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<meta name="description" content="Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo pr …"><meta name="keywords" content="pmid:27479907, PMC5988037, doi:10.1038/ng.3627, Comparative Study, Research Support, Non-U.S. Gov&#x27;t, Alejandro Sifrim, Marc-Phillip Hitz, Matthew E Hurles, Autoantigens / genetics*, CDC2 Protein Kinase / chemistry, CDC2 Protein Kinase / genetics*, Exome / genetics, Female, Heart Defects, Congenital / genetics*, Humans, Male, Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics*, Mutation / genetics*, Protein Conformation, Protein Kinase C / genetics*, Sequence Deletion, Syndrome, 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 property="og:title" content="Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing - PubMed"><meta property="og:url" content="https://pubmed.ncbi.nlm.nih.gov/27479907/"><meta property="og:description" content="Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo pr …"><meta property="og:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:image:secure_url" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:type" content="website"><meta property="og:site_name" content="PubMed"><meta name="twitter:domain" content="pubmed.ncbi.nlm.nih.gov"><meta name="twitter:card" content="summary_large_image"><meta name="twitter:title" content="Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing - PubMed"><meta name="twitter:url" content="https://pubmed.ncbi.nlm.nih.gov/27479907/"><meta name="twitter:description" content="Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo pr …"><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">
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<span class="email-subject" id="email-subject" aria-label="Email subject">1 selected item: 27479907 - PubMed</span>
<input type="hidden" name="email-subject" value="1 selected item: 27479907"/>
<input type="hidden" name="email-subject-hash" value="039c2ee9d364e10c8076b28a1335f862674be40ca95d6664b35378386baa9286"/>
</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>
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<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" />
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<div id="collections-action-panel"
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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/">
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<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
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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/"
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<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
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<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/">
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<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:
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<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
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<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?
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<option value="Tuesday">The first Tuesday</option>
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<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
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<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
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<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>
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</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
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<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>
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</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
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<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>
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</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">
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Send even when there aren't any new results
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</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
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Optional text in email:
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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
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<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
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</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
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class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
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<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"
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data-search-form-term-value="">
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<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:
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<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>
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Full text links
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<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://doi.org/10.1038/ng.3627"
target="_blank"
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Full text links
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<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"
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data-citation-style="nlm"
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aria-label="Save article in MyNCBI collections."
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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%2F27479907%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"
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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"
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class="collections-existing"
name="collections"
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<h1 class="heading-title">
Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
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18
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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1
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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16
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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19
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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11
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pediatric Cardiology, Heart Center, University of Leipzig, Leipzig, Germany." href="#full-view-affiliation-20" ref="linksrc=author_aff">
20
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Daly+A&amp;cauthor_id=27479907"
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data-ga-label="Allan Daly">Allan Daly</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Wellcome Trust Sanger Institute, Cambridge, UK." href="#full-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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1
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK." href="#full-view-affiliation-21" ref="linksrc=author_aff">
21
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK." href="#full-view-affiliation-22" ref="linksrc=author_aff">
22
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Fryer+A&amp;cauthor_id=27479907"
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data-ga-label="Alan Fryer">Alan Fryer</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Clinical Genetics, Liverpool Women&#x27;s NHS Foundation Trust, Liverpool, UK." href="#full-view-affiliation-23" ref="linksrc=author_aff">
23
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Marc Gewillig">Marc Gewillig</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium." href="#full-view-affiliation-24" ref="linksrc=author_aff">
24
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Emma Hobson">Emma Hobson</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK." href="#full-view-affiliation-25" ref="linksrc=author_aff">
25
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Hoff+K&amp;cauthor_id=27479907"
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data-ga-label="Kirstin Hoff">Kirstin Hoff</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany." href="#full-view-affiliation-2" ref="linksrc=author_aff">
2
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="German Center for Cardiovascular Research (DZHK), Berlin, Germany." href="#full-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=Homfray+T&amp;cauthor_id=27479907"
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data-ga-label="Tessa Homfray">Tessa Homfray</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="South West Thames Regional Genetics Centre, St George&#x27;s Healthcare NHS Trust, University of London, London, UK." href="#full-view-affiliation-26" ref="linksrc=author_aff">
26
</a></sup><span class="semicolon">;&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="INTERVAL Study">INTERVAL Study</a><span class="semicolon">;&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Anne-Karin Kahlert">Anne-Karin Kahlert</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany." href="#full-view-affiliation-2" ref="linksrc=author_aff">
2
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="German Center for Cardiovascular Research (DZHK), Berlin, Germany." href="#full-view-affiliation-3" ref="linksrc=author_aff">
3
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Institute for Clinical Genetics, Carl Gustav Carus Faculty of Medicine, Dresden, Germany." href="#full-view-affiliation-27" ref="linksrc=author_aff">
27
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Ami Ketley">Ami Ketley</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="School of Life Sciences, University of Nottingham, Queen&#x27;s Medical Centre, Nottingham, UK." href="#full-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="Hans-Heiner Kramer">Hans-Heiner Kramer</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany." href="#full-view-affiliation-2" ref="linksrc=author_aff">
2
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="German Center for Cardiovascular Research (DZHK), Berlin, Germany." href="#full-view-affiliation-3" ref="linksrc=author_aff">
3
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany." href="#full-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"
href="/?term=Lachlan+K&amp;cauthor_id=27479907"
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data-ga-label="Katherine Lachlan">Katherine Lachlan</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK." href="#full-view-affiliation-28" ref="linksrc=author_aff">
28
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK." href="#full-view-affiliation-29" ref="linksrc=author_aff">
29
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Faculty of Medicine, University of Southampton, Southampton, UK." href="#full-view-affiliation-30" ref="linksrc=author_aff">
30
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Lampe+AK&amp;cauthor_id=27479907"
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data-ga-label="Anne Katrin Lampe">Anne Katrin Lampe</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="South East of Scotland Clinical Genetic Service, IGMM North, Western General Hospital, Edinburgh, UK." href="#full-view-affiliation-31" ref="linksrc=author_aff">
31
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Louw+JJ&amp;cauthor_id=27479907"
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data-ga-label="Jacoba J Louw">Jacoba J Louw</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium." href="#full-view-affiliation-24" ref="linksrc=author_aff">
24
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Manickara+AK&amp;cauthor_id=27479907"
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data-ga-label="Ashok Kumar Manickara">Ashok Kumar Manickara</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Hospital for Sick Children, Toronto, Ontario, Canada." href="#full-view-affiliation-32" ref="linksrc=author_aff">
32
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Manase+D&amp;cauthor_id=27479907"
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data-ga-label="Dorin Manase">Dorin Manase</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Hospital for Sick Children, Toronto, Ontario, Canada." href="#full-view-affiliation-32" ref="linksrc=author_aff">
32
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=McCarthy+KP&amp;cauthor_id=27479907"
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data-ga-label="Karen P McCarthy">Karen P McCarthy</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Cardiac Morphology Unit, Royal Brompton Hospital and the National Heart and Lung Institute, Imperial College, UK." href="#full-view-affiliation-33" ref="linksrc=author_aff">
33
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Metcalfe+K&amp;cauthor_id=27479907"
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data-ga-label="Kay Metcalfe">Kay Metcalfe</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 University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK." href="#full-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=Moore+C&amp;cauthor_id=27479907"
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data-ga-label="Carmel Moore">Carmel Moore</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK." href="#full-view-affiliation-22" ref="linksrc=author_aff">
22
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Newbury-Ecob+R&amp;cauthor_id=27479907"
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data-ga-label="Ruth Newbury-Ecob">Ruth Newbury-Ecob</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Clinical Genetics, St Michael&#x27;s Hospital, Bristol, UK." href="#full-view-affiliation-34" ref="linksrc=author_aff">
34
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Omer+SO&amp;cauthor_id=27479907"
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data-ga-label="Seham Osman Omer">Seham Osman Omer</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Division of Pediatric Cardiology, King Abdulaziz Cardiac Center, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia." href="#full-view-affiliation-35" ref="linksrc=author_aff">
35
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Ouwehand+WH&amp;cauthor_id=27479907"
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data-ga-label="Willem H Ouwehand">Willem H Ouwehand</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Wellcome Trust Sanger Institute, Cambridge, UK." href="#full-view-affiliation-1" ref="linksrc=author_aff">
1
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK." href="#full-view-affiliation-21" ref="linksrc=author_aff">
21
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Haematology, University of Cambridge, Cambridge, UK." href="#full-view-affiliation-36" ref="linksrc=author_aff">
36
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="NHS Blood and Transplant, Cambridge, UK." href="#full-view-affiliation-37" ref="linksrc=author_aff">
37
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Park+SM&amp;cauthor_id=27479907"
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data-ga-label="Soo-Mi Park">Soo-Mi Park</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK." href="#full-view-affiliation-38" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Parker+MJ&amp;cauthor_id=27479907"
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data-ga-label="Michael J Parker">Michael J Parker</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Sheffield Children&#x27;s Hospital NHS Foundation Trust, Western Bank, Sheffield, UK." href="#full-view-affiliation-39" ref="linksrc=author_aff">
39
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Pickardt+T&amp;cauthor_id=27479907"
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data-ga-label="Thomas Pickardt">Thomas Pickardt</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany." href="#full-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"
href="/?term=Pollard+MO&amp;cauthor_id=27479907"
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data-ga-label="Martin O Pollard">Martin O Pollard</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Wellcome Trust Sanger Institute, Cambridge, UK." href="#full-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"
href="/?term=Robert+L&amp;cauthor_id=27479907"
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data-ga-label="Leema Robert">Leema Robert</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="South East Thames Regional Genetics Centre, Guy&#x27;s and St Thomas&#x27; NHS Foundation Trust, Guy&#x27;s Hospital, London, UK." href="#full-view-affiliation-40" ref="linksrc=author_aff">
40
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Roberts+DJ&amp;cauthor_id=27479907"
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data-ga-label="David J Roberts">David J Roberts</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK." href="#full-view-affiliation-21" ref="linksrc=author_aff">
21
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK." href="#full-view-affiliation-41" ref="linksrc=author_aff">
41
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK." href="#full-view-affiliation-42" ref="linksrc=author_aff">
42
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Sambrook+J&amp;cauthor_id=27479907"
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data-ga-label="Jennifer Sambrook">Jennifer Sambrook</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK." href="#full-view-affiliation-22" ref="linksrc=author_aff">
22
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Haematology, University of Cambridge, Cambridge, UK." href="#full-view-affiliation-36" ref="linksrc=author_aff">
36
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Setchfield+K&amp;cauthor_id=27479907"
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data-ga-label="Kerry Setchfield">Kerry Setchfield</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="School of Life Sciences, University of Nottingham, Queen&#x27;s Medical Centre, Nottingham, UK." href="#full-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"
href="/?term=Stiller+B&amp;cauthor_id=27479907"
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data-ga-label="Brigitte Stiller">Brigitte Stiller</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany." href="#full-view-affiliation-11" ref="linksrc=author_aff">
11
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Congenital Heart Defects and Pediatric Cardiology, Heart Centre, University of Freiburg, Freiburg, Germany." href="#full-view-affiliation-43" ref="linksrc=author_aff">
43
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Thornborough+C&amp;cauthor_id=27479907"
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17
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11
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Friedrich Alexander Universität Erlangen-Nürnberg (FAU), Department of Pediatric Cardiology, Erlangen, Germany." href="#full-view-affiliation-44" ref="linksrc=author_aff">
44
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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16
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19
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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45
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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32
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46
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47
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48
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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49
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35
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia." href="#full-view-affiliation-50" ref="linksrc=author_aff">
50
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia." href="#full-view-affiliation-51" ref="linksrc=author_aff">
51
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3
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany." href="#full-view-affiliation-11" ref="linksrc=author_aff">
11
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Experimental and Clinical Research Center (ECRC), Charité Medical Faculty and Max Delbruck Center for Molecular Medicine, Berlin, Germany." href="#full-view-affiliation-52" ref="linksrc=author_aff">
52
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pediatric Cardiology, Charité University Medicine, Berlin, Germany." href="#full-view-affiliation-53" ref="linksrc=author_aff">
53
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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1
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54
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1
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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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55
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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4
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data-ga-label="Matthew E Hurles">Matthew E Hurles</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Wellcome Trust Sanger Institute, Cambridge, UK." href="#full-view-affiliation-1" ref="linksrc=author_aff">
1
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<h3 class="title">
Affiliations
</h3>
<ul class="item-list">
<li data-affiliation-id="full-view-affiliation-1"
id="full-view-affiliation-1"
><sup class="key">1</sup> Wellcome Trust Sanger Institute, Cambridge, UK.</li>
<li data-affiliation-id="full-view-affiliation-2"
id="full-view-affiliation-2"
><sup class="key">2</sup> Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany.</li>
<li data-affiliation-id="full-view-affiliation-3"
id="full-view-affiliation-3"
><sup class="key">3</sup> German Center for Cardiovascular Research (DZHK), Berlin, Germany.</li>
<li data-affiliation-id="full-view-affiliation-4"
id="full-view-affiliation-4"
><sup class="key">4</sup> School of Life Sciences, University of Nottingham, Queen&#x27;s Medical Centre, Nottingham, UK.</li>
<li data-affiliation-id="full-view-affiliation-5"
id="full-view-affiliation-5"
><sup class="key">5</sup> Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.</li>
<li data-affiliation-id="full-view-affiliation-6"
id="full-view-affiliation-6"
><sup class="key">6</sup> Department of Pathology, King Abdulaziz Medical City, Riyadh, Saudi Arabia.</li>
<li data-affiliation-id="full-view-affiliation-7"
id="full-view-affiliation-7"
><sup class="key">7</sup> Genetics Training Program, Harvard Medical School, Boston, Massachusetts, USA.</li>
<li data-affiliation-id="full-view-affiliation-8"
id="full-view-affiliation-8"
><sup class="key">8</sup> Vesalius Research Center, VIB, Leuven, Belgium.</li>
<li data-affiliation-id="full-view-affiliation-9"
id="full-view-affiliation-9"
><sup class="key">9</sup> Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.</li>
<li data-affiliation-id="full-view-affiliation-10"
id="full-view-affiliation-10"
><sup class="key">10</sup> Department of Pediatric Cardiology, Saarland University, Homburg, Germany.</li>
<li data-affiliation-id="full-view-affiliation-11"
id="full-view-affiliation-11"
><sup class="key">11</sup> Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany.</li>
<li data-affiliation-id="full-view-affiliation-12"
id="full-view-affiliation-12"
><sup class="key">12</sup> Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.</li>
<li data-affiliation-id="full-view-affiliation-13"
id="full-view-affiliation-13"
><sup class="key">13</sup> Manchester Centre for Genomic Medicine, St Mary&#x27;s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.</li>
<li data-affiliation-id="full-view-affiliation-14"
id="full-view-affiliation-14"
><sup class="key">14</sup> Department of Paediatric Cardiology, Yorkshire Heart Centre, Leeds, UK.</li>
<li data-affiliation-id="full-view-affiliation-15"
id="full-view-affiliation-15"
><sup class="key">15</sup> Department of Congenital Heart Disease and Pediatric Cardiology, German Heart Institute Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany.</li>
<li data-affiliation-id="full-view-affiliation-16"
id="full-view-affiliation-16"
><sup class="key">16</sup> Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.</li>
<li data-affiliation-id="full-view-affiliation-17"
id="full-view-affiliation-17"
><sup class="key">17</sup> East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester, UK.</li>
<li data-affiliation-id="full-view-affiliation-18"
id="full-view-affiliation-18"
><sup class="key">18</sup> North West Thames Regional Genetics Centre, London North West Healthcare NHS Trust, Harrow, UK.</li>
<li data-affiliation-id="full-view-affiliation-19"
id="full-view-affiliation-19"
><sup class="key">19</sup> West Midlands Regional Genetics Service, Birmingham Women&#x27;s NHS Foundation Trust, Birmingham Women&#x27;s Hospital, Birmingham, UK.</li>
<li data-affiliation-id="full-view-affiliation-20"
id="full-view-affiliation-20"
><sup class="key">20</sup> Department of Pediatric Cardiology, Heart Center, University of Leipzig, Leipzig, Germany.</li>
<li data-affiliation-id="full-view-affiliation-21"
id="full-view-affiliation-21"
><sup class="key">21</sup> NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.</li>
<li data-affiliation-id="full-view-affiliation-22"
id="full-view-affiliation-22"
><sup class="key">22</sup> INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.</li>
<li data-affiliation-id="full-view-affiliation-23"
id="full-view-affiliation-23"
><sup class="key">23</sup> Department of Clinical Genetics, Liverpool Women&#x27;s NHS Foundation Trust, Liverpool, UK.</li>
<li data-affiliation-id="full-view-affiliation-24"
id="full-view-affiliation-24"
><sup class="key">24</sup> Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium.</li>
<li data-affiliation-id="full-view-affiliation-25"
id="full-view-affiliation-25"
><sup class="key">25</sup> Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.</li>
<li data-affiliation-id="full-view-affiliation-26"
id="full-view-affiliation-26"
><sup class="key">26</sup> South West Thames Regional Genetics Centre, St George&#x27;s Healthcare NHS Trust, University of London, London, UK.</li>
<li data-affiliation-id="full-view-affiliation-27"
id="full-view-affiliation-27"
><sup class="key">27</sup> Institute for Clinical Genetics, Carl Gustav Carus Faculty of Medicine, Dresden, Germany.</li>
<li data-affiliation-id="full-view-affiliation-28"
id="full-view-affiliation-28"
><sup class="key">28</sup> Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK.</li>
<li data-affiliation-id="full-view-affiliation-29"
id="full-view-affiliation-29"
><sup class="key">29</sup> Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.</li>
<li data-affiliation-id="full-view-affiliation-30"
id="full-view-affiliation-30"
><sup class="key">30</sup> Faculty of Medicine, University of Southampton, Southampton, UK.</li>
<li data-affiliation-id="full-view-affiliation-31"
id="full-view-affiliation-31"
><sup class="key">31</sup> South East of Scotland Clinical Genetic Service, IGMM North, Western General Hospital, Edinburgh, UK.</li>
<li data-affiliation-id="full-view-affiliation-32"
id="full-view-affiliation-32"
><sup class="key">32</sup> Hospital for Sick Children, Toronto, Ontario, Canada.</li>
<li data-affiliation-id="full-view-affiliation-33"
id="full-view-affiliation-33"
><sup class="key">33</sup> Cardiac Morphology Unit, Royal Brompton Hospital and the National Heart and Lung Institute, Imperial College, UK.</li>
<li data-affiliation-id="full-view-affiliation-34"
id="full-view-affiliation-34"
><sup class="key">34</sup> Department of Clinical Genetics, St Michael&#x27;s Hospital, Bristol, UK.</li>
<li data-affiliation-id="full-view-affiliation-35"
id="full-view-affiliation-35"
><sup class="key">35</sup> Division of Pediatric Cardiology, King Abdulaziz Cardiac Center, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia.</li>
<li data-affiliation-id="full-view-affiliation-36"
id="full-view-affiliation-36"
><sup class="key">36</sup> Department of Haematology, University of Cambridge, Cambridge, UK.</li>
<li data-affiliation-id="full-view-affiliation-37"
id="full-view-affiliation-37"
><sup class="key">37</sup> NHS Blood and Transplant, Cambridge, UK.</li>
<li data-affiliation-id="full-view-affiliation-38"
id="full-view-affiliation-38"
><sup class="key">38</sup> East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.</li>
<li data-affiliation-id="full-view-affiliation-39"
id="full-view-affiliation-39"
><sup class="key">39</sup> Sheffield Children&#x27;s Hospital NHS Foundation Trust, Western Bank, Sheffield, UK.</li>
<li data-affiliation-id="full-view-affiliation-40"
id="full-view-affiliation-40"
><sup class="key">40</sup> South East Thames Regional Genetics Centre, Guy&#x27;s and St Thomas&#x27; NHS Foundation Trust, Guy&#x27;s Hospital, London, UK.</li>
<li data-affiliation-id="full-view-affiliation-41"
id="full-view-affiliation-41"
><sup class="key">41</sup> NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK.</li>
<li data-affiliation-id="full-view-affiliation-42"
id="full-view-affiliation-42"
><sup class="key">42</sup> Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.</li>
<li data-affiliation-id="full-view-affiliation-43"
id="full-view-affiliation-43"
><sup class="key">43</sup> Department of Congenital Heart Defects and Pediatric Cardiology, Heart Centre, University of Freiburg, Freiburg, Germany.</li>
<li data-affiliation-id="full-view-affiliation-44"
id="full-view-affiliation-44"
><sup class="key">44</sup> Friedrich Alexander Universität Erlangen-Nürnberg (FAU), Department of Pediatric Cardiology, Erlangen, Germany.</li>
<li data-affiliation-id="full-view-affiliation-45"
id="full-view-affiliation-45"
><sup class="key">45</sup> Northern Genetics Service, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Newcastle-upon-Tyne, UK.</li>
<li data-affiliation-id="full-view-affiliation-46"
id="full-view-affiliation-46"
><sup class="key">46</sup> Division of Paediatric Cardiology, Royal Brompton Hospital, London, UK.</li>
<li data-affiliation-id="full-view-affiliation-47"
id="full-view-affiliation-47"
><sup class="key">47</sup> Paediatric Cardiology, Imperial College, London, UK.</li>
<li data-affiliation-id="full-view-affiliation-48"
id="full-view-affiliation-48"
><sup class="key">48</sup> Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK.</li>
<li data-affiliation-id="full-view-affiliation-49"
id="full-view-affiliation-49"
><sup class="key">49</sup> Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.</li>
<li data-affiliation-id="full-view-affiliation-50"
id="full-view-affiliation-50"
><sup class="key">50</sup> King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.</li>
<li data-affiliation-id="full-view-affiliation-51"
id="full-view-affiliation-51"
><sup class="key">51</sup> King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.</li>
<li data-affiliation-id="full-view-affiliation-52"
id="full-view-affiliation-52"
><sup class="key">52</sup> Experimental and Clinical Research Center (ECRC), Charité Medical Faculty and Max Delbruck Center for Molecular Medicine, Berlin, Germany.</li>
<li data-affiliation-id="full-view-affiliation-53"
id="full-view-affiliation-53"
><sup class="key">53</sup> Department of Pediatric Cardiology, Charité University Medicine, Berlin, Germany.</li>
<li data-affiliation-id="full-view-affiliation-54"
id="full-view-affiliation-54"
><sup class="key">54</sup> East Anglian Medical Genetics, Cambridge University Hospitals NHS Foundation Trust, Biomedical Campus, Cambridge, UK.</li>
<li data-affiliation-id="full-view-affiliation-55"
id="full-view-affiliation-55"
><sup class="key">55</sup> Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh, UK.</li>
</ul>
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<div class="publication-type" >Comparative Study</div>
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Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
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</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany." href="#short-view-affiliation-2" ref="linksrc=author_aff">
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data-ga-label="Marc Gewillig">Marc Gewillig</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium." href="#short-view-affiliation-24" ref="linksrc=author_aff">
24
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Emma Hobson">Emma Hobson</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK." href="#short-view-affiliation-25" ref="linksrc=author_aff">
25
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Kirstin Hoff">Kirstin Hoff</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany." href="#short-view-affiliation-2" ref="linksrc=author_aff">
2
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="German Center for Cardiovascular Research (DZHK), Berlin, Germany." 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=Homfray+T&amp;cauthor_id=27479907"
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data-ga-label="Tessa Homfray">Tessa Homfray</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="South West Thames Regional Genetics Centre, St George&#x27;s Healthcare NHS Trust, University of London, London, UK." href="#short-view-affiliation-26" ref="linksrc=author_aff">
26
</a></sup><span class="semicolon">;&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Anne-Karin Kahlert">Anne-Karin Kahlert</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany." href="#short-view-affiliation-2" ref="linksrc=author_aff">
2
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="German Center for Cardiovascular Research (DZHK), Berlin, Germany." href="#short-view-affiliation-3" ref="linksrc=author_aff">
3
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Institute for Clinical Genetics, Carl Gustav Carus Faculty of Medicine, Dresden, Germany." href="#short-view-affiliation-27" ref="linksrc=author_aff">
27
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Ami Ketley">Ami Ketley</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="School of Life Sciences, University of Nottingham, Queen&#x27;s Medical Centre, Nottingham, 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="Hans-Heiner Kramer">Hans-Heiner Kramer</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany." href="#short-view-affiliation-2" ref="linksrc=author_aff">
2
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="German Center for Cardiovascular Research (DZHK), Berlin, Germany." href="#short-view-affiliation-3" ref="linksrc=author_aff">
3
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany." 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"
href="/?term=Lachlan+K&amp;cauthor_id=27479907"
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data-ga-label="Katherine Lachlan">Katherine Lachlan</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK." href="#short-view-affiliation-28" ref="linksrc=author_aff">
28
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK." href="#short-view-affiliation-29" ref="linksrc=author_aff">
29
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Faculty of Medicine, University of Southampton, Southampton, UK." href="#short-view-affiliation-30" ref="linksrc=author_aff">
30
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Lampe+AK&amp;cauthor_id=27479907"
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data-ga-label="Anne Katrin Lampe">Anne Katrin Lampe</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="South East of Scotland Clinical Genetic Service, IGMM North, Western General Hospital, Edinburgh, UK." href="#short-view-affiliation-31" ref="linksrc=author_aff">
31
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Jacoba J Louw">Jacoba J Louw</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium." href="#short-view-affiliation-24" ref="linksrc=author_aff">
24
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Manickara+AK&amp;cauthor_id=27479907"
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data-ga-label="Ashok Kumar Manickara">Ashok Kumar Manickara</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Hospital for Sick Children, Toronto, Ontario, Canada." href="#short-view-affiliation-32" ref="linksrc=author_aff">
32
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Dorin Manase">Dorin Manase</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Hospital for Sick Children, Toronto, Ontario, Canada." href="#short-view-affiliation-32" ref="linksrc=author_aff">
32
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=McCarthy+KP&amp;cauthor_id=27479907"
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data-ga-label="Karen P McCarthy">Karen P McCarthy</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Cardiac Morphology Unit, Royal Brompton Hospital and the National Heart and Lung Institute, Imperial College, UK." href="#short-view-affiliation-33" ref="linksrc=author_aff">
33
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Kay Metcalfe">Kay Metcalfe</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 University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK." 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=Moore+C&amp;cauthor_id=27479907"
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data-ga-label="Carmel Moore">Carmel Moore</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK." href="#short-view-affiliation-22" ref="linksrc=author_aff">
22
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Ruth Newbury-Ecob">Ruth Newbury-Ecob</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Clinical Genetics, St Michael&#x27;s Hospital, Bristol, UK." href="#short-view-affiliation-34" ref="linksrc=author_aff">
34
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Omer+SO&amp;cauthor_id=27479907"
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data-ga-label="Seham Osman Omer">Seham Osman Omer</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Division of Pediatric Cardiology, King Abdulaziz Cardiac Center, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia." href="#short-view-affiliation-35" ref="linksrc=author_aff">
35
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Ouwehand+WH&amp;cauthor_id=27479907"
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data-ga-label="Willem H Ouwehand">Willem H Ouwehand</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Wellcome Trust Sanger Institute, Cambridge, UK." href="#short-view-affiliation-1" ref="linksrc=author_aff">
1
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK." href="#short-view-affiliation-21" ref="linksrc=author_aff">
21
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Haematology, University of Cambridge, Cambridge, UK." href="#short-view-affiliation-36" ref="linksrc=author_aff">
36
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="NHS Blood and Transplant, Cambridge, UK." href="#short-view-affiliation-37" ref="linksrc=author_aff">
37
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Park+SM&amp;cauthor_id=27479907"
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data-ga-label="Soo-Mi Park">Soo-Mi Park</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK." href="#short-view-affiliation-38" ref="linksrc=author_aff">
38
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Michael J Parker">Michael J Parker</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Sheffield Children&#x27;s Hospital NHS Foundation Trust, Western Bank, Sheffield, UK." href="#short-view-affiliation-39" ref="linksrc=author_aff">
39
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Thomas Pickardt">Thomas Pickardt</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany." 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"
href="/?term=Pollard+MO&amp;cauthor_id=27479907"
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data-ga-label="Martin O Pollard">Martin O Pollard</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Wellcome Trust Sanger Institute, Cambridge, UK." 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"
href="/?term=Robert+L&amp;cauthor_id=27479907"
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data-ga-label="Leema Robert">Leema Robert</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="South East Thames Regional Genetics Centre, Guy&#x27;s and St Thomas&#x27; NHS Foundation Trust, Guy&#x27;s Hospital, London, UK." href="#short-view-affiliation-40" ref="linksrc=author_aff">
40
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Roberts+DJ&amp;cauthor_id=27479907"
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data-ga-label="David J Roberts">David J Roberts</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK." href="#short-view-affiliation-21" ref="linksrc=author_aff">
21
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK." href="#short-view-affiliation-41" ref="linksrc=author_aff">
41
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK." href="#short-view-affiliation-42" ref="linksrc=author_aff">
42
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Sambrook+J&amp;cauthor_id=27479907"
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data-ga-label="Jennifer Sambrook">Jennifer Sambrook</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK." href="#short-view-affiliation-22" ref="linksrc=author_aff">
22
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Haematology, University of Cambridge, Cambridge, UK." href="#short-view-affiliation-36" ref="linksrc=author_aff">
36
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Setchfield+K&amp;cauthor_id=27479907"
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data-ga-label="Kerry Setchfield">Kerry Setchfield</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="School of Life Sciences, University of Nottingham, Queen&#x27;s Medical Centre, Nottingham, 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"
href="/?term=Stiller+B&amp;cauthor_id=27479907"
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data-ga-label="Brigitte Stiller">Brigitte Stiller</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany." href="#short-view-affiliation-11" ref="linksrc=author_aff">
11
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Congenital Heart Defects and Pediatric Cardiology, Heart Centre, University of Freiburg, Freiburg, Germany." href="#short-view-affiliation-43" ref="linksrc=author_aff">
43
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Thornborough+C&amp;cauthor_id=27479907"
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data-ga-label="Chris Thornborough">Chris Thornborough</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester, UK." href="#short-view-affiliation-17" ref="linksrc=author_aff">
17
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Toka+O&amp;cauthor_id=27479907"
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data-ga-label="Okan Toka">Okan Toka</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany." href="#short-view-affiliation-11" ref="linksrc=author_aff">
11
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Friedrich Alexander Universität Erlangen-Nürnberg (FAU), Department of Pediatric Cardiology, Erlangen, Germany." href="#short-view-affiliation-44" ref="linksrc=author_aff">
44
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Watkins+H&amp;cauthor_id=27479907"
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data-ga-label="Hugh Watkins">Hugh Watkins</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Cardiovascular Medicine, University of Oxford, Oxford, UK." href="#short-view-affiliation-16" ref="linksrc=author_aff">
16
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Williams+D&amp;cauthor_id=27479907"
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data-ga-label="Denise Williams">Denise Williams</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="West Midlands Regional Genetics Service, Birmingham Women&#x27;s NHS Foundation Trust, Birmingham Women&#x27;s Hospital, Birmingham, UK." href="#short-view-affiliation-19" ref="linksrc=author_aff">
19
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Wright+M&amp;cauthor_id=27479907"
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data-ga-label="Michael Wright">Michael Wright</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Northern Genetics Service, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Newcastle-upon-Tyne, UK." href="#short-view-affiliation-45" ref="linksrc=author_aff">
45
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Mital+S&amp;cauthor_id=27479907"
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data-ga-label="Seema Mital">Seema Mital</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Hospital for Sick Children, Toronto, Ontario, Canada." href="#short-view-affiliation-32" ref="linksrc=author_aff">
32
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Daubeney+PE&amp;cauthor_id=27479907"
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data-ga-label="Piers E F Daubeney">Piers E F Daubeney</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Division of Paediatric Cardiology, Royal Brompton Hospital, London, UK." href="#short-view-affiliation-46" ref="linksrc=author_aff">
46
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Paediatric Cardiology, Imperial College, London, UK." href="#short-view-affiliation-47" ref="linksrc=author_aff">
47
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Keavney+B&amp;cauthor_id=27479907"
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data-ga-label="Bernard Keavney">Bernard Keavney</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK." href="#short-view-affiliation-48" ref="linksrc=author_aff">
48
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Goodship+J&amp;cauthor_id=27479907"
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49
</a></sup><span class="semicolon">;&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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35
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia." href="#short-view-affiliation-50" ref="linksrc=author_aff">
50
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia." href="#short-view-affiliation-51" ref="linksrc=author_aff">
51
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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3
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany." href="#short-view-affiliation-11" ref="linksrc=author_aff">
11
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Experimental and Clinical Research Center (ECRC), Charité Medical Faculty and Max Delbruck Center for Molecular Medicine, Berlin, Germany." href="#short-view-affiliation-52" ref="linksrc=author_aff">
52
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pediatric Cardiology, Charité University Medicine, Berlin, Germany." href="#short-view-affiliation-53" ref="linksrc=author_aff">
53
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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1
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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54
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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1
</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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data-ga-label="David R FitzPatrick">David R FitzPatrick</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh, UK." href="#short-view-affiliation-55" ref="linksrc=author_aff">
55
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="J David Brook">J David Brook</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="School of Life Sciences, University of Nottingham, Queen&#x27;s Medical Centre, Nottingham, UK." href="#short-view-affiliation-4" ref="linksrc=author_aff">
4
</a></sup><span class="semicolon">;&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Matthew E Hurles">Matthew E Hurles</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Wellcome Trust Sanger Institute, Cambridge, UK." href="#short-view-affiliation-1" ref="linksrc=author_aff">
1
</a></sup></span>
</div>
</div>
<div class="affiliations">
<h3 class="title">
Affiliations
</h3>
<ul class="item-list">
<li data-affiliation-id="short-view-affiliation-1"
id="short-view-affiliation-1"
><sup class="key">1</sup> Wellcome Trust Sanger Institute, Cambridge, UK.</li>
<li data-affiliation-id="short-view-affiliation-2"
id="short-view-affiliation-2"
><sup class="key">2</sup> Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany.</li>
<li data-affiliation-id="short-view-affiliation-3"
id="short-view-affiliation-3"
><sup class="key">3</sup> German Center for Cardiovascular Research (DZHK), Berlin, Germany.</li>
<li data-affiliation-id="short-view-affiliation-4"
id="short-view-affiliation-4"
><sup class="key">4</sup> School of Life Sciences, University of Nottingham, Queen&#x27;s Medical Centre, Nottingham, UK.</li>
<li data-affiliation-id="short-view-affiliation-5"
id="short-view-affiliation-5"
><sup class="key">5</sup> Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.</li>
<li data-affiliation-id="short-view-affiliation-6"
id="short-view-affiliation-6"
><sup class="key">6</sup> Department of Pathology, King Abdulaziz Medical City, Riyadh, Saudi Arabia.</li>
<li data-affiliation-id="short-view-affiliation-7"
id="short-view-affiliation-7"
><sup class="key">7</sup> Genetics Training Program, Harvard Medical School, Boston, Massachusetts, USA.</li>
<li data-affiliation-id="short-view-affiliation-8"
id="short-view-affiliation-8"
><sup class="key">8</sup> Vesalius Research Center, VIB, Leuven, Belgium.</li>
<li data-affiliation-id="short-view-affiliation-9"
id="short-view-affiliation-9"
><sup class="key">9</sup> Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.</li>
<li data-affiliation-id="short-view-affiliation-10"
id="short-view-affiliation-10"
><sup class="key">10</sup> Department of Pediatric Cardiology, Saarland University, Homburg, Germany.</li>
<li data-affiliation-id="short-view-affiliation-11"
id="short-view-affiliation-11"
><sup class="key">11</sup> Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany.</li>
<li data-affiliation-id="short-view-affiliation-12"
id="short-view-affiliation-12"
><sup class="key">12</sup> Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.</li>
<li data-affiliation-id="short-view-affiliation-13"
id="short-view-affiliation-13"
><sup class="key">13</sup> Manchester Centre for Genomic Medicine, St Mary&#x27;s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.</li>
<li data-affiliation-id="short-view-affiliation-14"
id="short-view-affiliation-14"
><sup class="key">14</sup> Department of Paediatric Cardiology, Yorkshire Heart Centre, Leeds, UK.</li>
<li data-affiliation-id="short-view-affiliation-15"
id="short-view-affiliation-15"
><sup class="key">15</sup> Department of Congenital Heart Disease and Pediatric Cardiology, German Heart Institute Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany.</li>
<li data-affiliation-id="short-view-affiliation-16"
id="short-view-affiliation-16"
><sup class="key">16</sup> Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.</li>
<li data-affiliation-id="short-view-affiliation-17"
id="short-view-affiliation-17"
><sup class="key">17</sup> East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester, UK.</li>
<li data-affiliation-id="short-view-affiliation-18"
id="short-view-affiliation-18"
><sup class="key">18</sup> North West Thames Regional Genetics Centre, London North West Healthcare NHS Trust, Harrow, UK.</li>
<li data-affiliation-id="short-view-affiliation-19"
id="short-view-affiliation-19"
><sup class="key">19</sup> West Midlands Regional Genetics Service, Birmingham Women&#x27;s NHS Foundation Trust, Birmingham Women&#x27;s Hospital, Birmingham, UK.</li>
<li data-affiliation-id="short-view-affiliation-20"
id="short-view-affiliation-20"
><sup class="key">20</sup> Department of Pediatric Cardiology, Heart Center, University of Leipzig, Leipzig, Germany.</li>
<li data-affiliation-id="short-view-affiliation-21"
id="short-view-affiliation-21"
><sup class="key">21</sup> NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.</li>
<li data-affiliation-id="short-view-affiliation-22"
id="short-view-affiliation-22"
><sup class="key">22</sup> INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.</li>
<li data-affiliation-id="short-view-affiliation-23"
id="short-view-affiliation-23"
><sup class="key">23</sup> Department of Clinical Genetics, Liverpool Women&#x27;s NHS Foundation Trust, Liverpool, UK.</li>
<li data-affiliation-id="short-view-affiliation-24"
id="short-view-affiliation-24"
><sup class="key">24</sup> Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium.</li>
<li data-affiliation-id="short-view-affiliation-25"
id="short-view-affiliation-25"
><sup class="key">25</sup> Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.</li>
<li data-affiliation-id="short-view-affiliation-26"
id="short-view-affiliation-26"
><sup class="key">26</sup> South West Thames Regional Genetics Centre, St George&#x27;s Healthcare NHS Trust, University of London, London, UK.</li>
<li data-affiliation-id="short-view-affiliation-27"
id="short-view-affiliation-27"
><sup class="key">27</sup> Institute for Clinical Genetics, Carl Gustav Carus Faculty of Medicine, Dresden, Germany.</li>
<li data-affiliation-id="short-view-affiliation-28"
id="short-view-affiliation-28"
><sup class="key">28</sup> Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK.</li>
<li data-affiliation-id="short-view-affiliation-29"
id="short-view-affiliation-29"
><sup class="key">29</sup> Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.</li>
<li data-affiliation-id="short-view-affiliation-30"
id="short-view-affiliation-30"
><sup class="key">30</sup> Faculty of Medicine, University of Southampton, Southampton, UK.</li>
<li data-affiliation-id="short-view-affiliation-31"
id="short-view-affiliation-31"
><sup class="key">31</sup> South East of Scotland Clinical Genetic Service, IGMM North, Western General Hospital, Edinburgh, UK.</li>
<li data-affiliation-id="short-view-affiliation-32"
id="short-view-affiliation-32"
><sup class="key">32</sup> Hospital for Sick Children, Toronto, Ontario, Canada.</li>
<li data-affiliation-id="short-view-affiliation-33"
id="short-view-affiliation-33"
><sup class="key">33</sup> Cardiac Morphology Unit, Royal Brompton Hospital and the National Heart and Lung Institute, Imperial College, UK.</li>
<li data-affiliation-id="short-view-affiliation-34"
id="short-view-affiliation-34"
><sup class="key">34</sup> Department of Clinical Genetics, St Michael&#x27;s Hospital, Bristol, UK.</li>
<li data-affiliation-id="short-view-affiliation-35"
id="short-view-affiliation-35"
><sup class="key">35</sup> Division of Pediatric Cardiology, King Abdulaziz Cardiac Center, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia.</li>
<li data-affiliation-id="short-view-affiliation-36"
id="short-view-affiliation-36"
><sup class="key">36</sup> Department of Haematology, University of Cambridge, Cambridge, UK.</li>
<li data-affiliation-id="short-view-affiliation-37"
id="short-view-affiliation-37"
><sup class="key">37</sup> NHS Blood and Transplant, Cambridge, UK.</li>
<li data-affiliation-id="short-view-affiliation-38"
id="short-view-affiliation-38"
><sup class="key">38</sup> East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.</li>
<li data-affiliation-id="short-view-affiliation-39"
id="short-view-affiliation-39"
><sup class="key">39</sup> Sheffield Children&#x27;s Hospital NHS Foundation Trust, Western Bank, Sheffield, UK.</li>
<li data-affiliation-id="short-view-affiliation-40"
id="short-view-affiliation-40"
><sup class="key">40</sup> South East Thames Regional Genetics Centre, Guy&#x27;s and St Thomas&#x27; NHS Foundation Trust, Guy&#x27;s Hospital, London, UK.</li>
<li data-affiliation-id="short-view-affiliation-41"
id="short-view-affiliation-41"
><sup class="key">41</sup> NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK.</li>
<li data-affiliation-id="short-view-affiliation-42"
id="short-view-affiliation-42"
><sup class="key">42</sup> Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.</li>
<li data-affiliation-id="short-view-affiliation-43"
id="short-view-affiliation-43"
><sup class="key">43</sup> Department of Congenital Heart Defects and Pediatric Cardiology, Heart Centre, University of Freiburg, Freiburg, Germany.</li>
<li data-affiliation-id="short-view-affiliation-44"
id="short-view-affiliation-44"
><sup class="key">44</sup> Friedrich Alexander Universität Erlangen-Nürnberg (FAU), Department of Pediatric Cardiology, Erlangen, Germany.</li>
<li data-affiliation-id="short-view-affiliation-45"
id="short-view-affiliation-45"
><sup class="key">45</sup> Northern Genetics Service, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Newcastle-upon-Tyne, UK.</li>
<li data-affiliation-id="short-view-affiliation-46"
id="short-view-affiliation-46"
><sup class="key">46</sup> Division of Paediatric Cardiology, Royal Brompton Hospital, London, UK.</li>
<li data-affiliation-id="short-view-affiliation-47"
id="short-view-affiliation-47"
><sup class="key">47</sup> Paediatric Cardiology, Imperial College, London, UK.</li>
<li data-affiliation-id="short-view-affiliation-48"
id="short-view-affiliation-48"
><sup class="key">48</sup> Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK.</li>
<li data-affiliation-id="short-view-affiliation-49"
id="short-view-affiliation-49"
><sup class="key">49</sup> Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.</li>
<li data-affiliation-id="short-view-affiliation-50"
id="short-view-affiliation-50"
><sup class="key">50</sup> King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.</li>
<li data-affiliation-id="short-view-affiliation-51"
id="short-view-affiliation-51"
><sup class="key">51</sup> King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.</li>
<li data-affiliation-id="short-view-affiliation-52"
id="short-view-affiliation-52"
><sup class="key">52</sup> Experimental and Clinical Research Center (ECRC), Charité Medical Faculty and Max Delbruck Center for Molecular Medicine, Berlin, Germany.</li>
<li data-affiliation-id="short-view-affiliation-53"
id="short-view-affiliation-53"
><sup class="key">53</sup> Department of Pediatric Cardiology, Charité University Medicine, Berlin, Germany.</li>
<li data-affiliation-id="short-view-affiliation-54"
id="short-view-affiliation-54"
><sup class="key">54</sup> East Anglian Medical Genetics, Cambridge University Hospitals NHS Foundation Trust, Biomedical Campus, Cambridge, UK.</li>
<li data-affiliation-id="short-view-affiliation-55"
id="short-view-affiliation-55"
><sup class="key">55</sup> Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh, UK.</li>
</ul>
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Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.
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<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one"><bold>Competing financial interests</bold></p>
<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">M.E.H. is a co-founder of, and holds shares in, Congenica Ltd, a genetics diagnostic company.</p>
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39df/5988037/dcb0aaff29ac/emss-69098-f001.gif"
alt="Figure 1" />
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<p> Figure 1. Burden of <i> de novo </i> and… </p>
</strong>
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</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 1. Burden of <i> de novo </i> and inherited variants in NS-CHD compared to S-CHD </p>
</strong>
<div class="figure-caption-contents"><p> (A)… </p></div>
</div>
<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 1. Burden of <i>de novo</i> and inherited variants in NS-CHD compared to S-CHD
</strong>
<div class="figure-caption-contents">(A) Excess of DNMs compared to null mutation model. Excess of DNMs was computed as the ratio of the observed number of DNMs over the expectation given random mutation using a null gene-wise mutation rate model. P-values were computed using a Poisson model parameterized by the cumulative mutation rate across the gene set for the same number of probands (n<sub>S-CHD</sub>= 518, n<sub>NS-CHD</sub>= 847). We stratify by variant consequence and within known autosomal dominant CHD genes (n=78), autosomal dominant developmental disorder genes excluding autosomal dominant CHD genes (n=203) and all autosomal protein coding genes excluding autosomal dominant developmental disorder and CHD genes (n=17,404). No data is shown for silent variants in CHD genes for syndromic probands as no variants were detected. Error bars represent the 95% confidence interval. (B) Comparison of exome-wide excess of DNMs across different diseases stratified by variant consequence. (C) Excess of rare inherited variants (n<sub>S-CHD</sub>= 471, n<sub>NS-CHD</sub>= 663) compared to 12,031 controls of matched ancestry: Excess of DNMs was computed as the ratio of the observed number of rare inherited variants over the expected numbers as seen in controls. (D) Counts of <i>de novo</i> PTVs in S-CHD probands and rare inherited (INH) PTVs in NS-CHD probands in known monoallelic CHD-associated genes.</div>
</figcaption>
</figure>
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itemprop="contentUrl"
aria-describedby="figure-caption-1"
role="button"
data-image-width="800"
data-image-height="396"
data-image-alt="Figure 2"
data-pmc-id="PMC5988037"
data-figure-id="F2">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-1"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39df/5988037/ec7e049afc0f/emss-69098-f002.gif"
alt="Figure 2" />
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<p> Figure 2. Gene-wise enrichment of <i> de novo… </i> </p>
</strong>
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</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 2. Gene-wise enrichment of <i> de novo </i> mutations </p>
</strong>
<div class="figure-caption-contents"><p> Gene-wise DNM enrichment was computed for A)… </p></div>
</div>
<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 2. Gene-wise enrichment of <i>de novo</i> mutations
</strong>
<div class="figure-caption-contents">Gene-wise DNM enrichment was computed for A) the complete S-CHD cohort (n=518), B) unresolved S-CHD trios without a plausible pathogenic DNM in known developmental disorder and CHD-associated genes (n=398). The probability of enrichment was computed given a Poisson distribution with the rate given by the gene-specific mutation rate multiplied by the number of chromosomes considered. This was performed for <i>de novo</i> PTVs and <i>de novo</i> missense variants independently. The <i>de novo</i> missense-enrichment probability was further combined with the probability of non-random clustering of <i>de novo</i> mutations using Fishers method and the minimum was taken between the combined and the original p-value. The minimum probability (considering either <i>de novo</i> PTVs or <i>de novo</i> missense mutations) was plotted. The dashed horizontal line represents genome-wide significance (p&lt;1.31x10<sup>6</sup>, Bonferronni corrected P-value of 0.05 corrected for 2x19,252 protein coding genes).</div>
</figcaption>
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itemprop="contentUrl"
aria-describedby="figure-caption-2"
role="button"
data-image-width="800"
data-image-height="804"
data-image-alt="Figure 3"
data-pmc-id="PMC5988037"
data-figure-id="F3">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-2"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39df/5988037/e6ea30693e52/emss-69098-f003.gif"
alt="Figure 3" />
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<strong class="figure-label">
<p> Figure 3. Overview of <i> CDK13 </i> mutations in… </p>
</strong>
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</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 3. Overview of <i> CDK13 </i> mutations in S-CHD cases </p>
</strong>
<div class="figure-caption-contents"><p> A) Phenotype summary of probands carrying… </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">
<strong class="figure-label">
Figure 3. Overview of <i>CDK13</i> mutations in S-CHD cases
</strong>
<div class="figure-caption-contents">A) Phenotype summary of probands carrying missense mutations in <i>CDK13</i>. Colors indicate the number of times a certain phenotype was observed in individuals carrying a <i>de novo</i> mutation in <i>CDK13</i>. Photographs of affected probands are shown for which consent could be obtained for publication. B) clustering of DNMs in Serine-Threonine kinase domain. Density plot displays a sliding window (±10 amino acids) missense variant count in the Non-Finnish European population of the Exome Aggregation Consortium data, showing a marked reduction of missense variants in the kinase domain. C) 3D protein structure of <i>CDK13</i> by homology modelling adapted from <i>CDK12</i>. Mutated residues are marked in bright green. Catalysing Magnesium ion is highlighted in magenta, and the co-crystallized AMP ligand is portrayed in orange.</div>
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data-slide-index="3"
data-label-slug="figure-4">
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href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39df/5988037/47c594161861/emss-69098-f004.jpg"
itemprop="contentUrl"
aria-describedby="figure-caption-3"
role="button"
data-image-width="800"
data-image-height="416"
data-image-alt="Figure 4"
data-pmc-id="PMC5988037"
data-figure-id="F4">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-3"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39df/5988037/21e8402c42b1/emss-69098-f004.gif"
alt="Figure 4" />
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<p> Figure 4. Integrated analysis of <i> de novo… </i> </p>
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<strong class="figure-label">
<p> Figure 4. Integrated analysis of <i> de novo </i> and inherited variant enrichment using Hierarchical Bayesian modelling </p>
</strong>
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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">
Figure 4. Integrated analysis of <i>de novo</i> and inherited variant enrichment using Hierarchical Bayesian modelling
</strong>
<div class="figure-caption-contents">Scatter plots representing Bayes factors (ratio of the evidence given the alternative model of the gene being associated with CHD over the evidence given the null model of the gene not being associated with CHD) for the <i>de novo</i> and inherited components of the model for PTVs and missense variants. The diagonal solid line represents the identity line, where equal signal is obtained from <i>de novo</i> variation compared to inherited variation. Genes at an FDR &lt; 10% are labelled and colors represent different confidence thresholds.</div>
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<span class="docsum-authors full-authors">Tarr I, Hesselson S, Iismaa SE, Rath E, Monger S, Troup M, Mishra K, Wong CMY, Hsu PC, Junday K, Humphreys DT, Adlam D, Webb TR, Baranowska-Clarke AA, Hamby SE, Carss KJ, Samani NJ, Bax M, McGrath-Cadell L, Kovacic JC, Dunwoodie SL, Fatkin D, Muller DWM, Graham RM, Giannoulatou E.</span>
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<span class="docsum-journal-citation full-journal-citation">Circ Genom Precis Med. 2022 Aug;15(4):e003527. doi: 10.1161/CIRCGEN.121.003527. Epub 2022 May 18.</span>
<span class="docsum-journal-citation short-journal-citation">Circ Genom Precis Med. 2022.</span>
<span class="citation-part">PMID: <span class="docsum-pmid">35583931</span></span>
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Related information
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