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<title>Large-scale discovery of novel genetic causes of developmental disorders - PubMed</title>
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<meta name="description" content="Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. 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DNA-Binding Proteins / genetics, Developmental Disabilities / diagnosis*, Developmental Disabilities / genetics*, Dynamin I / genetics, Exome / genetics, Female, Gene Expression Regulation, Developmental, Genes, Dominant / genetics, Genome, Human / genetics, Guanine Nucleotide Exchange Factors / genetics, Homeodomain Proteins / genetics, Humans, Infant, Infant, Newborn, Male, Mutation, Missense / genetics, Nerve Tissue Proteins / genetics, Nuclear Proteins / genetics, Parents, Phosphoproteins / genetics, Polycomb Repressive Complex 1 / genetics, Protein Phosphatase 2 / genetics, Protein Serine-Threonine Kinases / genetics, Rare Diseases / genetics, Repressor Proteins, Transcription Factors / genetics, Transposases / genetics, United Kingdom, Zebrafish / genetics, PubMed Abstract, NIH, NLM, NCBI, National Institutes of Health, National Center for Biotechnology Information, National Library of Medicine, MEDLINE"><meta name="robots" content="index,nofollow,noarchive"><meta 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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="wHAmvIcprmLp4Uv2ZmZao92dskHpGdhZNukr8yFL1XyTYlBSCFCcShyR0opBzOPj">
<div class="action-panel-control-wrap">
<label for="save-action-format" class="action-panel-label">
Format:
</label>
<select id="save-action-format" name="results-format" class="action-panel-selector">
<option value="summary-text">Summary (text)</option>
<option value="pubmed-text">PubMed</option>
<option value="pmid">PMID</option>
<option value="abstract">Abstract (text)</option>
<option value="csv">CSV</option>
</select>
</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="save"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Save citations to file' panel"
ref="linksrc=close_save_panel"
aria-controls="save-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="save"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="email-action-panel"
class="email-action-panel action-panel"
aria-hidden="true"
data-recaptcha-script-url="https://www.recaptcha.net/recaptcha/enterprise.js?render=explicit&onload=onloadCaptchaCallback"
data-recaptcha-enabled="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Email citation
</h2>
<form id="email-action-panel-form"
class="action-panel-content action-form"
action="/send-email/"
data-by-search-action="/results-export-email-by-search-data/"
data-by-ids-action="/send-email/"
data-by-search-method="post"
data-by-ids-method="post"
method="post"
>
<input type="hidden" name="csrfmiddlewaretoken" value="wHAmvIcprmLp4Uv2ZmZao92dskHpGdhZNukr8yFL1XyTYlBSCFCcShyR0opBzOPj">
<div class="action-panel-control-wrap">
<span class="action-panel-label">
Subject:
</span>
<span class="email-subject" id="email-subject" aria-label="Email subject">1 selected item: 25533962 - PubMed</span>
<input type="hidden" name="email-subject" value="1 selected item: 25533962"/>
<input type="hidden" name="email-subject-hash" value="bf86dffbe07dbdc05e41d8671b871d2aec6f94b3c24b7660e954122d57726e2b"/>
</div>
<div class="action-panel-control-wrap">
<label for="email-to" class="action-panel-label required-field-asterisk">
To:
</label>
<input type="email" aria-label="Recipient Email Address" placeholder="email@example.com" id="email-to" class="email-to" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="100" required>
</div>
<div class="action-panel-control-wrap">
<label for="email-from" class="action-panel-label">
From:
</label>
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" 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="wHAmvIcprmLp4Uv2ZmZao92dskHpGdhZNukr8yFL1XyTYlBSCFCcShyR0opBzOPj">
<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="wHAmvIcprmLp4Uv2ZmZao92dskHpGdhZNukr8yFL1XyTYlBSCFCcShyR0opBzOPj">
<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="wHAmvIcprmLp4Uv2ZmZao92dskHpGdhZNukr8yFL1XyTYlBSCFCcShyR0opBzOPj">
<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="wHAmvIcprmLp4Uv2ZmZao92dskHpGdhZNukr8yFL1XyTYlBSCFCcShyR0opBzOPj">
<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="wHAmvIcprmLp4Uv2ZmZao92dskHpGdhZNukr8yFL1XyTYlBSCFCcShyR0opBzOPj">
<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="25533962">
<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://doi.org/10.1038/nature14135"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3094&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=25533962&amp;db=pubmed&amp;nlmid=0410462"
title="See full text options at Nature Publishing Group"
data-ga-category="full_text"
data-ga-action="Nature Publishing Group"
data-ga-label="25533962"
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--www.nature.com-static-images-logos-nature-portfolio-120.png" alt="Nature Publishing Group full text link"><span class="text">
Nature Publishing Group
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/25533962/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=25533962&amp;db=pubmed&amp;nlmid=0410462"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="25533962"
><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>
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Large-scale discovery of novel genetic causes of developmental disorders
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Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.
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<p> EDF1. Characteristics of the families </p>
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<p> EDF1. Characteristics of the families </p>
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<div class="figure-caption-contents"><b> A. Gestation Adjusted Decimal Age at Last Clinical Assessment </b> .…</div>
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EDF1. Characteristics of the families
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<div class="figure-caption-contents"><b>A. Gestation Adjusted Decimal Age at Last Clinical Assessment</b>. Histogram showing the distribution of the gestation adjusted decimal age at last clinical assessment across the 1133 probands. The dashed red line shows the median age. <b>B. Frequency of HPO Term Usage</b>. Bar plot showing, for each used HPO term, the number of times it was observed across the 1133 proband patient records.<b> C. Projection PCA plot of the 1133 probands</b>. PCA plot of 1133 DDD probands projected onto a PCA analysis using 4 different HapMap populations from the 1000 genomes project. Black: African, Red: European, Green: East Asian, Blue: South Asian and the 1133 DDD probands are represented by orange triangles.<b> D. Self Declared and Genetically Defined Consanguinity</b>. Overlaid histogram showing the distribution of kinship coefficients from KING comparing parental samples for each trio. Green: Trios where consanguinity was not entered in the patient record on DECIPHER. Red: Trios consanguinity was declared in the patient record on DECIPHER.</div>
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<p> EDF2. Number of Validated <i> de novo </i> SNVs… </p>
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<p> EDF2. Number of Validated <i> de novo </i> SNVs and indels per Proband </p>
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<div class="figure-caption-contents"><p> Bar plot showing the… </p></div>
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EDF2. Number of Validated <i>de novo</i> SNVs and indels per Proband
</strong>
<div class="figure-caption-contents">Bar plot showing the distribution of the observed number of validated SNVs and indels per proband sample, and the expected distribution assuming a Poisson distribution with the same mean as the observed distribution.</div>
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<p> EDF3. Number of Diagnoses per Gene </p>
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<div class="figure-caption-contents"><p> Histogram… </p></div>
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<p> EDF3. Number of Diagnoses per Gene </p>
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<div class="figure-caption-contents"><p> Histogram showing the number of diagnoses per gene for… </p></div>
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<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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EDF3. Number of Diagnoses per Gene
</strong>
<div class="figure-caption-contents">Histogram showing the number of diagnoses per gene for genes with at least two diagnoses from different proband samples.</div>
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<p> EDF4. Burden of Large CNVs in 1133… </p>
</strong>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> EDF4. Burden of Large CNVs in 1133 DDD Proband Samples </p>
</strong>
<div class="figure-caption-contents"><p> Plot comparing the frequency of… </p></div>
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<figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
EDF4. Burden of Large CNVs in 1133 DDD Proband Samples
</strong>
<div class="figure-caption-contents">Plot comparing the frequency of rare CNVs in three sample groups against CNV size. Y-axis is the on a log scale. Red: DDD probands who have not had previous microarray based genetic testing, Purple: DDD probands who have had negative previous microarray based genetic testing Green: DDD controls.</div>
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<p> EDF5. Expected and observed numbers of <i> de… </i> </p>
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<p> EDF5. Expected and observed numbers of <i> de novo </i> mutations </p>
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<div class="figure-caption-contents"><p> The expected and observed numbers of… </p></div>
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EDF5. Expected and observed numbers of <i>de novo</i> mutations
</strong>
<div class="figure-caption-contents">The expected and observed numbers of mutations of different functional consequences in three mutually exclusive sets of genes are shown, along with the p value from an assessment of a statistical excess of observed mutations. The three classes of genes are described in the main text.</div>
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<p> EDF6. Haploinsufficiency analyses </p>
</strong>
<div class="figure-caption-contents"><b> A. Saturation analysis for… </b></div>
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<p> EDF6. Haploinsufficiency analyses </p>
</strong>
<div class="figure-caption-contents"><b> A. Saturation analysis for detecting haploinsufficient DD genes </b> . A boxplot showing…</div>
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<figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
EDF6. Haploinsufficiency analyses
</strong>
<div class="figure-caption-contents"><b>A. Saturation analysis for detecting haploinsufficient DD genes</b>. A boxplot showing the distribution of statistical power to detect a significant enrichment of LoF mutations across 18,272 genes in the genome, for different numbers of trios studied, from 1,000 trios to 12,000 trios. <b>B. Distribution of haplinsufficiency scores in selected sets of <i>de novo</i> mutations</b>. Violin plot of haploinsufficiency scores in five sets of <i>de novo</i> mutations: Silent - all synonymous mutations, Diagnostic - mutations in known DD genes in diagnosed individuals, Undiagnosed_Func - all functional mutations in undiagnosed individuals, Undiagnosed_LoF - All LoF mutations in undiagnosed individuals, Undiagnosed_recur - mutations in genes with recurrent functional mutations in undiagnosed individuals. P values for a Mann-Whitney test comparing each of the latter four distributions to that observed for the silent (synonymous) variants are plotted at the top of each violin.</div>
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<p> Figure 1. Excess of recurrently mutated genes </p>
</strong>
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<strong class="figure-label">
<p> Figure 1. Excess of recurrently mutated genes </p>
</strong>
<div class="figure-caption-contents"><p> Each panel shows the observed number of recurrently… </p></div>
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<figcaption id="figure-caption-6" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 1. Excess of recurrently mutated genes
</strong>
<div class="figure-caption-contents">Each panel shows the observed number of recurrently mutated genes (diamond) and the distribution of the number of recurrently mutated genes in 10,000 simulations (box indicates interquartile range, whiskers indicates 95% confidence interval) under a model of no gene-specific enrichment of mutations: <b>a</b>. all protein-altering mutations in all DDD children and undiagnosed DDD children, <b>b</b>. all LoF mutations in all DDD children and undiagnosed DDD children. Each diamond is annotated with the median excess of recurrently mutated genes, with 95% confidence intervals in brackets. P value of observed excess is &lt;0.0001 for all four tests.</div>
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<p> Figure 2. Gene-specific significance of enrichment for… </p>
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<p> Figure 2. Gene-specific significance of enrichment for DNMs </p>
</strong>
<div class="figure-caption-contents"><p> The log <sub> 10 </sub> (p) value of testing… </p></div>
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<strong class="figure-label">
Figure 2. Gene-specific significance of enrichment for DNMs
</strong>
<div class="figure-caption-contents">The log<sub>10</sub>(p) value of testing for mutation enrichment is plotted only for each gene with at least one mutation in DDD children. On the X-axis is the p value of the most significant test in the DDD dataset, and on the Y-axis is the minimal p value from the significance testing in the meta-analysis dataset. Red indicates genes already known to be associated with DDs (in DDG2P). Only genes with a p value of less than 0.05/18,272 (red lines) are labeled.</div>
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<p> Figure 3. Five novel genes with clustered… </p>
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<p> Figure 3. Five novel genes with clustered mutations </p>
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<div class="figure-caption-contents"><p> The domains (blue), post-translational modifications, and mutation… </p></div>
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Figure 3. Five novel genes with clustered mutations
</strong>
<div class="figure-caption-contents">The domains (blue), post-translational modifications, and mutation locations (red stars) are shown for five proteins with highly clustered <i>de novo</i> mutations in unrelated children with severe, undiagnosed DDs. For two proteins (COL4A3BP and PCGF2) where all observed mutations are identical, photos are shown to highlight the facial similarities of patients carrying the same mutation.</div>
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<p> Figure 4. Candidate gene Loss of Function… </p>
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<p> Figure 4. Candidate gene Loss of Function modeling in zebrafish reveals enrichment for developmentally important… </p>
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Figure 4. Candidate gene Loss of Function modeling in zebrafish reveals enrichment for developmentally important proteins
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<div class="figure-caption-contents"><b>a</b>, Examples of developmental phenotypes: Knockdown of <i>pkn2a</i> results in reduced cartilaginous jaw structures (black arrows), knockdown of <i>fryl</i> results in cardiac and craniofacial defects (white arrowheads and arrows, respectively), while knockdown of <i>psmd3</i> results in smaller ear primordia (red arrows), and mis-patterned CNS neurons (compare red double arrows and brackets). <b>b</b>, Knockdown outcomes of 7 genes with variants present in microcephaly patients: Interocular measurements of brightfield images from control and LoF embryos reveal significant decreases in head size. A neuronal antibody stain (anti-HuC/D, green channel) labels the brains of control and morphant zebrafish. Measurements taken across the widest extent of the midbrain identify significant reductions in brain size, likely underlying the concomitant head size reductions seen in brightfield. In <b>b</b>, tables show average percentage reduction in head and brain width, and p-values of a <i>t-</i>test.</div>
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<h2 class="title">
Related information
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Gene
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MedGen
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MedGen (Bookshelf cited)
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Nucleotide
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