Epilepsy with auditory features
Identifieur interne : 000071 ( Pmc/Corpus ); précédent : 000070; suivant : 000072Epilepsy with auditory features
Auteurs : Tommaso Pippucci ; Laura Licchetta ; Sara Baldassari ; Flavia Palombo ; Veronica Menghi ; Romina D'Aurizio ; Chiara Leta ; Carlotta Stipa ; Giovanni Boero ; Giuseppe D'Orsi ; Alberto Magi ; Ingrid Scheffer ; Marco Seri ; Paolo Tinuper ; Francesca BisulliSource :
- Neurology: Genetics [ 2376-7839 ] ; 2015.
Abstract
To identify novel genes implicated in epilepsy with auditory features (EAF) in phenotypically heterogeneous families with unknown molecular basis.
We identified 15 probands with EAF in whom an
WES revealed likely pathogenic variants in genes that had not been previously associated with EAF: a
EAF is a clinically and molecularly heterogeneous disease. The association of EAF with
Url:
DOI: 10.1212/NXG.0000000000000005
PubMed: 27066544
PubMed Central: 4821078
Links to Exploration step
PMC:4821078Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Epilepsy with auditory features</title>
<author><name sortKey="Pippucci, Tommaso" sort="Pippucci, Tommaso" uniqKey="Pippucci T" first="Tommaso" last="Pippucci">Tommaso Pippucci</name>
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<author><name sortKey="Licchetta, Laura" sort="Licchetta, Laura" uniqKey="Licchetta L" first="Laura" last="Licchetta">Laura Licchetta</name>
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<author><name sortKey="Baldassari, Sara" sort="Baldassari, Sara" uniqKey="Baldassari S" first="Sara" last="Baldassari">Sara Baldassari</name>
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<author><name sortKey="Palombo, Flavia" sort="Palombo, Flavia" uniqKey="Palombo F" first="Flavia" last="Palombo">Flavia Palombo</name>
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<author><name sortKey="Menghi, Veronica" sort="Menghi, Veronica" uniqKey="Menghi V" first="Veronica" last="Menghi">Veronica Menghi</name>
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<author><name sortKey="D Aurizio, Romina" sort="D Aurizio, Romina" uniqKey="D Aurizio R" first="Romina" last="D'Aurizio">Romina D'Aurizio</name>
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<author><name sortKey="Leta, Chiara" sort="Leta, Chiara" uniqKey="Leta C" first="Chiara" last="Leta">Chiara Leta</name>
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<author><name sortKey="Stipa, Carlotta" sort="Stipa, Carlotta" uniqKey="Stipa C" first="Carlotta" last="Stipa">Carlotta Stipa</name>
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<author><name sortKey="Boero, Giovanni" sort="Boero, Giovanni" uniqKey="Boero G" first="Giovanni" last="Boero">Giovanni Boero</name>
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<author><name sortKey="D Orsi, Giuseppe" sort="D Orsi, Giuseppe" uniqKey="D Orsi G" first="Giuseppe" last="D'Orsi">Giuseppe D'Orsi</name>
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<author><name sortKey="Magi, Alberto" sort="Magi, Alberto" uniqKey="Magi A" first="Alberto" last="Magi">Alberto Magi</name>
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<author><name sortKey="Scheffer, Ingrid" sort="Scheffer, Ingrid" uniqKey="Scheffer I" first="Ingrid" last="Scheffer">Ingrid Scheffer</name>
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<author><name sortKey="Seri, Marco" sort="Seri, Marco" uniqKey="Seri M" first="Marco" last="Seri">Marco Seri</name>
</author>
<author><name sortKey="Tinuper, Paolo" sort="Tinuper, Paolo" uniqKey="Tinuper P" first="Paolo" last="Tinuper">Paolo Tinuper</name>
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<author><name sortKey="Bisulli, Francesca" sort="Bisulli, Francesca" uniqKey="Bisulli F" first="Francesca" last="Bisulli">Francesca Bisulli</name>
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<idno type="pmc">4821078</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821078</idno>
<idno type="RBID">PMC:4821078</idno>
<idno type="doi">10.1212/NXG.0000000000000005</idno>
<date when="2015">2015</date>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Epilepsy with auditory features</title>
<author><name sortKey="Pippucci, Tommaso" sort="Pippucci, Tommaso" uniqKey="Pippucci T" first="Tommaso" last="Pippucci">Tommaso Pippucci</name>
</author>
<author><name sortKey="Licchetta, Laura" sort="Licchetta, Laura" uniqKey="Licchetta L" first="Laura" last="Licchetta">Laura Licchetta</name>
</author>
<author><name sortKey="Baldassari, Sara" sort="Baldassari, Sara" uniqKey="Baldassari S" first="Sara" last="Baldassari">Sara Baldassari</name>
</author>
<author><name sortKey="Palombo, Flavia" sort="Palombo, Flavia" uniqKey="Palombo F" first="Flavia" last="Palombo">Flavia Palombo</name>
</author>
<author><name sortKey="Menghi, Veronica" sort="Menghi, Veronica" uniqKey="Menghi V" first="Veronica" last="Menghi">Veronica Menghi</name>
</author>
<author><name sortKey="D Aurizio, Romina" sort="D Aurizio, Romina" uniqKey="D Aurizio R" first="Romina" last="D'Aurizio">Romina D'Aurizio</name>
</author>
<author><name sortKey="Leta, Chiara" sort="Leta, Chiara" uniqKey="Leta C" first="Chiara" last="Leta">Chiara Leta</name>
</author>
<author><name sortKey="Stipa, Carlotta" sort="Stipa, Carlotta" uniqKey="Stipa C" first="Carlotta" last="Stipa">Carlotta Stipa</name>
</author>
<author><name sortKey="Boero, Giovanni" sort="Boero, Giovanni" uniqKey="Boero G" first="Giovanni" last="Boero">Giovanni Boero</name>
</author>
<author><name sortKey="D Orsi, Giuseppe" sort="D Orsi, Giuseppe" uniqKey="D Orsi G" first="Giuseppe" last="D'Orsi">Giuseppe D'Orsi</name>
</author>
<author><name sortKey="Magi, Alberto" sort="Magi, Alberto" uniqKey="Magi A" first="Alberto" last="Magi">Alberto Magi</name>
</author>
<author><name sortKey="Scheffer, Ingrid" sort="Scheffer, Ingrid" uniqKey="Scheffer I" first="Ingrid" last="Scheffer">Ingrid Scheffer</name>
</author>
<author><name sortKey="Seri, Marco" sort="Seri, Marco" uniqKey="Seri M" first="Marco" last="Seri">Marco Seri</name>
</author>
<author><name sortKey="Tinuper, Paolo" sort="Tinuper, Paolo" uniqKey="Tinuper P" first="Paolo" last="Tinuper">Paolo Tinuper</name>
</author>
<author><name sortKey="Bisulli, Francesca" sort="Bisulli, Francesca" uniqKey="Bisulli F" first="Francesca" last="Bisulli">Francesca Bisulli</name>
</author>
</analytic>
<series><title level="j">Neurology: Genetics</title>
<idno type="eISSN">2376-7839</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
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<front><div type="abstract" xml:lang="en"><sec><title>Objective:</title>
<p>To identify novel genes implicated in epilepsy with auditory features (EAF) in phenotypically heterogeneous families with unknown molecular basis.</p>
</sec>
<sec><title>Methods:</title>
<p>We identified 15 probands with EAF in whom an <italic>LGI1</italic>
mutation had been excluded. We performed electroclinical phenotyping on all probands and available affected relatives. We used whole-exome sequencing (WES) in 20 individuals with EAF (including all the probands and 5 relatives) to identify single nucleotide variants, small insertions/deletions, and copy number variants.</p>
</sec>
<sec><title>Results:</title>
<p>WES revealed likely pathogenic variants in genes that had not been previously associated with EAF: a <italic>CNTNAP2</italic>
intragenic deletion, 2 truncating mutations of <italic>DEPDC5</italic>
, and a missense <italic>SCN1A</italic>
change.</p>
</sec>
<sec><title>Conclusions:</title>
<p>EAF is a clinically and molecularly heterogeneous disease. The association of EAF with <italic>CNTNAP2</italic>
, <italic>DEPDC5</italic>
, and <italic>SCN1A</italic>
mutations widens the phenotypic spectrum related to these genes. <italic>CNTNAP2</italic>
encodes CASPR2, a member of the voltage-gated potassium channel complex in which LGI1 plays a role. The finding of a <italic>CNTNAP2</italic>
deletion emphasizes the importance of this complex in EAF and shows biological convergence.</p>
</sec>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Neurol Genet</journal-id>
<journal-id journal-id-type="iso-abbrev">Neurol Genet</journal-id>
<journal-id journal-id-type="hwp">nng</journal-id>
<journal-id journal-id-type="publisher-id">NNG</journal-id>
<journal-title-group><journal-title>Neurology: Genetics</journal-title>
</journal-title-group>
<issn pub-type="epub">2376-7839</issn>
<publisher><publisher-name>Wolters Kluwer</publisher-name>
<publisher-loc>Baltimore</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">27066544</article-id>
<article-id pub-id-type="pmc">4821078</article-id>
<article-id pub-id-type="publisher-id">NG2015000026</article-id>
<article-id pub-id-type="doi">10.1212/NXG.0000000000000005</article-id>
<article-categories><subj-group subj-group-type="hwp-journal-coll"><subject>60</subject>
<subject>77</subject>
<subject>91</subject>
<subject>94</subject>
</subj-group>
<subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Epilepsy with auditory features</article-title>
<subtitle>A heterogeneous clinico-molecular disease</subtitle>
</title-group>
<contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Pippucci</surname>
<given-names>Tommaso</given-names>
</name>
<degrees>PhD</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>Hospital: Azienda Ospedaliero-Universitaria Careggi, Teaching and training activities</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>Italian Ministry of Health, Young Investigators Program in Biomedical Research (2011-2014)</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>Telethon Foundation (2014-)</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<contrib contrib-type="author"><name><surname>Licchetta</surname>
<given-names>Laura</given-names>
</name>
<degrees>MD</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<contrib contrib-type="author"><name><surname>Baldassari</surname>
<given-names>Sara</given-names>
</name>
<degrees>BSc</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>(1) Italian Ministry of Health Young Investigators Project, GR-20102318960, Data Analysis, 2013-2014.</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>(1) Telethon Foundation Project, GGP13200</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<contrib contrib-type="author"><name><surname>Palombo</surname>
<given-names>Flavia</given-names>
</name>
<degrees>BSc</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>(1) Italian Ministry of Health Young Investigators project GR-2009-1574072</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>(1) Telethon Foundation Project GGP13082</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<contrib contrib-type="author"><name><surname>Menghi</surname>
<given-names>Veronica</given-names>
</name>
<degrees>MD</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<contrib contrib-type="author"><name><surname>D'Aurizio</surname>
<given-names>Romina</given-names>
</name>
<degrees>PhD</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<contrib contrib-type="author"><name><surname>Leta</surname>
<given-names>Chiara</given-names>
</name>
<degrees>MD</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<contrib contrib-type="author"><name><surname>Stipa</surname>
<given-names>Carlotta</given-names>
</name>
<degrees>MD</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<contrib contrib-type="author"><name><surname>Boero</surname>
<given-names>Giovanni</given-names>
</name>
<degrees>MD</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<contrib contrib-type="author"><name><surname>d'Orsi</surname>
<given-names>Giuseppe</given-names>
</name>
<degrees>MD</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<contrib contrib-type="author"><name><surname>Magi</surname>
<given-names>Alberto</given-names>
</name>
<degrees>PhD</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<contrib contrib-type="author"><name><surname>Scheffer</surname>
<given-names>Ingrid</given-names>
</name>
<degrees>PhD, MD</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>Travel (1) Sanofi China 2015 (2) UCB Japan 2013 Honoraria (1) Sanofi 2015 (2) UCB speaker 2014 (3) Transgenomics 2013</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>(1) Neurology, Editorial Board, 2014-present (2) Epilepsy Currents, Editorial Board, 2014-present (2) Annals of Neurology, Editorial Board, 2007-present (3) Epileptic Disorders, Editorial Board, 2006-present (4) Progress in Epileptic Disorders series, Editorial Board, 2005-present (5) Virtual Neuro Centre, Editorial Board, 2005-present</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>Has received revenue for: (1) Diagnostic and therapeutic methods for EFMR Issued patents: (1) Methods of treatment and diagnosis of epilepsy by detecting mutations in the SCN1A gene (2) A Diagnostic Method for Epilepsy (also published as Methods for the Diagnosis and Treatment of Epilepsy) (3) Mutations in Ion Channels (4) Diagnostic and Treatment Methods Relating to Autosomal Dominant Nocturnal Frontal Lobe Epilepsy Pending Patents: (1) Gene and mutations thereof associated with seizure disorders (2) A gene and mutations thereof associated with seizure and movement disorders (3) Diagnostic and therapeutic methods for EFMR</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>(1) NHMRC Program Grant #628952 CI 2011-2015, 2016-2020 (2) NHMRC Practitioner Fellowship 2011-2015 (3) NHMRC Project Grant 2013-2015 (4) NIH Centre Without Walls funding “Epi4K” 2011-2015</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>(1) The University of Melbourne 2008 (2) Austin Health Medical Research Foundation 2009, 2010</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>(1) Melbourne Neurosciences Institute 2014 (2) Weizmann Institute 2013-2014 (3) CURE SUDEP Award 2012-2013 (4) Perpetual Philanthropic Services 2012-2013</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<contrib contrib-type="author"><name><surname>Seri</surname>
<given-names>Marco</given-names>
</name>
<degrees>MD</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<contrib contrib-type="author"><name><surname>Tinuper</surname>
<given-names>Paolo</given-names>
</name>
<degrees>MD</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>1) Dr Tinuper seved on scientific advisory boards of UCB Pharma and Cyberonics</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>Dr Tinuper received sponsorisation for partecipation to International Congresses (Cyberonics)</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>Dr Tinuper served as editorial advisory board member of Seizures</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<contrib contrib-type="author"><name><surname>Bisulli</surname>
<given-names>Francesca</given-names>
</name>
<degrees>PhD, MD</degrees>
<author-comment content-type="disclosure"><p><list list-type="order"><title>Scientific Advisory Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Gifts:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Funding for Travel or Speaker Honoraria:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Editorial Boards:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Patents:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Publishing Royalties:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Employment, Commercial Entity:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Consultancies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Speakers' Bureaus:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Other Activities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Clinical Procedures or Imaging Studies:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Commercial Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Government Entities:</title>
<list-item><p>Italian Ministry of Health Young Investigators /euros 16.316; grant number: GR-2009-1574072, Coordinator of the Second Unit; 3 years</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Academic Entities:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Research Support, Foundations and Societies:</title>
<list-item><p>Telethon foundation (grant GGP 13200 to P.T.)</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options/Board of Directors Compensation:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>License Fee Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Royalty Payments, Technology or Inventions:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Research Sponsor:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Stock/Stock Options, Medical Equipment & Materials:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
<p><list list-type="order"><title>Legal Proceedings:</title>
<list-item><p>NONE</p>
</list-item>
</list>
</p>
</author-comment>
</contrib>
<aff>From the U.O. Medical Genetics (T.P., M.S.), Polyclinic Sant'Orsola-Malpighi, Bologna, Italy; Department of Medical and Surgical Sciences (S.B., F.P., M.S.) and Department of Biomedical and Neuromotor Sciences (L.L., V.M., C.L., C.S., P.T., F.B.), University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna (L.L., V.M., C.L., C.S., P.T., F.B.), Bologna, Italy; Laboratory of Integrative Systems Medicine (LISM) (R.D'.A.), Institute of Informatics and Telematics and Institute of Clinical Physiology, National Research Council, Pisa, Italy; S.C. of Neurology (G.B.), SS. Annunziata Hospital, Taranto, Italy; Epilepsy Centre (G.d'.O.), Clinic of Nervous System Diseases, University of Foggia, Riuniti Hospital, Foggia, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Florence, Florence, Italy; and Florey Institute (I.S.), University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Australia.</aff>
</contrib-group>
<author-notes><corresp>Correspondence to Dr. Pippucci: <email>tommaso.pippucci@unibo.it</email>
</corresp>
<fn fn-type="financial-disclosure"><p>Funding information and disclosures are provided at the end of the article. Go to <ext-link ext-link-type="doi" xlink:href="10.1212/NXG.0000000000000005">Neurology.org/ng</ext-link>
for full disclosure forms. The Article Processing Charge was paid by the authors.</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>14</day>
<month>5</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="collection"><month>6</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>14</day>
<month>5</month>
<year>2015</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
. </pmc-comment>
<volume>1</volume>
<issue>1</issue>
<elocation-id>e5</elocation-id>
<history><date date-type="received"><day>18</day>
<month>3</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>02</day>
<month>4</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>© 2015 American Academy of Neurology</copyright-statement>
<copyright-year>2015</copyright-year>
<copyright-holder>American Academy of Neurology</copyright-holder>
<license license-type="open-access"><license-p>This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivative 4.0 License, which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.</license-p>
</license>
</permissions>
<self-uri xlink:title="pdf" xlink:type="simple" xlink:href="NG2015000026.pdf"></self-uri>
<abstract><sec><title>Objective:</title>
<p>To identify novel genes implicated in epilepsy with auditory features (EAF) in phenotypically heterogeneous families with unknown molecular basis.</p>
</sec>
<sec><title>Methods:</title>
<p>We identified 15 probands with EAF in whom an <italic>LGI1</italic>
mutation had been excluded. We performed electroclinical phenotyping on all probands and available affected relatives. We used whole-exome sequencing (WES) in 20 individuals with EAF (including all the probands and 5 relatives) to identify single nucleotide variants, small insertions/deletions, and copy number variants.</p>
</sec>
<sec><title>Results:</title>
<p>WES revealed likely pathogenic variants in genes that had not been previously associated with EAF: a <italic>CNTNAP2</italic>
intragenic deletion, 2 truncating mutations of <italic>DEPDC5</italic>
, and a missense <italic>SCN1A</italic>
change.</p>
</sec>
<sec><title>Conclusions:</title>
<p>EAF is a clinically and molecularly heterogeneous disease. The association of EAF with <italic>CNTNAP2</italic>
, <italic>DEPDC5</italic>
, and <italic>SCN1A</italic>
mutations widens the phenotypic spectrum related to these genes. <italic>CNTNAP2</italic>
encodes CASPR2, a member of the voltage-gated potassium channel complex in which LGI1 plays a role. The finding of a <italic>CNTNAP2</italic>
deletion emphasizes the importance of this complex in EAF and shows biological convergence.</p>
</sec>
</abstract>
<custom-meta-group><custom-meta><meta-name>OPEN-ACCESS</meta-name>
<meta-value>TRUE</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<body><p>Epilepsy with auditory features (EAF) is an uncommon presentation of focal epilepsy characterized by focal seizures with auditory auras and symptoms suggesting lateral temporal onset.<sup><xref rid="R1" ref-type="bibr">1</xref>
</sup>
EAF is the hallmark of autosomal dominant EAF (ADEAF),<sup><xref rid="R1" ref-type="bibr">1</xref>
<xref ref-type="bibr" rid="R2">–</xref>
<xref rid="R3" ref-type="bibr">3</xref>
</sup>
a familial epilepsy syndrome due to mutations of the leucine-rich, glioma-inactivated 1 (<italic>LGI1</italic>
) gene (Online Mendelian Inheritance in Man [OMIM] *604619)<sup><xref rid="R4" ref-type="bibr">4</xref>
</sup>
in 50% of families.<sup><xref rid="R5" ref-type="bibr">5</xref>
</sup>
In ADEAF, affected members typically have EAF, although to make the diagnosis only 2 family members need to have EAF, irrespective of their degree of relatedness and the total number of individuals with epilepsy in the family.<sup><xref rid="R5" ref-type="bibr">5</xref>
,<xref rid="R6" ref-type="bibr">6</xref>
</sup>
</p>
<p>EAF also occurs in sporadic cases or in pedigrees with no <italic>LGI1</italic>
mutation. In these pedigrees, EAF is indistinguishable from <italic>LGI1</italic>
-positive ADEAF. However, the pattern of inheritance may be unclear, there may be phenotypic heterogeneity and EAF may occur in only a minority of cases. Such families do not usually fulfill the criteria for any specific familial epilepsy syndrome.</p>
<p>The small size, clinical heterogeneity, and incomplete penetrance displayed by such families with EAF may have hampered gene mapping through traditional approaches, such as linkage analysis. No mutation in genes other than <italic>LGI1</italic>
has been identified so far in EAF.<sup><xref rid="R7" ref-type="bibr">7</xref>
<xref ref-type="bibr" rid="R8">–</xref>
<xref rid="R10" ref-type="bibr">10</xref>
</sup>
The advent of next-generation sequencing has made the identification of causal variants possible even in small families. In this study, we describe a comprehensive whole-exome sequencing (WES) approach that enabled us to identify likely pathogenic variants in EAF probands and their affected relatives, demonstrating genetic heterogeneity underlying this epilepsy phenotype.</p>
<sec sec-type="methods" id="s1"><title>METHODS</title>
<sec id="s1-1"><title>Families.</title>
<p>From 2001 to 2014, we recruited consecutive probands with EAF and family history of epilepsy (at least 1 relative within 3 degrees of kinship affected with EAF or other epilepsy).</p>
<p>All affected family members underwent phenotyping, including medical and seizure history, neurologic examination, EEG recordings, and brain MRI. Previous medical records were obtained.</p>
</sec>
<sec id="s1-2"><title>Standard protocol approvals, registrations, and patient consents.</title>
<p>We received approval from institutional ethical standards committee on human experimentation, and written informed consent was obtained from all patients participating in the study or their parents in the case of minors.</p>
</sec>
<sec id="s1-3"><title>Molecular genetic analysis.</title>
<p>WES was performed on 20 individuals: 15 probands and 5 relatives with EAF. DNA was extracted from peripheral blood using the QIAamp DNA Blood Mini Kit (Qiagen, Venlo, the Netherlands) following the manufacturer's protocol. Whole-exome DNA was captured using the NimbleGenSeqCap EZ Exome v3 array (Nimblegen Inc., Madison, WI) and sequenced as 91-bp paired-end reads on the Illumina HiSeq2000 platform (Illumina Inc., Santa Clara, CA) at Beijing Genomic Institute (Shenzhen, China). Reads were processed following a general analysis pipeline described elsewhere.<sup><xref rid="R11" ref-type="bibr">11</xref>
</sup>
</p>
<p>Single nucleotide variants (SNVs) and small insertions and deletions (InDels) were called with the Genome Analysis ToolKit,<sup><xref rid="R12" ref-type="bibr">12</xref>
</sup>
and copy number variants (CNVs) were called from WES data using EXCAVATOR.<sup><xref rid="R13" ref-type="bibr">13</xref>
</sup>
Among SNVs and InDels, nonsynonymous SNVs, splice-site substitutions, and coding small insertions/deletions with a population allele frequency <1‰ in public databases (1000 Genomes, <ext-link ext-link-type="uri" xlink:href="http://www.1000genomes.org">http://www.1000genomes.org</ext-link>
; Exome Variant Server, <ext-link ext-link-type="uri" xlink:href="http://evs.gs.washington.edu/EVS/">http://evs.gs.washington.edu/EVS/</ext-link>
; ExAC, <ext-link ext-link-type="uri" xlink:href="http://exac.broadinstitute.org">http://exac.broadinstitute.org</ext-link>
) and absent from approximately 200 patients without epilepsy in our internal exome database were considered further.</p>
<p>The priority assigned to variants was higher in those with a lower Residual Variation Intolerance Score (RVIS) percentile (indicating greater intolerance to functional variation)<sup><xref rid="R14" ref-type="bibr">14</xref>
</sup>
and in those predicted to have a likely functional effect by Combined Annotation-Dependent Depletion (CADD) score<sup><xref rid="R15" ref-type="bibr">15</xref>
</sup>
(higher CADD scores indicate that the variant is more likely to be functionally relevant), or predicted to alter splicing or to be protein-truncating (frame-shift InDels or nonsense SNVs). Among CNVs, a higher priority was assigned to events that were not observed to occur in regions known to be involved in segmental duplications or were rare (allele frequency <1‰) in the Database of Genomic Variants (http://dgv.tcag.ca/dgv/app/home) by manual inspection. When WES of 2 affected members of the family (<xref ref-type="table" rid="T1">table 1</xref>
) had been performed, only the variants shared by the 2 were retained.</p>
<table-wrap id="T1" position="float"><label>Table 1</label>
<caption><p>Clinical features of the affected members belonging to the 15 pedigrees</p>
</caption>
<graphic xlink:href="NG2015000026TT1"></graphic>
</table-wrap>
<p>Validation and segregation analysis of candidate variants and CNVs were performed using Sanger sequencing and quantitative PCR analyses, respectively, following standard protocols.</p>
</sec>
</sec>
<sec sec-type="results" id="s2"><title>RESULTS</title>
<p>We included 12 consecutive probands of Italian ancestry attending the Epilepsy Center of our Institute in Bologna. Three additional cases were referred by 2 other epilepsy centers in Italy. A mutation or CNV of <italic>LGI1</italic>
<sup><xref rid="R16" ref-type="bibr">16</xref>
</sup>
was excluded in all 15 probands with EAF. Pedigree analysis revealed a total of 34 affected relatives: 6 with EAF (in the 5 families A, D, G, H, and I in <xref ref-type="table" rid="T1">table 1</xref>
) and 28 with other epilepsy (<xref ref-type="table" rid="T1">table 1</xref>
). Two families have been previously reported,<sup><xref rid="R6" ref-type="bibr">6</xref>
,<xref rid="R17" ref-type="bibr">17</xref>
</sup>
while the remaining 13 pedigrees are described here for the first time.</p>
<sec id="s2-1"><title>Molecular genetic findings in 344 “epilepsy genes.”</title>
<p>To analyze WES data, we initially focused on a set of 344 genes (table e-1 at <ext-link ext-link-type="doi" xlink:href="10.1212/NXG.0000000000000005">Neurology.org/ng</ext-link>
) implicated in monogenic disorders including epilepsy as a phenotypic feature based on previously published work<sup><xref rid="R18" ref-type="bibr">18</xref>
</sup>
and the OMIM database (<ext-link ext-link-type="uri" xlink:href="http://www.omim.org">www.omim.org</ext-link>
). We identified 7 candidate variants of 5 genes, each in one of 7 families. These variants were validated in every individual who underwent exome testing. We then tested segregation in all the available family members, both unaffected and affected by EAF or other epilepsies, who had no WES performed. After testing segregation, 6 variants remained: 1 CNV in <italic>CNTNAP2</italic>
(contactin-associated protein-like 2; OMIM *604569), 1 SNV and 1 InDel in <italic>DEPDC5</italic>
(DEP domain-containing protein 5; OMIM *614191), 1 SNV in <italic>SCN1A</italic>
(sodium channel, voltage-gated, type 1, alpha subunit; OMIM *182389), 1 SNV in <italic>CACNA1H</italic>
(calcium channel, voltage-dependent, T type, alpha-1H subunit; OMIM *607904), and 1 SNV in <italic>RELN</italic>
(REELIN, OMIM *600514).</p>
</sec>
<sec id="s2-2"><title>Likely pathogenic variants.</title>
<sec id="s2-2-1"><title><italic>CNTNAP2</italic>
.</title>
<p>An intragenic deletion of <italic>CNTNAP2</italic>
(p.Gln33Argfs*7) was identified in both the affected members of family A (<xref ref-type="fig" rid="F1">figure 1</xref>
). The proband (A:IV:1), aged 47 years, presented at 9 years with episodes characterized by confusion, distortion of voices, and inability to speak, occasionally followed by a bilateral tonic-clonic seizure. From 37 years of age, she had an aura of the noise of a train followed by an aphasic phase and sometimes twitching of her mouth and left arm, drooling, and head deviation to the right. Interictal EEG showed left temporal theta activity, and brain MRI was unremarkable. Her father (A:III:1) experienced seizures with auditory phenomena and rare bilateral tonic-clonic seizures from 15 to 18 years. The CNV of <italic>CNTNAP2</italic>
identified spans about 270 kb across exons 2-3 and is predicted to produce an out-of-frame transcript p.Gln33Argfs*7 (NM_014141:c.98_402del) and to result in loss of function.</p>
<fig id="F1" position="float"><label>Figure 1</label>
<caption><title>Segregation and localization of the identified variants</title>
<p>Pedigrees of the mutated families with mutations and schematic representation of the genes and the identified variants are presented. Phenotype labels: EAF = epilepsy with auditory features; GTCS = generalized tonic-clonic seizures; GS = generalized seizures; FS = febrile seizures; unclassified: it is undetermined whether the seizure type is focal or generalized. Gene diagrams and variants: blue lines represent the genomic regions spanned by the gene, while the blue bars represent the exons. Colored blocks surrounding gene regions correspond to the protein domains encoded by the embedded exons. DEP = Dishevelled, Egl-10 and Pleckstrin domain; D1-4 = domains 1–4; F5/8 = discoidin domain; LGL = laminin G-like domain; EL = EGF-like domain; FCT = fibrinogen C-terminal domain; TM = transmembrane domain. The probands' Sanger sequencing electropherogram surrounding the variant site is reported. The histogram plot represents the result of the real-time PCR. Log2ratios of ΔΔCt from patient A:III:1, patient A:IV:1, and a normal individual each against a control sample are plotted. The control sample is one that was negative for <italic>CNTNAP2</italic>
rearrangements by array comparative genomic hybridization analyses. Four probes were tested. Probe 1 and probe 2 are located in intron 1, while probe 3 and probe 4 are located in intron 3.</p>
</caption>
<graphic xlink:href="NG2015000026FF1"></graphic>
</fig>
</sec>
<sec id="s2-2-2"><title>DEPDC5.</title>
<p>Two different truncating mutations of <italic>DEPDC5</italic>
were found in 2 probands. Both <italic>DEPDC5</italic>
variants were predicted to be loss-of-function alleles.</p>
<p>A single base out-of-frame deletion p.Leu1371Argfs*14 (NM_001136029:c.4112delT) was detected in 3 affected members of family B (<xref ref-type="fig" rid="F1">figure 1</xref>
). The proband (B:III:1) with EAF had onset at 12 years of episodes comprising “a sensation of a whistle in the right ear,” sometimes associated with a rising epigastric sensation and followed by impairment of awareness and gestural automatisms. Interictal EEG showed bitemporal theta activity. The other 2 affected members have other types of focal epilepsy. Her mother (B:II:1) developed focal seizures at 9 years characterized by a rising epigastric sensation and autonomic phenomena followed by impaired awareness and head deviation. Her maternal aunt (B:II:2) experienced focal seizures from 9 years that began with a nonspecific aura and sometimes evolved to a bilateral tonic-clonic seizure. Her EEG showed right temporal sharp wave complexes.</p>
<p>In family C (<xref ref-type="fig" rid="F1">figure 1</xref>
), we identified a stop-gain substitution p.Tyr306*(NM_001136029:c.C918G). The proband (C:IV:1) had a single febrile seizure (FS) at 6 months of age and then had rare right tonic seizures, occasionally followed by a bilateral tonic-clonic seizure, predominantly during sleep until 2 years of age. Since childhood, she has also had seizures preceded by auditory phenomena and/or déjà vécu, sometimes followed by impaired consciousness. By 29 years, seizures occurred weekly, despite trials of several antiepileptic drugs. Interictal EEG showed bitemporal theta activity. Her mother (C:III:2) had FSs at 2 years and focal seizures beginning with visual phenomena, déjà vu, and an epigastric aura between 12 and 35 years. Brain MRI was normal in all patients from both families.</p>
</sec>
<sec id="s2-2-3"><title>SCN1A.</title>
<p>In family D (<xref ref-type="fig" rid="F1">figure 1</xref>
), a missense change p.Met956Thr (NM_001165963:c.T2867C) of <italic>SCN1A</italic>
was identified in the proband (D:III:1) and her daughter (D:IV:1) with EAF. The family comprised 10 affected members (3 male, 7 female; mean age at onset: 4.5 years, range: 2–12). Seven had epilepsy (D:III:1, D:III:7, D:III:8, D:IV:1, D:IV:6, D:IV:7, and D:IV:8), while 3 had FSs alone (D:III:6, D:III:11, and D:IV:4). In addition to individuals D:III:1 and D:IV:1 with EAF, 1 patient had focal epilepsy (D:III:8), 3 had generalized seizures in childhood (D:III:7, D:IV:6, and D:IV:8), and 1 had infantile epileptic encephalopathy (D:IV:7). Three of the family members with epilepsy had a history of prolonged FSs (D:III:8, D:IV:1, and D:IV:8). The <italic>SCN1A</italic>
change segregated with affected status in this large pedigree. There was incomplete penetrance (61.5%) since 2 unaffected obligate carriers (D:II:4 and D:III:4) and 3 healthy individuals (D:III:3, D:III:5, and D:III:9) were heterozygous for the mutation. The same mutation has been recently reported in a family with intractable childhood epilepsy with generalized tonic-clonic seizures where it was described as a loss-of-function, fully penetrant allele that led to incorrect folding of the alpha 1 subunit of the voltage-gated sodium channel type 1 (Nav1.1) encoded by <italic>SCN1A</italic>
.<sup><xref rid="R19" ref-type="bibr">19</xref>
</sup>
</p>
</sec>
</sec>
<sec id="s2-3"><title>Variants of unclear significance.</title>
<sec id="s2-3-1"><title>CACNA1H.</title>
<p>A missense change p.Arg1669Gln (NM_001005407:c.G5006A) of <italic>CACNA1H</italic>
was identified in the 38-year-old proband of family E (<xref ref-type="table" rid="T1">table 1</xref>
).</p>
<p>The <italic>CACNA1H</italic>
SNV identified was inherited by her mother (E:I:1), who experienced sleep-related bilateral tonic-clonic seizures at 36 years of age. Rare amino acid substitutions altering function of the channel encoded by <italic>CACNA1H</italic>
have been reported in families with predominantly generalized epilepsies, as well as temporal lobe epilepsy.<sup><xref rid="R20" ref-type="bibr">20</xref>
</sup>
The present change was potentially deleterious (table e-2). Functional assessment of the pathogenic potential was not performed as part of this study but is needed to confirm a causal role.</p>
</sec>
<sec id="s2-3-2"><title>RELN.</title>
<p>A missense change p.Asp3323Glu (NM_005045:c.T9969G) of <italic>RELN</italic>
was identified in the 52-year-old proband of family F (<xref ref-type="table" rid="T1">table 1</xref>
). Segregation of the variant could not be tested since no relative was available for this study. The father's grandfather, who was the only other affected member of the family (<xref ref-type="table" rid="T1">table 1</xref>
), was already deceased at the time of enrollment. <italic>RELN</italic>
encodes reelin, which is essential for cerebral cortex development and synaptic function in the adult brain.<sup><xref rid="R21" ref-type="bibr">21</xref>
</sup>
Homozygous recessive loss-of-function <italic>RELN</italic>
alleles have been shown to cause lissencephaly<sup><xref rid="R22" ref-type="bibr">22</xref>
</sup>
(OMIM #257320), while heterozygous variants have been purported to play a role in neuropsychiatric disorders.<sup><xref rid="R21" ref-type="bibr">21</xref>
</sup>
Reelin is a huge protein (3460 aa, Uniprot ID P78509). Although <italic>RELN</italic>
is highly intolerant to functional variation and the present variant is potentially deleterious (table e-2), many rare missense variants accumulate in <italic>RELN</italic>
(ExAC database). Due to the lack of segregation testing and uncertainty of its functional effect, we cannot assess a causal role of this heterozygous variant.</p>
</sec>
</sec>
<sec id="s2-4"><title>Possible novel candidate genes.</title>
<p>We further analyzed WES data looking at variants in genes beyond the initial set. In order to identify possible candidates for EAF, we examined variants within genes shared by at least 2 unrelated probands. We validated and tested the segregation of variants in 4 genes, selected based on the lowest RVIS scores and the highest pathogenic potential. After testing the segregation, only the echinoderm microtubule associated protein-like 6 gene (<italic>EML6</italic>
) remained as a possible candidate gene. <italic>EML6</italic>
showed a novel p.Ala186fs frameshift event (c.558delA) in family M and a rare p.Thr918Ala missense variant (c.A2752G) in family F (table e-2). The function of <italic>EML6</italic>
is largely unknown, and apart from its reported expression in cerebral temporal cortex (<ext-link ext-link-type="uri" xlink:href="http://www.braineac.org/">http://www.braineac.org/</ext-link>
), no data support its possible dysfunction being implicated in epilepsy. Moreover, a major role in disease for any of the variants in <italic>EML6</italic>
and <italic>RELN</italic>
, which have both been found in family F, is difficult to ascertain. Study of larger cohorts will be needed to assess whether this gene can contribute to EAF.</p>
</sec>
</sec>
<sec sec-type="discussion" id="s3"><title>DISCUSSION</title>
<p>In this study, we describe defects in novel genes contributing to the genetic architecture of EAF. We identified likely pathogenic genetic variants in 4 of 15 unrelated EAF probands: an intragenic deletion of <italic>CNTNAP2</italic>
, 2 truncating mutations of <italic>DEPDC5</italic>
, and 1 missense mutation in <italic>SCN1A</italic>
. All genes have been previously associated with other forms of focal epilepsy but not EAF.<sup><xref rid="R23" ref-type="bibr">23</xref>
<xref ref-type="bibr" rid="R24">–</xref>
<xref rid="R26" ref-type="bibr">26</xref>
</sup>
Several factors support the pathogenicity of the identified mutations, including their rarity, their predicted deleterious nature, their segregation with affected status within kindreds, and the recognized role of mutations of these genes in the etiology of the associated epilepsies. In these families, EAF is a phenotype that occurs in few (often the minority) of the affected members. Such phenotypically heterogeneous families are generally of small size and have usually been considered poorly informative for genetic studies, as recurrence of the disease tends to be low, expressivity of the phenotype widely variable, and penetrance reduced. These families likely reflect the more common scenario in clinical practice compared with the rare familial epilepsy syndrome of ADEAF. <italic>LGI1</italic>
mutations are associated with ADEAF in about half of the large multigenerational families displaying autosomal dominant inheritance of EAF. However, <italic>LGI1</italic>
mutations have been rarely detected in pedigrees with EAF and a less clear-cut pattern of inheritance or phenotypic heterogeneity.<sup><xref rid="R5" ref-type="bibr">5</xref>
</sup>
</p>
<p>The discovery of <italic>DEPDC5</italic>
mutations in 2 of 15 probands is in line with the frequency of <italic>DEPDC5</italic>
mutations observed in other focal epilepsies (around 10%).<sup><xref rid="R23" ref-type="bibr">23</xref>
,<xref rid="R27" ref-type="bibr">27</xref>
</sup>
The 2 identified <italic>DEPDC5</italic>
mutations (c.C918G and c.4112delT) are loss-of-function events, both predicted to generate a prematurely truncated product. These mutated transcripts likely undergo nonsense-mediated decay leading to haploinsufficiency, which is the main mechanism believed to underlie pathogenesis.<sup><xref rid="R23" ref-type="bibr">23</xref>
,<xref rid="R28" ref-type="bibr">28</xref>
</sup>
These results enlarge the <italic>DEPDC5</italic>
-related phenotypic spectrum to include EAF with lateral temporal lobe semiology, further strengthening the emerging association of defects in this gene with a broad range of focal epilepsies. It could be anticipated that different epilepsy phenotypes, including EAF, will be associated with <italic>DEPDC5</italic>
mutations in other small families.</p>
<p>Similarly, the discovery of an <italic>SCN1A</italic>
c.T2867C change in family D widens the already large compendium of epilepsy phenotypes associated with <italic>SCN1A</italic>
mutations. In this interesting pedigree, the EAF phenotype is limited to the proband and her daughter, but expanding the clinical and genetic study of this family allowed us to define the diagnosis of the familial epilepsy syndrome of generalized epilepsy with febrile seizures plus (GEFS+). <italic>SCN1A</italic>
has been implicated in different epilepsy syndromes ranging from GEFS+<sup><xref rid="R29" ref-type="bibr">29</xref>
</sup>
to Dravet syndrome (OMIM #607208)<sup><xref rid="R30" ref-type="bibr">30</xref>
</sup>
and occasionally includes focal seizures.<sup><xref rid="R24" ref-type="bibr">24</xref>
,<xref rid="R25" ref-type="bibr">25</xref>
</sup>
Lateral temporal semiology with auditory symptoms due to <italic>SCN1A</italic>
mutation has not been previously reported, and our findings indicate EAF as a novel phenotype within the <italic>SCN1A</italic>
phenotypic spectrum.</p>
<p>Mutations in <italic>SCN1A</italic>
and <italic>DEPDC5</italic>
result in specific epilepsy syndromes, whereas <italic>CNTNAP2</italic>
is disrupted in a broad range of neurologic conditions<sup><xref rid="R31" ref-type="bibr">31</xref>
<xref ref-type="bibr" rid="R32">–</xref>
<xref rid="R33" ref-type="bibr">33</xref>
</sup>
in which seizures play a part.<sup><xref rid="R26" ref-type="bibr">26</xref>
</sup>
Diallelic loss of normal <italic>CNTNAP2</italic>
has been linked to complex phenotypes, including cortical dysplasia and focal epilepsy,<sup><xref rid="R34" ref-type="bibr">34</xref>
,<xref rid="R35" ref-type="bibr">35</xref>
</sup>
but most of the disruptive events involving <italic>CNTNAP2</italic>
are heterozygous and show incomplete penetrance. These include heterogeneous alterations ranging from intronic/exonic deletions to splice-site mutations and truncating and missense changes. Family A consists of a nuclear pedigree with only 2 affected members, father and daughter, who both have EAF. The exon 2-3 deletion we report, predicted to code for an abnormal product (p.Gln33Argfs*7), lies within the CNV hotspot spanning the <italic>CNTNAP2</italic>
exon 2-9 genomic region implicated in complex neuropsychiatric disorders (<xref ref-type="fig" rid="F2">figure 2</xref>
). Epilepsy or seizures are reported in many of the patients with this deletion, but they are not commonly the primary diagnosis and are therefore not described in detail. Accurate epilepsy phenotyping in these patients may reveal other EAF cases associated with deletions of this gene. Neither affected member of family A showed features of intellectual disability, speech delay, or psychiatric disturbances. Notably, CASPR2, the protein product of <italic>CNTNAP2</italic>
, and LGI1 are closely associated with the voltage-gated potassium channel (VGKC) complex in the human brain (<xref ref-type="fig" rid="F2">figure 2</xref>
),<sup><xref rid="R36" ref-type="bibr">36</xref>
</sup>
and LGI1 has been found to be part of the CASPR2 interactome.<sup><xref rid="R37" ref-type="bibr">37</xref>
</sup>
This functional relationship highlights the possible molecular link between <italic>CNTNAP2</italic>
disruption and the EAF phenotype. Haploinsufficient Lgi1 in adult rat brains has been demonstrated to cause changes in the inactivation gating of presynaptic A-type channels, of which Kv1.1 is a major constituent.<sup><xref rid="R38" ref-type="bibr">38</xref>
</sup>
This has been proposed to be the molecular mechanism promoting epileptic activity in patients with defective LGI1 protein. In addition, the predicted haploinsufficiency of CASPR2, another protein complexed with Kv1.1, may alter channel kinetics. Recently, consistent evidence has shown that mutations in the same gene can increase the risk of a broad range of complex neuropsychiatric disorders.<sup><xref rid="R39" ref-type="bibr">39</xref>
</sup>
This suggests the involvement of genetic or environmental modifiers. Notwithstanding the challenge in interpreting the complexity of <italic>CNTNAP2</italic>
genotype-phenotype correlations, the present data together with the accumulated knowledge about <italic>CNTNAP2</italic>
mutations and CASPR2 function strongly suggest that disrupted <italic>CNTNAP2</italic>
contributes to EAF in family A. This perspective is fascinating because other pre- or postsynaptic membrane-bound proteins (ADAM22, ADAM23, and Kv1 channel genes) have been explored before in search for mutations in EAF, but no mutations were detected.<sup><xref rid="R8" ref-type="bibr">8</xref>
<xref ref-type="bibr" rid="R9">–</xref>
<xref rid="R10" ref-type="bibr">10</xref>
</sup>
</p>
<fig id="F2" position="float"><label>Figure 2</label>
<caption><title>The <italic>CNTNAP2</italic>
locus in disease and localization of its encoded product, CASPR2, at the synapse</title>
<p>(A) Schematic indicating the functional relationship linking LGI1 and CASPR2 proteins through the voltage-gated potassium channel (VGKC). (B) Schematic indicating the previously reported microdeletions (horizontal bars) of <italic>CNTNAP2</italic>
in neuropsychiatric conditions (modified from Rodenas-Cuadrado, 2013). The deletion reported in this study, spanning <italic>CNTNAP2</italic>
exons 2-3, overlaps most of the <italic>CNTNAP2</italic>
deletions implicated in disorder before. It is represented in red with a halo surrounding it. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder.</p>
</caption>
<graphic xlink:href="NG2015000026FF2"></graphic>
</fig>
<p>Additional variants were identified in different genes, either previously implicated in epilepsy (<italic>CACNA1H</italic>
, <italic>RELN</italic>
) or not (<italic>EML6</italic>
), but their actual contribution to EAF cannot be assessed based on our present observations.</p>
<p>Overall, defects in 3 novel genes were associated with EAF. Of the pedigrees in which these mutations were found, 1 with a <italic>CNTNAP2</italic>
deletion may have ADEAF, as both affected individuals have the EAF phenotype and the genetic inheritance model is autosomal dominant. The association of ADEAF with a <italic>CNTNAP2</italic>
deletion shows biological convergence and opens new perspectives on the contribution of non-LGI1 VGKC-complex proteins to the EAF phenotype. The identification of mutations in <italic>DEPDC5</italic>
and <italic>SCN1A</italic>
in families showing heterogeneous phenotypic patterns enlarges the phenotypic spectrum of the epilepsies associated with these genes. Overall, our results suggest that EAF is an epilepsy phenotype originating from alterations in a heterogeneous group of genes implicated in a broader range of epileptic syndromes or neurologic diseases. This overlap, frequently observed in other forms of epilepsy (e.g., autosomal dominant nocturnal frontal lobe epilepsy),<sup><xref rid="R27" ref-type="bibr">27</xref>
,<xref rid="R28" ref-type="bibr">28</xref>
</sup>
reflects the complexity of the involved molecular mechanisms and reveals the challenge of incorporating the underlying biology into the current classification of epilepsies. This study emphasizes the use of a comprehensive WES strategy, tackling both mutations and CNVs, in an effort to solve challenging diagnostic puzzles in epilepsy.</p>
</sec>
<sec sec-type="supplementary-material"><title>Supplementary Material</title>
<supplementary-material id="PMC_1" content-type="local-data"><caption><title>Data Supplement</title>
</caption>
<media mimetype="text" mime-subtype="html" xlink:href="supp_1_1_e5__index.html"></media>
<media xlink:role="associated-file" mimetype="application" mime-subtype="msword" xlink:href="supp_1.1.e5_Table_e-1.doc"></media>
<media xlink:role="associated-file" mimetype="application" mime-subtype="msword" xlink:href="supp_1.1.e5_Table_e-2.doc"></media>
</supplementary-material>
</sec>
</body>
<back><fn-group><fn fn-type="supplementary-material"><p>Supplemental data at <ext-link ext-link-type="doi" xlink:href="10.1212/NXG.0000000000000005">Neurology.org/ng</ext-link>
</p>
</fn>
</fn-group>
<ack><title>ACKNOWLEDGMENT</title>
<p>The authors are grateful to the families for participation in the study, especially to the probands for their valuable assistance during in loco assessment of the family. The authors acknowledge Mrs. Annalia Cesare for secretarial help in keeping in contact with patients, Ms. Elena Zoni for help in manuscript editing, and Dr. Lara Alvisi and the other EEG technicians at our institute for recording the patients. The authors acknowledge the genetic commission of the Italian League Against Epilepsy for discussion of the pedigrees and valuable suggestions for the study design.</p>
</ack>
<sec sec-type="contributions"><title>AUTHOR CONTRIBUTIONS</title>
<p content-type="contributions">Dr. Pippucci, Dr. Licchetta, S. Baldassari, and Dr. Bisulli conceptualized and designed the study and drafted the manuscript. Dr. Menghi, Dr. Leta, Dr. Stipa, Dr. Boero, Dr. d'Orsi, and Dr. Bisulli phenotyped the patients. Dr. Pippucci, Dr. Licchetta, S. Baldassari, F. Palombo, Dr. D'Aurizio, Dr. Magi, and Dr. Bisulli collected, analyzed, and interpreted the data. Dr. Scheffer, Dr. Seri, and Dr. Tinuper critically revised the manuscript for important intellectual content.</p>
</sec>
<sec sec-type="funding"><title>STUDY FUNDING</title>
<p content-type="funding">Italian Ministry of Health Young Investigators project GR-2009-1574072 to T.P. and F.B., Telethon Foundation Project GGP13200 to P.T. and T.P.</p>
</sec>
<sec sec-type="disclosure"><title>DISCLOSURE</title>
<p content-type="disclosure">Dr. Pippucci has worked for Azienda Ospedaliero-Universitaria Careggi and has received research support from the Italian Ministry of Health and Telethon Foundation. Dr. Licchetta reports no disclosures. S. Baldassari has received research support from the Italian Ministry of Health and Telethon Foundation. F. Palombo has received research support from the Italian Ministry of Health and Telethon Foundation. Dr. Menghi, Dr. D'Aurizio, Dr. Leta, Dr. Stipa, Dr. Boero, Dr. d'Orsi, and Dr. Magi report no disclosures. Dr. Scheffer has received funding for travel and/or speaker honoraria from Sanofi, UCB, and Transgenomics; has served on editorial boards for <italic>Neurology</italic>
, <italic>Epilepsy Currents</italic>
, <italic>Annals of Neurology</italic>
, <italic>Epileptic Disorders</italic>
, <italic>Progress in Epileptic Disorders</italic>
series, and <italic>Virtual Neuro Centre</italic>
; holds patents for methods of treatment and diagnosis of epilepsy by detecting mutations in the SCN1A gene, A Diagnostic Method for Epilepsy (also published as Methods for the Diagnosis and Treatment of Epilepsy), Mutations in Ion Channels, Diagnostic and Treatment Methods Relating to Autosomal Dominant Nocturnal Frontal Lobe Epilepsy and pending patents for gene and mutations thereof associated with seizure disorders, gene and mutations thereof associated with seizure and movement disorders, and diagnostic and therapeutic methods for EFMR; and has received research support from <funding-source>NHMRC</funding-source>
, <funding-source>NIH</funding-source>
, The University of Melbourne, <funding-source>Austin Health Medical Research Foundation</funding-source>
, Melbourne Neurosciences Institute, Weizmann Institute, CURE SUDEP, and Perpetual Philanthropic Services. Dr. Seri reports no disclosures. Dr. Tinuper has served on scientific advisory boards of UCB Pharma and Cyberonics; has received funding for travel and/or speaker honoraria from Cyberonics; and has served on the editorial board of <italic>Seizures</italic>
. Dr. Bisulli has received research support from the Italian Ministry of Health Young Investigators and Telethon. Go to <ext-link ext-link-type="doi" xlink:href="10.1212/NXG.0000000000000005">Neurology.org/ng</ext-link>
for full disclosure forms.</p>
</sec>
<glossary><title>GLOSSARY</title>
<def-list><def-item><term id="G1">ADEAF</term>
<def><p>autosomal dominant EAF</p>
</def>
</def-item>
<def-item><term id="G2">CADD</term>
<def><p>Combined Annotation-Dependent Depletion</p>
</def>
</def-item>
<def-item><term id="G3">CNV</term>
<def><p>copy number variant</p>
</def>
</def-item>
<def-item><term id="G4">EAF</term>
<def><p>epilepsy with auditory features</p>
</def>
</def-item>
<def-item><term id="G5">FS</term>
<def><p>febrile seizure</p>
</def>
</def-item>
<def-item><term id="G6">GEFS+</term>
<def><p>generalized epilepsy with febrile seizures plus</p>
</def>
</def-item>
<def-item><term id="G7">InDels</term>
<def><p>insertions and deletions</p>
</def>
</def-item>
<def-item><term id="G8">OMIM</term>
<def><p>Online Mendelian Inheritance in Man</p>
</def>
</def-item>
<def-item><term id="G9">RVIS</term>
<def><p>Residual Variation Intolerance Score</p>
</def>
</def-item>
<def-item><term id="G10">SNV</term>
<def><p>single nucleotide variant</p>
</def>
</def-item>
<def-item><term id="G11">VGKC</term>
<def><p>voltage-gated potassium channel</p>
</def>
</def-item>
<def-item><term id="G12">WES</term>
<def><p>whole-exome sequencing</p>
</def>
</def-item>
</def-list>
</glossary>
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<mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhu</surname>
<given-names>X</given-names>
</name>
<name><surname>Need</surname>
<given-names>AC</given-names>
</name>
<name><surname>Petrovski</surname>
<given-names>S</given-names>
</name>
<name><surname>Goldstein</surname>
<given-names>DB</given-names>
</name>
</person-group>
<article-title>One gene, many neuropsychiatric disorders: lessons from Mendelian diseases</article-title>
. <source>Nat Neurosci</source>
<year>2014</year>
;<volume>17</volume>
:<fpage>773</fpage>
–<lpage>781</lpage>
.<pub-id pub-id-type="pmid">24866043</pub-id>
</mixed-citation>
</ref>
</ref-list>
</back>
</pmc>
</record>
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