sup> Manchester Centre for Genomic Medicine, St. Mary&#x27;s Hospital, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK.</li>
<li data-affiliation-id="short-view-affiliation-7"
id="short-view-affiliation-7"
><sup class="key">7</sup> South East of Scotland Clinical Genetic Service, Western General Hospital, Edinburgh EH4 2XU, UK.</li>
<li data-affiliation-id="short-view-affiliation-8"
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><sup class="key">8</sup> Department of Clinical Genetics, Erasmus Medical Center, 3000 CA Rotterdam, the Netherlands.</li>
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><sup class="key">9</sup> Department of Clinical Genetics, Guy&#x27;s and St Thomas&#x27; Hospital, London SE1 7EH, UK.</li>
<li data-affiliation-id="short-view-affiliation-10"
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><sup class="key">10</sup> The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.</li>
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><sup class="key">11</sup> Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.</li>
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><sup class="key">12</sup> Division of Developmental Biology &amp; Medicine, Faculty of Biology, Medicine and Health, University of Manchester M13 9PL, UK.</li>
<li data-affiliation-id="short-view-affiliation-13"
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><sup class="key">13</sup> Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology &amp; Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands. Electronic address: han.brunner@radboudumc.nl.</li>
<li data-affiliation-id="short-view-affiliation-14"
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><sup class="key">14</sup> Manchester Centre for Genomic Medicine, St. Mary&#x27;s Hospital, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK. Electronic address: siddharth.banka@manchester.ac.uk.</li>
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RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G&gt;A (p.Cys18Tyr), c.116A&gt;G (p.Asn39Ser), c.218C&gt;T (p.Pro73Leu), and c.470G&gt;A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between -2.5 to -5 SD. In contrast, two individuals with c.151G&gt;A (p.Val51Met) and c.151G&gt;C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T&gt;G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of 10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.
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HACE1; RAC1; Rho GTPase; TRIO; cerebellar abnormalities; developmental disorders; intellectual disability; macrocephaly; microcephaly; neuronal proliferation.
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<div class="figure-caption-contents"><p> Properties of Germline <i> RAC1 </i> Variants… </p></div>
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<div class="figure-caption-contents"><p> Properties of Germline <i> RAC1 </i> Variants (A) <i> RAC1 </i> is located on human chromosome 7p22.1.… </p></div>
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<div class="figure-caption-contents">Properties of Germline <i>RAC1</i> Variants (A) <i>RAC1</i> is located on human chromosome 7p22.1. Exon-intron structure of the two protein-coding <i>RAC1</i> transcripts is shown. The ubiquitously expressed <i>RAC1</i> transcript is composed of six exons (blue vertical lines). <i>RAC1B</i> (mainly expressed in gastrointestinal and epithelial cells) contains an additional exon (exon 4; gray vertical line). (B) Schematic of <i>RAC1</i>, with the coding exons shown as blue rectangles and the introns as blue lines. Exon 4 that is expressed only in the longer <i>RAC1B</i> transcript is shown as a gray rectangle. The red triangles represent the positions of the mutations identified in this study. The red oval within exon 4 shows the two splice donor variants detected in the ExAC database. The purple ovals represent the missense variants in the ExAC database. (C) Amino acid sequence of the RAC1 across positions p.1-p.192. Red amino acids are highly conserved in >90% of the RAS family members and blue amino acids represent RAS protein G box consensus residues. Positions of the identified missense mutations (in red) are marked with dotted lines and the high conservation among different species of these amino acids is shown in the rectangle below. (D) Crystal structure of human RAC1 showing the position of the identified missense variants presented in this study. The sites of substitution are indicated by sticks in spheres and are color coded according to their putative impact on guanine nucleotide binding (cyan), protein-protein interactions (yellow), and structural stability (red). For reference, the non-hydrolyzable GTP analog GMPPNP bound to the structure is shown in sticks. The structure was analyzed and this figure was generated using the program ICM-Pro v3.8 (Molsoft, LLC).</div>
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<div class="figure-caption-contents"><p> Facial Dysmorphism and Brain Abnormalities… </p></div>
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<div class="figure-caption-contents"><p> Facial Dysmorphism and Brain Abnormalities Observed in Individuals with <i> RAC1 </i> Mutations (A) Frontal… </p></div>
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<div class="figure-caption-contents">Facial Dysmorphism and Brain Abnormalities Observed in Individuals with <i>RAC1</i> Mutations (A) Frontal and lateral photographs of the faces of individuals 13 and 57. Individuals 1, 2, and 3 were microcephalic, individual 5 had a normal occipital-frontal circumference, and individuals 6 and 7 had macrocephaly. Variable degrees of arched eyebrows, dysplastic ears, prominent nasal bridge, and overhanging columella were noted. Individuals with macrocephaly have prominent broad foreheads, slightly up-slanted palpebral fissures, open mouths, and “scooped out” appearance on lateral view. (B) Panel 1 shows brain MRI images of individual 1: axial T2 images showing dysgenetic vermis and right cerebellar hemisphere (left), cystis lesions in the right frontal deep white matter (middle, arrow), and sagittal T1 images (right) showing enlarged cisterna magna (arrow). Panel 2 shows brain MRI images of individual 2: axial T2 images showing hypoplastic cerebellar vermis (left), slightly enlarged lateral ventricles (middle), and sagittal T1 images (right) showing hypoplastic corpus callosum, pons (arrow head), hypoplastic lower vermis, enlarged 4th ventricle, and cisterna magna (arrow). Panel 6 shows brain MRI image of individual 6: axial T2 image showing non-specific white matter changes in the frontal and parietal lobes. No hydrocephalus or extra-axial fluid was observed. Panel 7 shows brain MRI of individual 7: T2 weighted MRI images. Left: axial image showing very discrete bilateral patchy high intensity signal changes in the deep white matter of the frontal and parietal lobes; right: mid-sagittal section showing, except for megalencephaly, normal brain structures.</div>
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<p> Figure 3 </p>
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<div class="figure-caption-contents"><p> Distinct <i> RAC1 </i> Mutations Genocopy Dominant-Negative… </p></div>
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<div class="figure-caption-contents"><p> Distinct <i> RAC1 </i> Mutations Genocopy Dominant-Negative or Constitutively Active Variants (A) NIH 3T3 fibroblasts… </p></div>
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Figure 3
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<div class="figure-caption-contents">Distinct <i>RAC1</i> Mutations Genocopy Dominant-Negative or Constitutively Active Variants (A) NIH 3T3 fibroblasts transfected with 500 ng of DNA per coverslip expressing the indicated Rac1 mutants and were fixed 30 min after plating onto fibronectin and stained with Alexa-568 phalloidin to reveal the actin cytoskeleton and anti-GFP to reveal the expressed construct. Cells were imaged by confocal microscopy and divided into the three indicated categories. At least 50 cells were analyzed for each dataset except p.Asn39Ser, p.Tyr64Asp, p.Cys157Tyr (40 cells), and p.Gln61Leu (25 cells). Data were pooled from three independent experiments. (B) Graph showing mean circularity index of cells expressing indicated Rac1 mutants. Error bars indicate SEM. Datasets statistically analyzed using ANOVA test with Dunnetts correction for multiple comparisons. Asterisks indicate datasets significantly different to WT (<sup></sup>p &lt; 0.05, <sup></sup>p &lt; 0.01, <sup></sup>p &lt; 0.001). (C) Images of cells expressing the indicated RAC1 mutation. In each case the cell is a representative example of the most common morphological category for that mutation (see A). Top panels show Alexa-568 phalloidin staining to reveal F-actin distribution, while the panels immediately below show a magnified view of the boxed region from the top panels to highlight the morphology of actin protrusions at the cell periphery. The third row of panels show the GFP channel of the same cells to reveal the distribution of the expressed RAC1 mutation, and the bottom panels show a merge of the F-actin (red) and GFP (green) channels. All scale bars indicate 10 μm.</div>
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<div class="figure-caption-contents"><p> Overexpression of Human RAC1 p.Cys18Tyr… </p></div>
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<div class="figure-caption-contents"><p> Overexpression of Human RAC1 p.Cys18Tyr and p.Asn39Ser Cause Microcephaly, while p.Gln61Leu Causes the… </p></div>
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<div class="figure-caption-contents">Overexpression of Human RAC1 p.Cys18Tyr and p.Asn39Ser Cause Microcephaly, while p.Gln61Leu Causes the Mirror Phenotype in Zebrafish Embryos Functional assessment of <i>de novo</i> variants in <i>RAC1</i> by <i>in vivo</i> complementation in zebrafish larvae. (A) Dorsal view of 5 days post fertilization (dpf) control and overexpressant larvae. For each experiment, embryos were injected with either WT or mutant <i>RAC1</i> human mRNA message. The embryos were allowed to grow to 5 dpf and imaged live for head size. The midbrain area between the eyes highlighted with the dashed red line was measured for every imaged embryo, to produce a quantitative score. (B) Bar graph of normalized values showing the quantification of the head size phenotype in control embryos and embryos injected with either WT or mutant human <i>RAC1</i> message, from two plotted experiments. Statistical analyses were performed by Students t test. (C) Dorsal view of 2 dpf control and overexpressant larvae, fixed in Dents fixative and whole-mount immuno-stained with an anti-phospho histone 3 (PH3) antibody that marks proliferating cells. For each experiment, embryos were injected with either WT or mutant <i>RAC1</i> human mRNA message. The embryos were allowed to grow to 2 dpf and subsequently were fixed, stained, and imaged. Embryos were imaged dorsally and z stacks were acquired every 100 nm. The z stacks were collapsed to produce an extended depth of focus (EDF) image that was then processed for scoring. The PH3-positive cells were counted for every embryo imaged using the ITCN plugin from ImageJ, to produce a quantitative score. (D) Bar graph of normalized values showing the quantification of the proliferating cell count phenotype, across three biological replicas. Statistical analyses for the neuronal proliferation experiments were performed by Students t test. (E) Dorsal view of 3 dpf control and overexpressant larvae for <i>RAC1</i> WT and mutant conditions. The area of the cerebellum consisting of the neuronal axons that cross the midline is highlighted with a green dashed box. At least 50 embryos per condition were imaged live and evaluated at 3 dpf for the depletion of axons within the area highlighted. (F) Bar graph of cumulative plotted experiments across three biological replicas showing percentages of embryos with cerebellar defects. Statistical analyses for the cerebellar integrity assay using a χ<sup>2</sup> test. Error bars define 95% confidence interval.</div>
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<div id="substances" class="substances keywords-section">
<h2 class="title">
Substances
</h2>
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<div id="related-links" class="related-links">
<h2 class="title">
Related information
</h2>
<ul class="related-links-list"><li><a title="PubMed links associated with Books" href="https://www.ncbi.nlm.nih.gov/books?linkname=pubmed_books_refs&amp;from_uid=28886345"
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Cited in Books
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ClinVar
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Gene
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Gene (GeneRIF)
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MedGen
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ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=28886345&ordinalpos=1&linkpos=6">
MedGen (Bookshelf cited)
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ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=28886345&ordinalpos=1&linkpos=7">
OMIM (cited)
</a></li><li><a title="Published protein sequences" href="https://www.ncbi.nlm.nih.gov/protein?linkname=pubmed_protein&amp;from_uid=28886345"
ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=28886345&ordinalpos=1&linkpos=8">
Protein
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Protein (RefSeq)
</a></li></ul>
</div>
<div id="grants" class="grants">
<h2 class="title">
Grants and funding
</h2>
<div class="grants-list"><ul id="grants-head-list"><li class="grant-item"><a
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Wellcome Trust/United Kingdom
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</div>
<div id="linkout" class="linkout">
<h2 class="title">
LinkOut - more resources
</h2>
<ul class="linkout-list"><li><h3 class="linkout-category">Full Text Sources</h3><ul class="linkout-category-links"><li><a
href="https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(17)30329-4"
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Elsevier Science
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Europe PubMed Central
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PubMed Central
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scite Smart Citations
</a></li></ul></li><li><h3 class="linkout-category">Medical</h3><ul class="linkout-category-links"><li><a
href="https://medlineplus.gov/developmentaldisabilities.html"
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MedlinePlus Health Information
</a></li></ul></li><li><h3 class="linkout-category">Molecular Biology Databases</h3><ul class="linkout-category-links"><li><a
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BioCyc
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Gene Ontology
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GlyGen glycoinformatics resource
</a></li><li><a
href="https://www.malacards.org/card/intellectual_developmental_disorder_autosomal_dominant_48"
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ZFIN
</a></li></ul></li><li><h3 class="linkout-category">Research Materials</h3><ul class="linkout-category-links"><li><a
href="https://antibodies.cancer.gov/detail/CPTC-RAC1-1"
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