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<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="xLVE7twPeQ9NrEJIjZCFn93PhvjxSA1VOyFJKjZbOrWhl5PyWifHRhztPz1JLbzf">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="xLVE7twPeQ9NrEJIjZCFn93PhvjxSA1VOyFJKjZbOrWhl5PyWifHRhztPz1JLbzf">
<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="xLVE7twPeQ9NrEJIjZCFn93PhvjxSA1VOyFJKjZbOrWhl5PyWifHRhztPz1JLbzf">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="xLVE7twPeQ9NrEJIjZCFn93PhvjxSA1VOyFJKjZbOrWhl5PyWifHRhztPz1JLbzf">
<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="xLVE7twPeQ9NrEJIjZCFn93PhvjxSA1VOyFJKjZbOrWhl5PyWifHRhztPz1JLbzf">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="29909962">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(18)30165-4"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3048&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=29909962&amp;db=pubmed&amp;nlmid=0370475"
title="See full text options at Elsevier Science"
data-ga-category="full_text"
data-ga-action="Elsevier Science"
data-ga-label="29909962"
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--linkinghub.elsevier.com-ihub-images-celloa.png" alt="Elsevier Science full text link"><span class="text">
Elsevier Science
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/29909962/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=29909962&amp;db=pubmed&amp;nlmid=0370475"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="29909962"
><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="/29909962/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/29909962/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="29909962" 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%2F29909962%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="xLVE7twPeQ9NrEJIjZCFn93PhvjxSA1VOyFJKjZbOrWhl5PyWifHRhztPz1JLbzf"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
id="collections-action-dialog-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
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<h1 class="heading-title">
Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis
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><sup class="key">4</sup> Discipline of Child &amp; Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.</li>
<li data-affiliation-id="full-view-affiliation-5"
id="full-view-affiliation-5"
><sup class="key">5</sup> Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, 105 AZ Amsterdam, the Netherlands.</li>
<li data-affiliation-id="full-view-affiliation-6"
id="full-view-affiliation-6"
><sup class="key">6</sup> Division of Neurology, Children&#x27;s Hospital, Philadelphia, PA 19104, USA.</li>
<li data-affiliation-id="full-view-affiliation-7"
id="full-view-affiliation-7"
><sup class="key">7</sup> Division of Neurology, Cincinnati Children&#x27;s Medical Centre, Cincinnati, OH 45229, USA.</li>
<li data-affiliation-id="full-view-affiliation-8"
id="full-view-affiliation-8"
><sup class="key">8</sup> Institute of Metabolic Disease, Baylor Scott &amp; White Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA.</li>
<li data-affiliation-id="full-view-affiliation-9"
id="full-view-affiliation-9"
><sup class="key">9</sup> Translational Metabolic Laboratory - 830 TML, Department of Laboratory Medicine, Radboud University Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.</li>
<li data-affiliation-id="full-view-affiliation-10"
id="full-view-affiliation-10"
><sup class="key">10</sup> University of Arkansas for Medical Sciences College of Medicine, Department of Pediatrics Little Rock, Arkansas, AR 72205, USA.</li>
<li data-affiliation-id="full-view-affiliation-11"
id="full-view-affiliation-11"
><sup class="key">11</sup> Department of Paediatrics, Wesley Hospital, Brisbane, QLD 4066, Australia.</li>
<li data-affiliation-id="full-view-affiliation-12"
id="full-view-affiliation-12"
><sup class="key">12</sup> Department of Metabolic Medicine, Lady Cilento Children&#x27;s Hospital, Brisbane, QLD 4101, Australia; Department of Chemical Pathology, Pathology Queensland, Royal Brisbane &amp; Women&#x27;s Hospital, Brisbane, QLD 4006, Australia; School of Medicine, University of Queensland, Brisbane, QLD 4067, Australia.</li>
<li data-affiliation-id="full-view-affiliation-13"
id="full-view-affiliation-13"
><sup class="key">13</sup> Department of Metabolic Medicine, Lady Cilento Children&#x27;s Hospital, Brisbane, QLD 4101, Australia.</li>
<li data-affiliation-id="full-view-affiliation-14"
id="full-view-affiliation-14"
><sup class="key">14</sup> Department of Chemical Pathology, Pathology Queensland, Royal Brisbane &amp; Women&#x27;s Hospital, Brisbane, QLD 4006, Australia.</li>
<li data-affiliation-id="full-view-affiliation-15"
id="full-view-affiliation-15"
><sup class="key">15</sup> Genetic Metabolic Disorders Research Group, Sydney Children&#x27;s Hospital Network, Sydney, NSW 2145, Australia; Discipline of Child &amp; Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Neurodevelopmental Genomics Research Group, Murdoch Children&#x27;s Research Institute, Melbourne VIC 3052, Australia; Genetic Metabolic Disorders Research Group, Sydney Children&#x27;s Hospital Network, Sydney NSW 2145, Australia; Victorian Clinical Genetics Services, Murdoch Children&#x27;s Research Institute, Melbourne, VIC 3052, Australia.</li>
<li data-affiliation-id="full-view-affiliation-16"
id="full-view-affiliation-16"
><sup class="key">16</sup> Victorian Clinical Genetics Services, Murdoch Children&#x27;s Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: james.pitt@vcgs.org.au.</li>
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Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis
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<span class="authors-list-item "><span class="full-name">David Coman</span><span class="citation-separator">&nbsp;et al.</span></span>
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<span class="authors-list-item "><a class="full-name"
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data-ga-label="David Coman">David Coman</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Metabolic Medicine, Lady Cilento Children&#x27;s Hospital, Brisbane, QLD 4101, Australia; Department of Paediatrics, Wesley Hospital, Brisbane, QLD 4066, Australia; School of Medicine, University of Queensland, Brisbane, QLD 4067, Australia; School of Medicine, Griffith University, Gold Coast, QLD 4222, Australia. Electronic address: david.coman@health.qld.gov.au." href="#short-view-affiliation-1" ref="linksrc=author_aff">
1
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Vissers+LELM&amp;cauthor_id=29909962"
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data-ga-label="Lisenka E L M Vissers">Lisenka E L M Vissers</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands." href="#short-view-affiliation-2" ref="linksrc=author_aff">
2
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Riley+LG&amp;cauthor_id=29909962"
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data-ga-label="Lisa G Riley">Lisa G Riley</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Genetic Metabolic Disorders Research Group, Sydney Children&#x27;s Hospital Network, Sydney, NSW 2145, Australia; Discipline of Child &amp; Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia." href="#short-view-affiliation-3" ref="linksrc=author_aff">
3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Kwint+MP&amp;cauthor_id=29909962"
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data-ga-label="Michael P Kwint">Michael P Kwint</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands." href="#short-view-affiliation-2" ref="linksrc=author_aff">
2
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Hauck+R&amp;cauthor_id=29909962"
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data-ga-label="Roxanna Hauck">Roxanna Hauck</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Discipline of Child &amp; Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia." href="#short-view-affiliation-4" ref="linksrc=author_aff">
4
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Koster+J&amp;cauthor_id=29909962"
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data-ga-label="Janet Koster">Janet Koster</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, 105 AZ Amsterdam, the Netherlands." href="#short-view-affiliation-5" ref="linksrc=author_aff">
5
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Geuer+S&amp;cauthor_id=29909962"
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data-ga-label="Sinje Geuer">Sinje Geuer</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands." href="#short-view-affiliation-2" ref="linksrc=author_aff">
2
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Sarah Hopkins">Sarah Hopkins</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Division of Neurology, Children&#x27;s Hospital, Philadelphia, PA 19104, USA." href="#short-view-affiliation-6" ref="linksrc=author_aff">
6
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Hallinan+B&amp;cauthor_id=29909962"
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data-ga-label="Barbra Hallinan">Barbra Hallinan</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Division of Neurology, Cincinnati Children&#x27;s Medical Centre, Cincinnati, OH 45229, USA." href="#short-view-affiliation-7" ref="linksrc=author_aff">
7
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Sweetman+L&amp;cauthor_id=29909962"
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data-ga-label="Larry Sweetman">Larry Sweetman</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Institute of Metabolic Disease, Baylor Scott &amp; White Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA." href="#short-view-affiliation-8" ref="linksrc=author_aff">
8
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Engelke+UFH&amp;cauthor_id=29909962"
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data-ga-label="Udo F H Engelke">Udo F H Engelke</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Translational Metabolic Laboratory - 830 TML, Department of Laboratory Medicine, Radboud University Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands." href="#short-view-affiliation-9" ref="linksrc=author_aff">
9
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="T Andrew Burrow">T Andrew Burrow</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="University of Arkansas for Medical Sciences College of Medicine, Department of Pediatrics Little Rock, Arkansas, AR 72205, USA." href="#short-view-affiliation-10" ref="linksrc=author_aff">
10
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Cardinal+J&amp;cauthor_id=29909962"
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data-ga-label="John Cardinal">John Cardinal</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Paediatrics, Wesley Hospital, Brisbane, QLD 4066, Australia." href="#short-view-affiliation-11" ref="linksrc=author_aff">
11
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=McGill+J&amp;cauthor_id=29909962"
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data-ga-label="James McGill">James McGill</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Metabolic Medicine, Lady Cilento Children&#x27;s Hospital, Brisbane, QLD 4101, Australia; Department of Chemical Pathology, Pathology Queensland, Royal Brisbane &amp; Women&#x27;s Hospital, Brisbane, QLD 4006, Australia; School of Medicine, University of Queensland, Brisbane, QLD 4067, Australia." href="#short-view-affiliation-12" ref="linksrc=author_aff">
12
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Inwood+A&amp;cauthor_id=29909962"
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data-ga-label="Anita Inwood">Anita Inwood</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Metabolic Medicine, Lady Cilento Children&#x27;s Hospital, Brisbane, QLD 4101, Australia." href="#short-view-affiliation-13" ref="linksrc=author_aff">
13
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Gurnsey+C&amp;cauthor_id=29909962"
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data-ga-label="Christine Gurnsey">Christine Gurnsey</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Chemical Pathology, Pathology Queensland, Royal Brisbane &amp; Women&#x27;s Hospital, Brisbane, QLD 4006, Australia." href="#short-view-affiliation-14" ref="linksrc=author_aff">
14
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Waterham+HR&amp;cauthor_id=29909962"
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data-ga-label="Hans R Waterham">Hans R Waterham</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, 105 AZ Amsterdam, the Netherlands." href="#short-view-affiliation-5" ref="linksrc=author_aff">
5
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="John Christodoulou">John Christodoulou</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Genetic Metabolic Disorders Research Group, Sydney Children&#x27;s Hospital Network, Sydney, NSW 2145, Australia; Discipline of Child &amp; Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Neurodevelopmental Genomics Research Group, Murdoch Children&#x27;s Research Institute, Melbourne VIC 3052, Australia; Genetic Metabolic Disorders Research Group, Sydney Children&#x27;s Hospital Network, Sydney NSW 2145, Australia; Victorian Clinical Genetics Services, Murdoch Children&#x27;s Research Institute, Melbourne, VIC 3052, Australia." href="#short-view-affiliation-15" ref="linksrc=author_aff">
15
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Wevers+RA&amp;cauthor_id=29909962"
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data-ga-label="Ron A Wevers">Ron A Wevers</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Translational Metabolic Laboratory - 830 TML, Department of Laboratory Medicine, Radboud University Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands." href="#short-view-affiliation-9" ref="linksrc=author_aff">
9
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Pitt+J&amp;cauthor_id=29909962"
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data-ga-label="James Pitt">James Pitt</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Victorian Clinical Genetics Services, Murdoch Children&#x27;s Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: james.pitt@vcgs.org.au." href="#short-view-affiliation-16" ref="linksrc=author_aff">
16
</a></sup></span>
</div>
</div>
<div class="affiliations">
<h3 class="title">
Affiliations
</h3>
<ul class="item-list">
<li data-affiliation-id="short-view-affiliation-1"
id="short-view-affiliation-1"
><sup class="key">1</sup> Department of Metabolic Medicine, Lady Cilento Children&#x27;s Hospital, Brisbane, QLD 4101, Australia; Department of Paediatrics, Wesley Hospital, Brisbane, QLD 4066, Australia; School of Medicine, University of Queensland, Brisbane, QLD 4067, Australia; School of Medicine, Griffith University, Gold Coast, QLD 4222, Australia. Electronic address: david.coman@health.qld.gov.au.</li>
<li data-affiliation-id="short-view-affiliation-2"
id="short-view-affiliation-2"
><sup class="key">2</sup> Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.</li>
<li data-affiliation-id="short-view-affiliation-3"
id="short-view-affiliation-3"
><sup class="key">3</sup> Genetic Metabolic Disorders Research Group, Sydney Children&#x27;s Hospital Network, Sydney, NSW 2145, Australia; Discipline of Child &amp; Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.</li>
<li data-affiliation-id="short-view-affiliation-4"
id="short-view-affiliation-4"
><sup class="key">4</sup> Discipline of Child &amp; Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.</li>
<li data-affiliation-id="short-view-affiliation-5"
id="short-view-affiliation-5"
><sup class="key">5</sup> Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, 105 AZ Amsterdam, the Netherlands.</li>
<li data-affiliation-id="short-view-affiliation-6"
id="short-view-affiliation-6"
><sup class="key">6</sup> Division of Neurology, Children&#x27;s Hospital, Philadelphia, PA 19104, USA.</li>
<li data-affiliation-id="short-view-affiliation-7"
id="short-view-affiliation-7"
><sup class="key">7</sup> Division of Neurology, Cincinnati Children&#x27;s Medical Centre, Cincinnati, OH 45229, USA.</li>
<li data-affiliation-id="short-view-affiliation-8"
id="short-view-affiliation-8"
><sup class="key">8</sup> Institute of Metabolic Disease, Baylor Scott &amp; White Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA.</li>
<li data-affiliation-id="short-view-affiliation-9"
id="short-view-affiliation-9"
><sup class="key">9</sup> Translational Metabolic Laboratory - 830 TML, Department of Laboratory Medicine, Radboud University Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.</li>
<li data-affiliation-id="short-view-affiliation-10"
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><sup class="key">10</sup> University of Arkansas for Medical Sciences College of Medicine, Department of Pediatrics Little Rock, Arkansas, AR 72205, USA.</li>
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><sup class="key">11</sup> Department of Paediatrics, Wesley Hospital, Brisbane, QLD 4066, Australia.</li>
<li data-affiliation-id="short-view-affiliation-12"
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><sup class="key">12</sup> Department of Metabolic Medicine, Lady Cilento Children&#x27;s Hospital, Brisbane, QLD 4101, Australia; Department of Chemical Pathology, Pathology Queensland, Royal Brisbane &amp; Women&#x27;s Hospital, Brisbane, QLD 4006, Australia; School of Medicine, University of Queensland, Brisbane, QLD 4067, Australia.</li>
<li data-affiliation-id="short-view-affiliation-13"
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><sup class="key">13</sup> Department of Metabolic Medicine, Lady Cilento Children&#x27;s Hospital, Brisbane, QLD 4101, Australia.</li>
<li data-affiliation-id="short-view-affiliation-14"
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><sup class="key">14</sup> Department of Chemical Pathology, Pathology Queensland, Royal Brisbane &amp; Women&#x27;s Hospital, Brisbane, QLD 4006, Australia.</li>
<li data-affiliation-id="short-view-affiliation-15"
id="short-view-affiliation-15"
><sup class="key">15</sup> Genetic Metabolic Disorders Research Group, Sydney Children&#x27;s Hospital Network, Sydney, NSW 2145, Australia; Discipline of Child &amp; Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Neurodevelopmental Genomics Research Group, Murdoch Children&#x27;s Research Institute, Melbourne VIC 3052, Australia; Genetic Metabolic Disorders Research Group, Sydney Children&#x27;s Hospital Network, Sydney NSW 2145, Australia; Victorian Clinical Genetics Services, Murdoch Children&#x27;s Research Institute, Melbourne, VIC 3052, Australia.</li>
<li data-affiliation-id="short-view-affiliation-16"
id="short-view-affiliation-16"
><sup class="key">16</sup> Victorian Clinical Genetics Services, Murdoch Children&#x27;s Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: james.pitt@vcgs.org.au.</li>
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Mendelian disorders of cholesterol biosynthesis typically result in multi-system clinical phenotypes, underlining the importance of cholesterol in embryogenesis and development. FDFT1 encodes for an evolutionarily conserved enzyme, squalene synthase (SS, farnesyl-pyrophosphate farnesyl-transferase 1), which catalyzes the first committed step in cholesterol biosynthesis. We report three individuals with profound developmental delay, brain abnormalities, 2-3 syndactyly of the toes, and facial dysmorphisms, resembling Smith-Lemli-Opitz syndrome, the most common cholesterol biogenesis defect. The metabolite profile in plasma and urine suggested that their defect was at the level of squalene synthase. Whole-exome sequencing was used to identify recessive disease-causing variants in FDFT1. Functional characterization of one variant demonstrated a partial splicing defect and altered promoter and/or enhancer activity, reflecting essential mechanisms for regulating cholesterol biosynthesis/uptake in steady state.
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FDFT1; cholesterol biosynthesis; dysmorphism; syndactyly.
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<div class="figure-caption-contents"><p> Schematic Representation of the Isoprenoid/Cholesterol… </p></div>
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<div class="figure-caption-contents"><p> Schematic Representation of the Isoprenoid/Cholesterol Biosynthesis Pathway Metabolites that accumulate as a result… </p></div>
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<div class="figure-caption-contents">Schematic Representation of the Isoprenoid/Cholesterol Biosynthesis Pathway Metabolites that accumulate as a result of squalene synthase deficiency are underlined (pathway re-drawn based on Tansey and Shechter<sup>13</sup>).</div>
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<div class="figure-caption-contents"><p> Facial Characteristics Individual 1 at… </p></div>
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<div class="figure-caption-contents">Facial Characteristics Individual 1 at 3 years of age (A) and 6 years of age (B) and individual 2 at 5 weeks of age (C) and 3 years of age (D). Dysmorphic features include depressed nasal bridge, low-set posteriorly rotated ears, square nasal tip, epicanthic folds, mild micrognathia, and retrognathia.</div>
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<div class="figure-caption-contents">Urine Metabolite Profiles (A) Urine organic acid GC-MS profiles of individual 1 (top) and a control subject (bottom). Normal urine components are indicated in italics. Numbered peaks indicate abnormal metabolites: (1) methylsuccinic, (2) mevalonic lactone, (3) mesaconic acid, (4) 2-methylgluatic acid, (5) 3-methyladipic acid, (6) 3-methylhex-3-enedioic acid, (7) 3-methylhex-2-endioic acid, (8) 2,6-dimethylheptanedioic acid, (9) unknown, (10) 3-methylhex-2,4-dienedioic, (11) 2,6-dimethylhept-2-enedioic acid, (12) 3,7-dimethyloctanedioic, and (13) 3,7-dimethyl-2,6-dienedioic. Control values are given in Figure S1. (B) One-dimensional 500 MHz <sup>1</sup>H-NMR spectra of urine of individual 1 and age-matched control subject measured at pH 2.5 (regions 5.606.50 ppm and 1.502.25 ppm). The insert shows the structure of 3-methylhex-2,4-dienedioic acid. Proton assignments of 3-methylhex-3,4-dienedioic acid (A) and other farnesol-derived dicarboxylic acids (asterisk).</div>
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<div class="figure-caption-contents"><p> Schematic Representation of <i> FDFT1 </i> ,… </p></div>
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<div class="figure-caption-contents"><p> Schematic Representation of <i> FDFT1 </i> , the Variants Identified in Individuals 1, 2, and… </p></div>
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<div class="figure-caption-contents">Schematic Representation of <i>FDFT1</i>, the Variants Identified in Individuals 1, 2, and 3, and Functional Follow-up (A) The maternal deletion identified in the sibship extends 50 kb more proximally, but no other genes are included. Genomic positions are based on hg19. Red horizontal lines indicate deleted sequence. For the paternal mutation in individuals 1 and 2, the wild-type protein amino acid sequence is provided in gray, whereas the predicted sequence of the splice mutation is shown in red. (B) Western blot analysis of individuals 1 (Ind 1) and 2 (Ind 2), using two different culturing conditions (fetal bovine serum [FBS] and lipid depleted [LD-] FBS), using an antibody to detect FDFT1 in fibroblast of individuals 1 and 2. Alpha-tubulin was used as loading control. FDFT1 reduction is more prominent when cells were cultured under lipid depletion. (C) Isoform-specific PCR using cDNA generated from EBV-transformed PBMCs of individual 3 (Ind 3) was used for the detection of FDFT1 isoforms. Three FDFT1 isoforms could not be detected in individual 3 whereas these were present in EBV-transformed PBMCs of a control individual. The addition of cycloheximide (CHX; - absent, + present) did not facilitate expression detection. Profile of all isoforms is presented in Figure S5. (D) The genomic segment containing the homozygous 16 bp deletion in individual 3 was tested for promoter activity using a luciferase assay, which showed significantly reduced activity when compared to the control construct containing the wild-type sequence (two-tailed t test, p = 2.9 × 10<sup>6</sup>). <sup></sup>p &lt; 0.001. Error bars represent one SD.</div>
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Protein
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