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||
Clipboard <span class="amount-in-clipboard"></span>
|
||
</a>
|
||
</div>
|
||
|
||
<span class="search-input-link user-guide-link" role="navigation" aria-label="User guide">
|
||
<a href="/help/"
|
||
data-ga-category="featured_link"
|
||
data-ga-action="user_guide">
|
||
User Guide
|
||
</a>
|
||
</span>
|
||
|
||
</div>
|
||
</div>
|
||
|
||
|
||
</form>
|
||
|
||
|
||
<div id="article-page-header">
|
||
<div id="article-top-actions-bar" class="article-top-actions-bar">
|
||
<div class="inner-wrap">
|
||
<div class="actions-container">
|
||
<div class="return-to-search">
|
||
|
||
|
||
</div>
|
||
|
||
<div class="multiple-results-actions " role="region" aria-label="save, email, send to">
|
||
<button id="save-results-panel-trigger"
|
||
type="button"
|
||
class="save-results save-results-panel-trigger"
|
||
aria-expanded="false"
|
||
aria-controls="save-action-panel"
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="open">
|
||
Save
|
||
</button><button id="email-results-panel-trigger"
|
||
type="button"
|
||
class="email-results email-results-panel-trigger"
|
||
aria-expanded="false"
|
||
aria-controls="email-action-panel"
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="open">
|
||
Email
|
||
</button><div class="more-actions dropdown-block"><button id="more-actions-trigger"
|
||
type="button"
|
||
class="trigger more-actions-trigger"
|
||
ref="linksrc=show_moreactions_btn"
|
||
aria-label="Send to"
|
||
aria-controls="more-actions-dropdown">Send to</button><div id="more-actions-dropdown" class="dropdown dropdown-container" hidden><div class="content"><ul class="more-actions-links"><li><a class="clipboard-panel-trigger dropdown-block-link "
|
||
href="#"
|
||
role="button"
|
||
data-ga-category="save_share"
|
||
data-ga-action="clipboard"
|
||
data-ga-label="send">
|
||
Clipboard
|
||
</a></li><li><a role="button" class="dropdown-block-link bibliography-trigger-target" href="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F25363768%2F%23open-bibliography-panel">My Bibliography</a></li><li><a role="button" class="dropdown-block-link collections-trigger-target" href="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F25363768%2F%23open-collections-panel">Collections</a></li><li><a role="button" class="citation-manager-panel-trigger dropdown-block-link citation-manager-trigger-target" href="#">Citation manager</a></li></ul></div></div></div>
|
||
</div>
|
||
|
||
|
||
|
||
<div class="display-options" data-format-key="format"
|
||
data-default-format-value="abstract"
|
||
data-current-format-value="abstract" role="region">
|
||
<button
|
||
class="trigger usa-button"
|
||
title="Change format"
|
||
data-ga-category="display_options"
|
||
data-ga-action="display_options_dialog">
|
||
<span class="button-label">Display options</span>
|
||
</button>
|
||
|
||
<div class="dropdown" hidden>
|
||
<div class="title">
|
||
Display options
|
||
</div>
|
||
|
||
<div class="content">
|
||
|
||
<div class="format-container">
|
||
<span class="option-label">
|
||
Format
|
||
</span>
|
||
<select name="format" data-initial-value="abstract" aria-label="Display format" id="article-display-format">
|
||
<option value="abstract">Abstract</option>
|
||
|
||
<option value="pubmed">PubMed</option>
|
||
|
||
<option value="pmid">PMID</option>
|
||
|
||
</select>
|
||
</div>
|
||
|
||
</div>
|
||
</div>
|
||
</div>
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="YuVkIi2MuRODd3aiZiYG8hkTIJKiVvblfhFpl8v84sB77ug8CBBICpQxgNsuO6JF">
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="article-panels-container" class="article-panels-container">
|
||
<div id="save-action-panel" class="save-action-panel action-panel" aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Save citation to file
|
||
</h2>
|
||
<form id="save-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/results-export-ids/"
|
||
data-by-search-action="/results-export-search-data/"
|
||
data-by-ids-action="/results-export-ids/"
|
||
method="post"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="YuVkIi2MuRODd3aiZiYG8hkTIJKiVvblfhFpl8v84sB77ug8CBBICpQxgNsuO6JF">
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="save-action-format" class="action-panel-label">
|
||
Format:
|
||
</label>
|
||
<select id="save-action-format" name="results-format" class="action-panel-selector">
|
||
<option value="summary-text">Summary (text)</option>
|
||
<option value="pubmed-text">PubMed</option>
|
||
<option value="pmid">PMID</option>
|
||
<option value="abstract">Abstract (text)</option>
|
||
<option value="csv">CSV</option>
|
||
</select>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Saving..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="save">
|
||
Create file
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Save citations to file' panel"
|
||
ref="linksrc=close_save_panel"
|
||
aria-controls="save-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="email-action-panel"
|
||
class="email-action-panel action-panel"
|
||
aria-hidden="true"
|
||
data-recaptcha-script-url="https://www.recaptcha.net/recaptcha/enterprise.js?render=explicit&onload=onloadCaptchaCallback"
|
||
data-recaptcha-enabled="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Email citation
|
||
</h2>
|
||
<form id="email-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/send-email/"
|
||
data-by-search-action="/results-export-email-by-search-data/"
|
||
data-by-ids-action="/send-email/"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post"
|
||
method="post"
|
||
>
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="YuVkIi2MuRODd3aiZiYG8hkTIJKiVvblfhFpl8v84sB77ug8CBBICpQxgNsuO6JF">
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<span class="action-panel-label">
|
||
Subject:
|
||
</span>
|
||
<span class="email-subject" id="email-subject" aria-label="Email subject">1 selected item: 25363768 - PubMed</span>
|
||
<input type="hidden" name="email-subject" value="1 selected item: 25363768"/>
|
||
<input type="hidden" name="email-subject-hash" value="f6469461983d9560f09ceed5c686c409d3f3cff283c202297b3583fb0c2120b2"/>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-to" class="action-panel-label required-field-asterisk">
|
||
To:
|
||
</label>
|
||
<input type="email" aria-label="Recipient Email Address" placeholder="email@example.com" id="email-to" class="email-to" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="100" required>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-from" class="action-panel-label">
|
||
From:
|
||
</label>
|
||
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
|
||
</div>
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-citation-format" class="action-panel-label">
|
||
Format:
|
||
</label>
|
||
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
|
||
<option selected="selected" value="summary">Summary</option>
|
||
<option value="summary-text">Summary (text)</option>
|
||
<option value="abstract">Abstract</option>
|
||
<option value="abstract-text">Abstract (text)</option>
|
||
|
||
</select>
|
||
</div>
|
||
<div class="include-supplemental-container">
|
||
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
|
||
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
|
||
</div>
|
||
|
||
|
||
|
||
<div class="form-field recaptcha ">
|
||
|
||
|
||
|
||
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
|
||
|
||
|
||
|
||
|
||
|
||
</div>
|
||
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
|
||
|
||
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Sending..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="send">
|
||
Send email
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Email citations' panel"
|
||
ref="linksrc=close_email_panel"
|
||
aria-controls="email-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
<input type="hidden" name="email-search-details" value="" />
|
||
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="collections-action-panel"
|
||
class="collections-action-panel action-panel in-progress-dots-panel"
|
||
aria-hidden="true"
|
||
data-collections-open-panel-enabled="false"
|
||
data-collections-open-panel-url-hash="#open-collections-panel">
|
||
<div class="inner-wrap">
|
||
<h3 class="action-panel-heading">
|
||
Add to Collections
|
||
</h3>
|
||
|
||
|
||
<form id="collections-action-panel-form"
|
||
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-existing-collections-url="/list-existing-collections/"
|
||
data-add-to-existing-collection-url="/add-to-existing-collection/"
|
||
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
|
||
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
|
||
data-myncbi-max-collection-name-length="100"
|
||
data-add-to-collection-max-amount="1000"
|
||
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="YuVkIi2MuRODd3aiZiYG8hkTIJKiVvblfhFpl8v84sB77ug8CBBICpQxgNsuO6JF">
|
||
|
||
|
||
|
||
<div class="choice-group" role="radiogroup">
|
||
<ul class="radio-group-items">
|
||
<li>
|
||
<input type="radio"
|
||
id="collections-action-panel-new"
|
||
class="collections-new"
|
||
name="collections"
|
||
value="new"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="collections_radio_new">
|
||
<label for="collections-action-panel-new">Create a new collection</label>
|
||
</li>
|
||
<li>
|
||
<input type="radio"
|
||
id="collections-action-panel-existing"
|
||
class="collections-existing"
|
||
name="collections"
|
||
value="existing"
|
||
checked="true"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="collections_radio_existing">
|
||
<label for="collections-action-panel-existing">Add to an existing collection</label>
|
||
</li>
|
||
</ul>
|
||
</div>
|
||
|
||
<div class="controls-wrapper">
|
||
<div class="action-panel-control-wrap new-collections-controls">
|
||
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
|
||
Name your collection:
|
||
</label>
|
||
<input
|
||
type="text"
|
||
name="add-to-new-collection"
|
||
id="collections-action-panel-add-to-new"
|
||
class="collections-action-add-to-new"
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"
|
||
maxlength="100"
|
||
data-ga-category="save_share"
|
||
data-ga-action="create_collection"
|
||
data-ga-label="non_favorties_collection">
|
||
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
|
||
Name must be less than 100 characters
|
||
</div>
|
||
</div>
|
||
<div class="action-panel-control-wrap existing-collections-controls">
|
||
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
|
||
Choose a collection:
|
||
</label>
|
||
<select id="collections-action-panel-add-to-existing"
|
||
class="action-panel-selector collections-action-add-to-existing"
|
||
data-ga-category="save_share"
|
||
data-ga-action="select_collection"
|
||
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
|
||
</select>
|
||
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
|
||
Unable to load your collection due to an error<br>
|
||
<a href="#">Please try again</a>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Adding..."
|
||
data-pinger-ignore
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="add">
|
||
Add
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Add to Collections' panel"
|
||
ref="linksrc=close_collections_panel"
|
||
aria-controls="collections-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="bibliography-action-panel"
|
||
class="bibliography-action-panel action-panel in-progress-dots-panel"
|
||
aria-hidden="true"
|
||
data-bibliography-open-panel-enabled="false"
|
||
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
|
||
<div class="inner-wrap">
|
||
<h3 class="action-panel-heading">
|
||
Add to My Bibliography
|
||
</h3>
|
||
<form id="bibliography-action-panel-form"
|
||
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-add-to-bibliography-max-amount="100"
|
||
data-add-to-bibliography-batch-size="10"
|
||
data-bibliography-delegates-url="/list-bibliography-delegates/"
|
||
data-add-to-bibliography-url="/add-to-bibliography/"
|
||
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
|
||
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="YuVkIi2MuRODd3aiZiYG8hkTIJKiVvblfhFpl8v84sB77ug8CBBICpQxgNsuO6JF">
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap bibliographies-controls">
|
||
<div class="choice-group">
|
||
<ul class="bibliographies-action-add radio-group-items">
|
||
<li>
|
||
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
|
||
<label for="my-bibliography">My Bibliography</label>
|
||
</li>
|
||
</ul>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
|
||
Unable to load your delegates due to an error<br>
|
||
<a href="#">Please try again</a>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Adding..."
|
||
data-pinger-ignore>
|
||
Add
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Add to bibliography' panel"
|
||
ref="linksrc=close_bibliography_panel"
|
||
aria-controls="bibliography-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="mybib"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
|
||
data-saved-search-open-panel-enabled="false"
|
||
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Your saved search
|
||
</h2>
|
||
|
||
<form id="saved-search-action-panel-form"
|
||
class="saved-search-action-panel-form action-panel-content action-form"
|
||
data-create-saved-search-url="/create-saved-search/"
|
||
data-try-search-terms-url="/try-search-term/"
|
||
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="YuVkIi2MuRODd3aiZiYG8hkTIJKiVvblfhFpl8v84sB77ug8CBBICpQxgNsuO6JF">
|
||
|
||
<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="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/">
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
|
||
Search terms:
|
||
</label>
|
||
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
|
||
</div>
|
||
<div class="test-search-term-wrap">
|
||
<a href="#" class="try-search-term">Test search terms</a>
|
||
</div>
|
||
<div class="choice-group action-panel-extra-margin-top">
|
||
<span class="action-panel-label" id="fieldset-label">
|
||
Would you like email updates of new search results?
|
||
</span>
|
||
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
|
||
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
|
||
<ul class="radio-group-items">
|
||
<li>
|
||
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
|
||
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
|
||
</li>
|
||
<li>
|
||
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
|
||
<label for="saved-search-alert-no" class="action-panel-label">No</label>
|
||
</li>
|
||
</ul>
|
||
</fieldset>
|
||
</div>
|
||
|
||
<div class="alert-schedule-wrap">
|
||
<div class="action-panel-control-wrap">
|
||
<label class="action-panel-label">
|
||
Email:
|
||
</label>
|
||
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
|
||
</div>
|
||
<div class="action-panel-control-wrap action-panel-extra-margin-top">
|
||
<label for="saved-search-frequency" class="action-panel-label">
|
||
Frequency:
|
||
</label>
|
||
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
|
||
<option value="monthly">Monthly</option>
|
||
<option value="weekly">Weekly</option>
|
||
<option value="daily">Daily</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap saved-search-monthly-additional">
|
||
<label for="saved-search-monthly-on-day" class="action-panel-label">
|
||
Which day?
|
||
</label>
|
||
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
|
||
<option value="Sunday">The first Sunday</option>
|
||
<option value="Monday">The first Monday</option>
|
||
<option value="Tuesday">The first Tuesday</option>
|
||
<option value="Wednesday">The first Wednesday</option>
|
||
<option value="Thursday">The first Thursday</option>
|
||
<option value="Friday">The first Friday</option>
|
||
<option value="Saturday">The first Saturday</option>
|
||
<option value="day">The first day</option>
|
||
<option value="weekday">The first weekday</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap saved-search-weekly-additional">
|
||
<label for="saved-search-weekly-on-day" class="action-panel-label">
|
||
Which day?
|
||
</label>
|
||
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
|
||
<option value="Sunday">Sunday</option>
|
||
<option value="Monday">Monday</option>
|
||
<option value="Tuesday">Tuesday</option>
|
||
<option value="Wednesday">Wednesday</option>
|
||
<option value="Thursday">Thursday</option>
|
||
<option value="Friday">Friday</option>
|
||
<option value="Saturday">Saturday</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-report" class="action-panel-label">
|
||
Report format:
|
||
</label>
|
||
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
|
||
<option value="DocSum">Summary</option>
|
||
<option value="DocSumText">Summary (text)</option>
|
||
<option value="Abstract">Abstract</option>
|
||
<option value="AbstractText">Abstract (text)</option>
|
||
<option value="MEDLINE">PubMed</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-amount" class="action-panel-label">
|
||
Send at most:
|
||
</label>
|
||
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
|
||
<option value="1">1 item</option>
|
||
<option value="5" selected>5 items</option>
|
||
<option value="10">10 items</option>
|
||
<option value="20">20 items</option>
|
||
<option value="50">50 items</option>
|
||
<option value="100">100 items</option>
|
||
<option value="200">200 items</option>
|
||
</select>
|
||
</div>
|
||
<div>
|
||
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
|
||
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
|
||
Send even when there aren't any new results
|
||
</label>
|
||
</div>
|
||
<div class="action-panel-control-wrap option-text-in-email-wrap">
|
||
<label for="saved-search-email-text" class="action-panel-label">
|
||
Optional text in email:
|
||
</label>
|
||
<textarea name="saved-search-email-text"
|
||
id="saved-search-email-text"
|
||
class="saved-search-email-text"></textarea>
|
||
</div>
|
||
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Saving..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="save">
|
||
Save
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Your saved search' panel"
|
||
ref="linksrc=close_saved_search_panel"
|
||
aria-controls="saved-search-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Create a file for external citation management software
|
||
</h2>
|
||
<form id="citation-manager-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/results-export-ids/"
|
||
data-by-search-action="/results-export-search-data/"
|
||
data-by-ids-action="/results-export-ids/"
|
||
method="post"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="YuVkIi2MuRODd3aiZiYG8hkTIJKiVvblfhFpl8v84sB77ug8CBBICpQxgNsuO6JF">
|
||
|
||
|
||
|
||
<input name="results-format" type="hidden" value="pubmed"/>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Sending..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="citation_manager"
|
||
data-ga-label="save">
|
||
Create file
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Send citations to citation manager' panel"
|
||
ref="linksrc=close_citation_manager_panel"
|
||
aria-controls="citation-manager-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="citation_manager"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Your RSS Feed
|
||
</h2>
|
||
|
||
<form id="rss-action-panel-form"
|
||
class="rss-action-panel-form action-panel-content action-form"
|
||
data-create-rss-feed-url="/create-rss-feed-url/"
|
||
data-search-form-term-value="">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="YuVkIi2MuRODd3aiZiYG8hkTIJKiVvblfhFpl8v84sB77ug8CBBICpQxgNsuO6JF">
|
||
|
||
<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="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/">
|
||
</div>
|
||
|
||
<div class="rss-limit-wrap">
|
||
<div class="action-panel-control-wrap action-panel-extra-margin-top">
|
||
<label for="rss-limit" class="action-panel-label">
|
||
Number of items displayed:
|
||
</label>
|
||
<select id="rss-limit" class="no-border-panel-selector rss-limit">
|
||
<option value="5">5</option>
|
||
<option value="10">10</option>
|
||
<option value="15" selected="selected">15</option>
|
||
<option value="20">20</option>
|
||
<option value="50">50</option>
|
||
<option value="100">100</option>
|
||
</select>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Creating..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="save">
|
||
Create RSS
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Your RSS' panel"
|
||
ref="linksrc=close_rss_panel"
|
||
aria-controls="rss-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap rss-link-copy-wrap">
|
||
<label for="rss-link" class="usa-sr-only">RSS Link</label>
|
||
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
|
||
<button
|
||
type="button"
|
||
disabled
|
||
class="rss-link-copy-button disabled"
|
||
data-ga-category="save_share"
|
||
data-ga-action="rss"
|
||
data-ga-label="copy">
|
||
Copy
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="article-page" id="article-page" data-article-pmid="25363768">
|
||
<aside class="page-sidebar">
|
||
<div class="inner-wrap">
|
||
|
||
<div class="full-text-links">
|
||
<div class="full-view">
|
||
<h3 class="title">
|
||
Full text links
|
||
</h3>
|
||
<div class="full-text-links-list">
|
||
<a class="link-item
|
||
|
||
dialog-focus"
|
||
href="https://doi.org/10.1038/nature13908"
|
||
target="_blank"
|
||
rel="noopener"
|
||
|
||
ref="linksrc=fulltextorjournal_fulltext&is_pmc=False&PrId=3094&itool=Abstract-def&log$=linkouticon&uid=25363768&db=pubmed&nlmid=0410462"
|
||
title="See full text options at Nature Publishing Group"
|
||
|
||
data-ga-category="full_text"
|
||
data-ga-action="Nature Publishing Group"
|
||
data-ga-label="25363768"
|
||
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--www.nature.com-static-images-logos-nature-portfolio-120.png" alt="Nature Publishing Group full text link"><span class="text">
|
||
|
||
Nature Publishing Group
|
||
|
||
</span></a><a class="link-item
|
||
pmc
|
||
"
|
||
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/25363768/"
|
||
target="_blank"
|
||
rel="noopener"
|
||
|
||
ref="linksrc=fulltextorjournal_fulltext&is_pmc=True&PrId=3494&itool=Abstract-def&log$=linkouticon&uid=25363768&db=pubmed&nlmid=0410462"
|
||
title="Free full text at PubMed Central"
|
||
|
||
data-ga-category="full_text"
|
||
data-ga-action="PMC"
|
||
data-ga-label="25363768"
|
||
><span class="text">
|
||
|
||
Free PMC article
|
||
|
||
</span></a>
|
||
</div>
|
||
|
||
</div>
|
||
|
||
<div class="short-view">
|
||
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
|
||
Full text links
|
||
</a>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
|
||
aria-label="Open dialog with citation text in different styles"
|
||
data-ga-category="save_share"
|
||
data-ga-action="cite"
|
||
data-ga-label="open"
|
||
data-all-citations-url="/25363768/citations/"
|
||
data-citation-style="nlm"
|
||
data-pubmed-format-link="/25363768/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="25363768" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
|
||
aria-label="Save article in MyNCBI collections."
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_button"
|
||
data-collections-open-dialog-enabled="false"
|
||
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F25363768%2F%23open-collections-dialog"
|
||
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
|
||
class="dialog collections-dialog"
|
||
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
|
||
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-existing-collections-url="/list-existing-collections/"
|
||
data-add-to-existing-collection-url="/add-to-existing-collection/"
|
||
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
|
||
data-myncbi-max-collection-name-length="100"
|
||
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="YuVkIi2MuRODd3aiZiYG8hkTIJKiVvblfhFpl8v84sB77ug8CBBICpQxgNsuO6JF"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
|
||
id="collections-action-dialog-new"
|
||
class="collections-new"
|
||
name="collections"
|
||
value="new"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
|
||
id="collections-action-dialog-existing"
|
||
class="collections-existing"
|
||
name="collections"
|
||
value="existing"
|
||
checked="true"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
|
||
Name your collection:
|
||
</label><input
|
||
type="text"
|
||
name="add-to-new-collection"
|
||
id="collections-action-dialog-add-to-new"
|
||
class="collections-action-add-to-new"
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"
|
||
maxlength="100"
|
||
data-ga-category="collections_button"
|
||
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-dialog-add-to-existing" class="action-panel-label">
|
||
Choose a collection:
|
||
</label><select id="collections-action-dialog-add-to-existing"
|
||
class="action-panel-selector collections-action-add-to-existing"
|
||
data-ga-category="collections_button"
|
||
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="collections_button"
|
||
data-ga-action="click"
|
||
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="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button></div></form></div></div></div></div><button class="more-actions-button more-actions-dialog-trigger"
|
||
title="Open dialog with more actions to take"
|
||
ref="linksrc=more_actions_btn"></button><div class="display-options" data-format-key="format"
|
||
data-default-format-value="abstract"
|
||
data-current-format-value="abstract" role="region"><button
|
||
class="trigger usa-button"
|
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The contribution of de novo coding mutations to autism spectrum disorder
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data-ga-label="Joshua D Smith">Joshua D Smith</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA." href="#full-view-affiliation-4" ref="linksrc=author_aff">
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4
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4
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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4
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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|
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5
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Shan Dong">Shan Dong</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="1] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China." href="#full-view-affiliation-6" ref="linksrc=author_aff">
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6
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data-ga-label="Luis E Gonzalez">Luis E Gonzalez</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA." href="#full-view-affiliation-7" ref="linksrc=author_aff">
|
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7
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Jeffrey D Mandell">Jeffrey D Mandell</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA." href="#full-view-affiliation-5" ref="linksrc=author_aff">
|
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5
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Shrikant M Mane">Shrikant M Mane</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, Connecticut 06520, USA." href="#full-view-affiliation-8" ref="linksrc=author_aff">
|
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8
|
||
</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Michael T Murtha">Michael T Murtha</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA." href="#full-view-affiliation-7" ref="linksrc=author_aff">
|
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7
|
||
</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Catherine A Sullivan">Catherine A Sullivan</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA." href="#full-view-affiliation-7" ref="linksrc=author_aff">
|
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7
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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href="/?term=Walker+MF&cauthor_id=25363768"
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data-ga-label="Michael F Walker">Michael F Walker</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA." href="#full-view-affiliation-5" ref="linksrc=author_aff">
|
||
5
|
||
</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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href="/?term=Waqar+Z&cauthor_id=25363768"
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data-ga-label="Zainulabedin Waqar">Zainulabedin Waqar</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA." href="#full-view-affiliation-7" ref="linksrc=author_aff">
|
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7
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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href="/?term=Wei+L&cauthor_id=25363768"
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data-ga-label="Liping Wei">Liping Wei</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="1] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China [2] National Institute of Biological Sciences, Beijing 102206, China." href="#full-view-affiliation-9" ref="linksrc=author_aff">
|
||
9
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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href="/?term=Willsey+AJ&cauthor_id=25363768"
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data-ga-label="A Jeremy Willsey">A Jeremy Willsey</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="1] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA." href="#full-view-affiliation-3" ref="linksrc=author_aff">
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3
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||
</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Boris Yamrom">Boris Yamrom</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA." href="#full-view-affiliation-1" ref="linksrc=author_aff">
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1
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Yoon-ha Lee">Yoon-ha Lee</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA." href="#full-view-affiliation-1" ref="linksrc=author_aff">
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1
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Ewa Grabowska">Ewa Grabowska</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] New York Genome Center, New York, New York 10013, USA." href="#full-view-affiliation-10" ref="linksrc=author_aff">
|
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10
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data-ga-label="Ertugrul Dalkic">Ertugrul Dalkic</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] Department of Medical Biology, Bulent Ecevit University School of Medicine, 67600 Zonguldak, Turkey." href="#full-view-affiliation-11" ref="linksrc=author_aff">
|
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11
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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href="/?term=Wang+Z&cauthor_id=25363768"
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data-ga-label="Zihua Wang">Zihua Wang</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA." href="#full-view-affiliation-1" ref="linksrc=author_aff">
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1
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Steven Marks">Steven Marks</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA." href="#full-view-affiliation-1" ref="linksrc=author_aff">
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1
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Peter Andrews">Peter Andrews</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA." href="#full-view-affiliation-1" ref="linksrc=author_aff">
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1
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Anthony Leotta">Anthony Leotta</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA." href="#full-view-affiliation-1" ref="linksrc=author_aff">
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1
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data-ga-label="Jude Kendall">Jude Kendall</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA." href="#full-view-affiliation-1" ref="linksrc=author_aff">
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1
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1
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1
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1
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data-ga-label="Linda Rodgers">Linda Rodgers</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA." href="#full-view-affiliation-1" ref="linksrc=author_aff">
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1
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1
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data-ga-label="Giuseppe Narzisi">Giuseppe Narzisi</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] New York Genome Center, New York, New York 10013, USA." href="#full-view-affiliation-10" ref="linksrc=author_aff">
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10
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data-ga-label="Seungtai Yoon">Seungtai Yoon</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA." href="#full-view-affiliation-1" ref="linksrc=author_aff">
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1
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data-ga-label="Michael C Schatz">Michael C Schatz</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA." href="#full-view-affiliation-1" ref="linksrc=author_aff">
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1
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data-ga-label="Kenny Ye">Kenny Ye</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA." href="#full-view-affiliation-12" ref="linksrc=author_aff">
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12
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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1
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data-ga-label="Jay Shendure">Jay Shendure</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA." href="#full-view-affiliation-4" ref="linksrc=author_aff">
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4
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data-ga-label="Evan E Eichler">Evan E Eichler</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA [2] Howard Hughes Medical Institute, Seattle, Washington 98195, USA." href="#full-view-affiliation-13" ref="linksrc=author_aff">
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13
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data-ga-label="Matthew W State">Matthew W State</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="1] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA [4] Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520, USA." href="#full-view-affiliation-14" ref="linksrc=author_aff">
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The contribution of de novo coding mutations to autism spectrum disorder
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4
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4
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4
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4
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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5
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Shan Dong">Shan Dong</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="1] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China." href="#short-view-affiliation-6" ref="linksrc=author_aff">
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6
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data-ga-label="Luis E Gonzalez">Luis E Gonzalez</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA." href="#short-view-affiliation-7" ref="linksrc=author_aff">
|
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7
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Jeffrey D Mandell">Jeffrey D Mandell</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA." href="#short-view-affiliation-5" ref="linksrc=author_aff">
|
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5
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Shrikant M Mane">Shrikant M Mane</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, Connecticut 06520, USA." href="#short-view-affiliation-8" ref="linksrc=author_aff">
|
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8
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Michael T Murtha">Michael T Murtha</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA." href="#short-view-affiliation-7" ref="linksrc=author_aff">
|
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7
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Catherine A Sullivan">Catherine A Sullivan</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA." href="#short-view-affiliation-7" ref="linksrc=author_aff">
|
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7
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Michael F Walker">Michael F Walker</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA." href="#short-view-affiliation-5" ref="linksrc=author_aff">
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5
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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|
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7
|
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Liping Wei">Liping Wei</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="1] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China [2] National Institute of Biological Sciences, Beijing 102206, China." href="#short-view-affiliation-9" ref="linksrc=author_aff">
|
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9
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="A Jeremy Willsey">A Jeremy Willsey</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="1] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA." href="#short-view-affiliation-3" ref="linksrc=author_aff">
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3
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data-ga-label="Boris Yamrom">Boris Yamrom</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA." href="#short-view-affiliation-1" ref="linksrc=author_aff">
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1
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1
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10
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data-ga-label="Ertugrul Dalkic">Ertugrul Dalkic</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] Department of Medical Biology, Bulent Ecevit University School of Medicine, 67600 Zonguldak, Turkey." href="#short-view-affiliation-11" ref="linksrc=author_aff">
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11
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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1
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1
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1
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1
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1
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1
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1
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1
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1
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1
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10
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1
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1
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12
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1
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4
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data-ga-action="author_link"
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data-ga-label="Evan E Eichler">Evan E Eichler</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA [2] Howard Hughes Medical Institute, Seattle, Washington 98195, USA." href="#short-view-affiliation-13" ref="linksrc=author_aff">
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</a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Matthew W State">Matthew W State</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="1] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA [4] Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520, USA." href="#short-view-affiliation-14" ref="linksrc=author_aff">
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data-ga-label="Michael Wigler">Michael Wigler</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA." href="#short-view-affiliation-1" ref="linksrc=author_aff">
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1
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</a></sup></span>
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<li data-affiliation-id="short-view-affiliation-2"
|
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id="short-view-affiliation-2"
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><sup class="key">2</sup> 1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA [2] Molecular &Medical Genetics, Oregon Health &Science University, Portland, Oregon 97208, USA.</li>
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<li data-affiliation-id="short-view-affiliation-3"
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id="short-view-affiliation-3"
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><sup class="key">3</sup> 1] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.</li>
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<li data-affiliation-id="short-view-affiliation-4"
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id="short-view-affiliation-4"
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><sup class="key">4</sup> Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.</li>
|
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|
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<li data-affiliation-id="short-view-affiliation-5"
|
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id="short-view-affiliation-5"
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><sup class="key">5</sup> Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA.</li>
|
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|
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<li data-affiliation-id="short-view-affiliation-6"
|
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id="short-view-affiliation-6"
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><sup class="key">6</sup> 1] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.</li>
|
||
|
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<li data-affiliation-id="short-view-affiliation-7"
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id="short-view-affiliation-7"
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><sup class="key">7</sup> Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.</li>
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<li data-affiliation-id="short-view-affiliation-8"
|
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id="short-view-affiliation-8"
|
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><sup class="key">8</sup> Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, Connecticut 06520, USA.</li>
|
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|
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<li data-affiliation-id="short-view-affiliation-9"
|
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id="short-view-affiliation-9"
|
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><sup class="key">9</sup> 1] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China [2] National Institute of Biological Sciences, Beijing 102206, China.</li>
|
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<li data-affiliation-id="short-view-affiliation-10"
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id="short-view-affiliation-10"
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><sup class="key">10</sup> 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] New York Genome Center, New York, New York 10013, USA.</li>
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||
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<li data-affiliation-id="short-view-affiliation-11"
|
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id="short-view-affiliation-11"
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><sup class="key">11</sup> 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] Department of Medical Biology, Bulent Ecevit University School of Medicine, 67600 Zonguldak, Turkey.</li>
|
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|
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<li data-affiliation-id="short-view-affiliation-12"
|
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id="short-view-affiliation-12"
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><sup class="key">12</sup> Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA.</li>
|
||
|
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<li data-affiliation-id="short-view-affiliation-13"
|
||
id="short-view-affiliation-13"
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><sup class="key">13</sup> 1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA [2] Howard Hughes Medical Institute, Seattle, Washington 98195, USA.</li>
|
||
|
||
<li data-affiliation-id="short-view-affiliation-14"
|
||
id="short-view-affiliation-14"
|
||
><sup class="key">14</sup> 1] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA [4] Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.</li>
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<strong class="current-id" title="PubMed ID">25363768</strong>
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<p>
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||
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Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.
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<div class="figures" id="figures">
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Figures
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d87/4313871/fe9479226121/nihms659757f5.gif"
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<strong class="figure-label">
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<p> Extended Data Figure 1. Number of families… </p>
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<p> Extended Data Figure 1. Number of families sequenced by center </p>
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<div class="figure-caption-contents"><p> The numbers of families sequenced… </p></div>
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Extended Data Figure 1. Number of families sequenced by center
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<div class="figure-caption-contents">The numbers of families sequenced at the three centers are plotted as a Venn diagram. Families sequenced at more than one center are indicated by the overlapping regions between circles. CSHL: Cold Spring Harbor Laboratory; UW: University of Washington, Seattle; YALE: Yale Medical Center.</div>
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<p> Extended Data Figure 2. SSC sequencing by pedigree type and nonverbal IQ </p>
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Extended Data Figure 2. SSC sequencing by pedigree type and nonverbal IQ
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<div class="figure-caption-contents">A summary of all SSC families sequenced is indicated across the “ALL” row. Numbers of SSC families with complete exome sequencing data are displayed by center in the following rows (see Extended Data Figure 1 legend for center designations). The top number in entries under the “Families” column indicates the total number of families sequenced, and the number in parentheses below indicates the total number of individuals. Family pedigree structures are shown across the top row with gender indicated by shape (square for male, circle for female) and affected status indicated by color (white for unaffected, gray for affected). Distributions of non-verbal IQ within each cohort are shown for male probands (blue) and female probands (red).</div>
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||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Extended Data Figure 3. Rates of de novo LGD and missense mutations in the SSC… </p>
|
||
</strong>
|
||
|
||
|
||
|
||
|
||
|
||
|
||
</div>
|
||
|
||
<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
Extended Data Figure 3. Rates of de novo LGD and missense mutations in the SSC by child status
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">On the left we show the LGD rate per child in six types of children, labeled on the X-axis, defined by their affected status, gender, and non-verbal IQ. We test for equal rates for every pair of child types and we show the ones with p-value >0.05 with thin lines on the top of the figure. Although not significant, the rates in affected females and in affected males of lower nvIQ are larger than the rate in males of higher nvIQ. On the right, we show the missense rates per child for the same six groups of children.</div>
|
||
|
||
|
||
|
||
|
||
</figcaption>
|
||
|
||
|
||
</figure>
|
||
|
||
<figure class="figure-item "
|
||
itemscope itemtype="http://schema.org/ImageObject"
|
||
itemprop="associatedMedia"
|
||
data-slide-index="3"
|
||
data-label-slug="extended-data-figure-4">
|
||
<a class="figure-link"
|
||
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d87/4313871/32fe94c97b80/nihms659757f8.jpg"
|
||
itemprop="contentUrl"
|
||
aria-describedby="figure-caption-3"
|
||
role="button"
|
||
data-image-width="1050"
|
||
data-image-height="1027"
|
||
data-image-alt="Extended Data Figure 4"
|
||
data-pmc-id="PMC4313871"
|
||
data-figure-id="F8">
|
||
<img class="figure-thumb" itemprop="thumbnail"
|
||
id="article-image-3"
|
||
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d87/4313871/b9d1c29df2ef/nihms659757f8.gif"
|
||
alt="Extended Data Figure 4" />
|
||
</a>
|
||
|
||
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="1050">
|
||
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1027">
|
||
|
||
|
||
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
|
||
|
||
<div class="caption-wrap">
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Extended Data Figure 4. Paternal age and… </p>
|
||
</strong>
|
||
|
||
|
||
|
||
|
||
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Extended Data Figure 4. Paternal age and de novo mutation rate at child birth </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Distribution… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
|
||
<figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
Extended Data Figure 4. Paternal age and de novo mutation rate at child birth
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">Distribution of paternal age at birth of children (top) and rates of de novo mutation in offspring as a function of paternal age are shown (bottom). Children were ordered by paternal age at birth and split into 20 groups of similar size, as shown in the lower panel. The red curve shows the mean observed rates of de novo exomic substitutions in each of the 20 groups, with the×coordinate equal to the mean each of the fathers’ ages within each group. The blue line shows a linear fit to the observed rates. The dotted green line represents de novo mutation rates from whole genome sequencing data (Kong <i>et al</i>., <i>Nature</i>
|
||
<b>488</b>, 471–475, 2012) scaled to rates per exome based on representation in the SeqCap EZ Human Exome Library v2.0 (Roche NimbleGen).</div>
|
||
|
||
|
||
|
||
|
||
</figcaption>
|
||
|
||
|
||
</figure>
|
||
|
||
<figure class="figure-item "
|
||
itemscope itemtype="http://schema.org/ImageObject"
|
||
itemprop="associatedMedia"
|
||
data-slide-index="4"
|
||
data-label-slug="extended-data-figure-5">
|
||
<a class="figure-link"
|
||
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d87/4313871/82c8041ab0f2/nihms659757f9.jpg"
|
||
itemprop="contentUrl"
|
||
aria-describedby="figure-caption-4"
|
||
role="button"
|
||
data-image-width="1050"
|
||
data-image-height="516"
|
||
data-image-alt="Extended Data Figure 5"
|
||
data-pmc-id="PMC4313871"
|
||
data-figure-id="F9">
|
||
<img class="figure-thumb" itemprop="thumbnail"
|
||
id="article-image-4"
|
||
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d87/4313871/c23e7b8d2d8c/nihms659757f9.gif"
|
||
alt="Extended Data Figure 5" />
|
||
</a>
|
||
|
||
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="1050">
|
||
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="516">
|
||
|
||
|
||
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
|
||
|
||
<div class="caption-wrap">
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Extended Data Figure 5. Coding region size… </p>
|
||
</strong>
|
||
|
||
|
||
|
||
|
||
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Extended Data Figure 5. Coding region size distribution for query sets of genes </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> PDFs and… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
|
||
<figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
Extended Data Figure 5. Coding region size distribution for query sets of genes
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">PDFs and CDFs (right bottom panel) of the distributions of the coding region length in base pairs of five sets of genes: a set of 1200 genes picked uniformly from the set of exome-targeted genes (blue); a separate set of 1200 genes picked with probabilities proportional to length of the coding region (green); the set of gene targets of neutral mutations, including 1) synonymous mutations in probands and siblings and 2) missense mutation in siblings (red); genes with de novo missense mutations in probands (cyan); and genes with de novo LGDs in probands (magenta). Black within the histograms shows the distribution of lengths of the recurrently hit genes from each class. Coding region length distribution under a uniform model does not fit the lengths of the genes with observed mutations, and genes with LGD mutations are longer than predicted by a simple length-based model (bottom right).</div>
|
||
|
||
|
||
|
||
|
||
</figcaption>
|
||
|
||
|
||
</figure>
|
||
|
||
<figure class="figure-item "
|
||
itemscope itemtype="http://schema.org/ImageObject"
|
||
itemprop="associatedMedia"
|
||
data-slide-index="5"
|
||
data-label-slug="extended-data-figure-6">
|
||
<a class="figure-link"
|
||
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d87/4313871/ef67f710d9e4/nihms659757f10.jpg"
|
||
itemprop="contentUrl"
|
||
aria-describedby="figure-caption-5"
|
||
role="button"
|
||
data-image-width="1050"
|
||
data-image-height="832"
|
||
data-image-alt="Extended Data Figure 6"
|
||
data-pmc-id="PMC4313871"
|
||
data-figure-id="F10">
|
||
<img class="figure-thumb" itemprop="thumbnail"
|
||
id="article-image-5"
|
||
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d87/4313871/a8e9a977bf70/nihms659757f10.gif"
|
||
alt="Extended Data Figure 6" />
|
||
</a>
|
||
|
||
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="1050">
|
||
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="832">
|
||
|
||
|
||
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
|
||
|
||
<div class="caption-wrap">
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Extended Data Figure 6. Distributions of sequencing… </p>
|
||
</strong>
|
||
|
||
|
||
|
||
|
||
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Extended Data Figure 6. Distributions of sequencing depth </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Distributions of sequencing depth (number of sequence… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
|
||
<figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
Extended Data Figure 6. Distributions of sequencing depth
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">Distributions of sequencing depth (number of sequence reads covering a given genomic position) per person per position for the three sequencing centers are plotted. Center designations are as in Extended Data Figure 1.</div>
|
||
|
||
|
||
|
||
|
||
</figcaption>
|
||
|
||
|
||
</figure>
|
||
|
||
<figure class="figure-item tail"
|
||
itemscope itemtype="http://schema.org/ImageObject"
|
||
itemprop="associatedMedia"
|
||
data-slide-index="6"
|
||
data-label-slug="extended-data-figure-7">
|
||
<a class="figure-link"
|
||
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d87/4313871/c10a2f1f87a3/nihms659757f11.jpg"
|
||
itemprop="contentUrl"
|
||
aria-describedby="figure-caption-6"
|
||
role="button"
|
||
data-image-width="1050"
|
||
data-image-height="346"
|
||
data-image-alt="Extended Data Figure 7"
|
||
data-pmc-id="PMC4313871"
|
||
data-figure-id="F11">
|
||
<img class="figure-thumb" itemprop="thumbnail"
|
||
id="article-image-6"
|
||
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d87/4313871/5842328a27af/nihms659757f11.gif"
|
||
alt="Extended Data Figure 7" />
|
||
</a>
|
||
|
||
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="1050">
|
||
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="346">
|
||
|
||
|
||
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
|
||
|
||
<div class="caption-wrap">
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Extended Data Figure 7. Yield of de… </p>
|
||
</strong>
|
||
|
||
|
||
|
||
|
||
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Extended Data Figure 7. Yield of de novo LGD and missense mutations </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> We plot the… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
|
||
<figcaption id="figure-caption-6" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
Extended Data Figure 7. Yield of de novo LGD and missense mutations
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">We plot the yield of de novo LGD and missense mutations per sequencing center (designations as in Extended Data Figure 1). In each case we show the number of mutations we expect to see based on the estimated rates per child, indicated by the numbers above the bars. We also show what percentage of the expected number we have observed. Black refers to strong calls in the 40× target, gray refers to strong calls outside of 40× target, and magenta refers to weak (but valid) calls. The white region represents the difference between the expected and observed numbers of variants.</div>
|
||
|
||
|
||
|
||
|
||
</figcaption>
|
||
|
||
|
||
</figure>
|
||
|
||
<figure class="figure-item tail"
|
||
itemscope itemtype="http://schema.org/ImageObject"
|
||
itemprop="associatedMedia"
|
||
data-slide-index="7"
|
||
data-label-slug="extended-data-figure-8">
|
||
<a class="figure-link"
|
||
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d87/4313871/a8883ef9ca3a/nihms659757f12.jpg"
|
||
itemprop="contentUrl"
|
||
aria-describedby="figure-caption-7"
|
||
role="button"
|
||
data-image-width="1050"
|
||
data-image-height="510"
|
||
data-image-alt="Extended Data Figure 8"
|
||
data-pmc-id="PMC4313871"
|
||
data-figure-id="F12">
|
||
<img class="figure-thumb" itemprop="thumbnail"
|
||
id="article-image-7"
|
||
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d87/4313871/dcc2baef9647/nihms659757f12.gif"
|
||
alt="Extended Data Figure 8" />
|
||
</a>
|
||
|
||
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="1050">
|
||
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="510">
|
||
|
||
|
||
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
|
||
|
||
<div class="caption-wrap">
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Extended Data Figure 8. Categorization of embryonically… </p>
|
||
</strong>
|
||
|
||
|
||
|
||
|
||
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Extended Data Figure 8. Categorization of embryonically expressed genes </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> We downloaded expression data (Kang, H.… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
|
||
<figcaption id="figure-caption-7" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
Extended Data Figure 8. Categorization of embryonically expressed genes
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">We downloaded expression data (Kang, H. J. <i>et al.</i>
|
||
<i>Nature</i>
|
||
<b>478</b>, 483–489, 2011) from <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.brainspan.org/static/download.html">http://www.brainspan.org/static/download.html</ext-link>. The data set provides normalized expression levels for ~17,000 genes across brain regions from 36 individuals, 18 of which were from embryos. Each brain was further subdivided into 14 anatomical regions for a total of 508 regions. We computed correlation values for the 17,000 genes, and generated a graph by connecting genes that had correlations >0.85. We then identified connected components and averaged the expression of genes within these components as a function of the annotated age of the brain and by region. Each region is sorted first by age, then by type. The averaged normalized expression of the 1,912 genes in the first component decreases after birth, and hence we call this set “embryonic.” See Supplementary Table 7 for the list of embryonic genes.</div>
|
||
|
||
|
||
|
||
|
||
</figcaption>
|
||
|
||
|
||
</figure>
|
||
|
||
<figure class="figure-item tail"
|
||
itemscope itemtype="http://schema.org/ImageObject"
|
||
itemprop="associatedMedia"
|
||
data-slide-index="8"
|
||
data-label-slug="fig-1">
|
||
<a class="figure-link"
|
||
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d87/4313871/46b43891ba65/nihms659757f1.jpg"
|
||
itemprop="contentUrl"
|
||
aria-describedby="figure-caption-8"
|
||
role="button"
|
||
data-image-width="1050"
|
||
data-image-height="674"
|
||
data-image-alt="Fig. 1"
|
||
data-pmc-id="PMC4313871"
|
||
data-figure-id="F1">
|
||
<img class="figure-thumb" itemprop="thumbnail"
|
||
id="article-image-8"
|
||
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d87/4313871/d742d8b6a95e/nihms659757f1.gif"
|
||
alt="Fig. 1" />
|
||
</a>
|
||
|
||
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="1050">
|
||
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="674">
|
||
|
||
|
||
<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
|
||
|
||
<div class="caption-wrap">
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Fig. 1. Rates of de novo events… </p>
|
||
</strong>
|
||
|
||
|
||
|
||
|
||
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Fig. 1. Rates of de novo events by mutational type in the SSC </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Rates per… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
|
||
<figcaption id="figure-caption-8" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
Fig. 1. Rates of de novo events by mutational type in the SSC
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">Rates per child are estimated from the 40× joint coverage target region, then extrapolated for the entire exome. Mutation types are displayed by class, and the combined rate for all LGDs is shown at the bottom right. For each event type, the significance between probands and unaffected is given.</div>
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<strong class="figure-label">
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<p> Fig. 2. Recurrently hit genes and non-verbal… </p>
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</strong>
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<strong class="figure-label">
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<p> Fig. 2. Recurrently hit genes and non-verbal intelligence quotient (IQ) </p>
|
||
</strong>
|
||
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||
<div class="figure-caption-contents"><p> Affected females account for 13.5%… </p></div>
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<strong class="figure-label">
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Fig. 2. Recurrently hit genes and non-verbal intelligence quotient (IQ)
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">Affected females account for 13.5% of the SSC with mean IQ of 78, whereas affected males have mean IQ of 86 (upper panel, p-value 10<sup>−7</sup> by Student's t-test). The vertical dashed line indicates an IQ of 90. The middle panel (left) shows IQ for affected children with LGD mutations in genes hit recurrently (right). Recurrently mutated genes are clustered into four categories as shown. The last four columns give overall numbers of DN LGD and missense (MS) mutations. In the bottom panel, we consider eight classes of DN mutations: all LGDs, recurrent LGDs, LGDs in FMRP targets (FXG), LGDs in chromatin modifiers (CHM), LGDs in embryonically expressed genes (EMB), all missense mutations, recurrent missense mutations and synonymous mutations. Probands are divided by the presence of DN mutations and gender. Means, 95% confidence intervals and p values (Student's t-test) are shown.</div>
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data-figure-id="F3">
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<strong class="figure-label">
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<p> Fig. 3. Number of vulnerable genes and… </p>
|
||
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<strong class="figure-label">
|
||
<p> Fig. 3. Number of vulnerable genes and class vulnerability </p>
|
||
</strong>
|
||
|
||
|
||
|
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<div class="figure-caption-contents"><p> We assume the property of being… </p></div>
|
||
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|
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</div>
|
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<figcaption id="figure-caption-10" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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<strong class="figure-label">
|
||
Fig. 3. Number of vulnerable genes and class vulnerability
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">We assume the property of being vulnerable gene is independent of gene length, but the probability of being hit by mutation is proportional to gene length. We use the observed rates of mutation of a given type in specified populations and number of recurrent mutations to estimate the number of genes vulnerable to those mutations (top). The degrees of vulnerability in those classes are the distributions shown in the lower panel (Methods).</div>
|
||
|
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data-pmc-id="PMC4313871"
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data-figure-id="F4">
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<img class="figure-thumb" itemprop="thumbnail"
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id="article-image-11"
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d87/4313871/fe68ae08a086/nihms659757f4.gif"
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alt="Fig. 4" />
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|
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|
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||
|
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|
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<strong class="figure-label">
|
||
<p> Fig. 4. Estimated contributions of CNVs, LGDs… </p>
|
||
</strong>
|
||
|
||
|
||
|
||
|
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|
||
|
||
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|
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|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Fig. 4. Estimated contributions of CNVs, LGDs and missense DN mutations to simplex ASD </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Ascertainment… </p></div>
|
||
|
||
|
||
|
||
|
||
</div>
|
||
|
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<figcaption id="figure-caption-11" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
|
||
|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
Fig. 4. Estimated contributions of CNVs, LGDs and missense DN mutations to simplex ASD
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents">Ascertainment differentials for three types of DN mutation (CNVs, LGDs and Missense) are interpreted as a measure of ‘Contribution,’ the percent of probands in whom the mutation contributed to diagnosis. We combine the three mutation types in ‘Total’ on the assumption of additivity. We present this measure for ‘All’ probands and selected subpopulations as indicated. We also show the expected contribution of all DN mutation in a simplex collection computed from a simple genetic model (‘Model’). Error bars represent 95% credibility intervals.</div>
|
||
|
||
|
||
|
||
|
||
</figcaption>
|
||
|
||
|
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Comment in
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The implications of de novo coding mutations in simplex autism families.
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</a>
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<div class="docsum-citation full-citation">
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<span class="docsum-authors full-authors">Utami KH.</span>
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<span class="docsum-authors short-authors">Utami KH.</span>
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<span class="docsum-journal-citation full-journal-citation">Clin Genet. 2015 May;87(5):428-9. doi: 10.1111/cge.12582. Epub 2015 Mar 30.</span>
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<span class="docsum-journal-citation short-journal-citation">Clin Genet. 2015.</span>
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<span class="citation-part">PMID: <span class="docsum-pmid">25753786</span></span>
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Autism genes: the continuum that connects us all.
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<span class="docsum-authors full-authors">Parihar R, Ganesh S.</span>
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<span class="docsum-authors short-authors">Parihar R, et al.</span>
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<span class="docsum-journal-citation full-journal-citation">J Genet. 2016 Sep;95(3):481-3. doi: 10.1007/s12041-016-0688-0.</span>
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<span class="docsum-journal-citation short-journal-citation">J Genet. 2016.</span>
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<span class="citation-part">PMID: <span class="docsum-pmid">27659318</span></span>
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PMC
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</a>
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|
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<a
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class="reference-link"
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|
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PubMed
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</li>
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</ol>
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</li>
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<li>
|
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<ol class="references-and-notes-list">
|
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|
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<li
|
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class="skip-numbering"
|
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value="1">
|
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|
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Sebat J, et al. Strong association of de novo copy number mutations with autism. Science. 2007;316:445–449.
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|
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|
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|
||
-
|
||
<a
|
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class="reference-link"
|
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href="https://pmc.ncbi.nlm.nih.gov/articles/PMC2993504/"
|
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PMC
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-
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<a
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PubMed
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</div>
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</div>
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<div id="publication-types" class="publication-types keywords-section">
|
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<h2 class="title">
|
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Publication types
|
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</h2>
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<ul class="keywords-list"><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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Research Support, Non-U.S. Gov't
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href="/?term=%22Research+Support%2C+Non-U.S.+Gov%27t%22%5Bpt%5D&sort=date&sort_order=desc"
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data-href="/?term=%22Research+Support%2C+Non-U.S.+Gov%27t%22%5Bpt%5D&sort=date&sort_order=desc"
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ref="linksrc=search_in_pubmed_keyword_link&keyword="Research Support, Non-U.S. Gov't"[pt]"
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</div>
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<div id="mesh-terms" class="mesh-terms keywords-section">
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<h2 class="title">
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MeSH terms
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</h2>
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<ul class="keywords-list"><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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Child
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</button><div id="keyword-actions-mesh-terms-0"
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class="keyword-actions-dropdown dropdown dropdown-container"
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hidden
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aria-label="Dropdown menu for keyword Child"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
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href="/?term=%22Child%22%5BMeSH%5D&sort=date&sort_order=desc"
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data-href="/?term=%22Child%22%5BMeSH%5D&sort=date&sort_order=desc"
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Child Development Disorders, Pervasive / genetics*
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Genetic Predisposition to Disease / genetics*
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hidden
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data-href="/?term=%22Genetic+Predisposition+to+Disease%2Fgenetics%22%5BMAJR%5D&sort=date&sort_order=desc"
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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aria-label="Toggle dropdown menu for keyword Humans"
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data-pinger-ignore>
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class="keyword-actions-dropdown dropdown dropdown-container"
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hidden
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aria-label="Dropdown menu for keyword Humans"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
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data-href="/?term=%22Humans%22%5BMeSH%5D&sort=date&sort_order=desc"
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<div id="related-links" class="related-links">
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<h2 class="title">
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Related information
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</h2>
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<ul class="related-links-list"><li><a title="PubMed links associated with Books" href="https://www.ncbi.nlm.nih.gov/books?linkname=pubmed_books_refs&from_uid=25363768"
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Cited in Books
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</a></li><li><a title="Clinical variations associated with publication" href="https://www.ncbi.nlm.nih.gov/clinvar?linkname=pubmed_clinvar&from_uid=25363768"
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ClinVar
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Gene
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MedGen
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MedGen (Bookshelf cited)
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</a></li><li><a title="OMIM (cited) Links" href="https://www.ncbi.nlm.nih.gov/omim?linkname=pubmed_omim_cited&from_uid=25363768"
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OMIM (cited)
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</a></li><li><a title="Link to Protein RefSeqs" href="https://www.ncbi.nlm.nih.gov/protein?linkname=pubmed_protein_refseq&from_uid=25363768"
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Protein (RefSeq)
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</a></li><li><a title="Link from PubMed to dbVar" href="https://www.ncbi.nlm.nih.gov/dbvar?linkname=pubmed_dbvar&from_uid=25363768"
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dbVar
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</a></li></ul>
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</div>
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<div id="grants" class="grants">
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<h2 class="title">
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Grants and funding
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