Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly
Identifieur interne : 000C65 ( Pmc/Curation ); précédent : 000C64; suivant : 000C66Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly
Auteurs : Patrick Rump [Pays-Bas] ; Omid Jazayeri [Pays-Bas] ; Krista K. Van Dijk-Bos [Pays-Bas] ; Lennart F. Johansson [Pays-Bas] ; Anthonie J. Van Essen [Pays-Bas] ; Johanna B. G. M. Verheij [Pays-Bas] ; Hermine E. Veenstra-Knol [Pays-Bas] ; Egbert J. W. Redeker [Pays-Bas] ; Marcel M. A. M. Mannens [Pays-Bas] ; Morris A. Swertz [Pays-Bas] ; Behrooz Z. Alizadeh [Pays-Bas] ; Conny M. A. Van Ravenswaaij-Arts [Pays-Bas] ; Richard J. Sinke [Pays-Bas] ; Birgit Sikkema-Raddatz [Pays-Bas]Source :
- BMC Medical Genomics [ 1755-8794 ] ; 2016.
Abstract
Clinical and genetic heterogeneity in monogenetic disorders represents a major diagnostic challenge. Although the presence of particular clinical features may aid in identifying a specific cause in some cases, the majority of patients remain undiagnosed.
Here, we investigated the utility of whole-exome sequencing as a diagnostic approach for establishing a molecular diagnosis in a highly heterogeneous group of patients with varied intellectual disability and microcephaly.
Whole-exome sequencing was performed in 38 patients, including three sib-pairs, in addition to or in parallel with genetic analyses that were performed during the diagnostic work-up of the study participants.
In ten out of these 35 families (29 %), we found mutations in genes already known to be related to a disorder in which microcephaly is a main feature. Two unrelated patients had mutations in the
We demonstrate that whole-exome sequencing is a powerful tool for the diagnostic evaluation of patients with highly heterogeneous neurodevelopmental disorders such as intellectual disability with microcephaly. Our results confirm that autosomal recessive disorders are highly prevalent among patients with microcephaly.
The online version of this article (doi:10.1186/s12920-016-0167-8) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/s12920-016-0167-8
PubMed: 26846091
PubMed Central: 4743197
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: Pour aller vers cette notice dans l'étape Curation :000C66
Links to Exploration step
PMC:4743197Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly</title>
<author><name sortKey="Rump, Patrick" sort="Rump, Patrick" uniqKey="Rump P" first="Patrick" last="Rump">Patrick Rump</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Jazayeri, Omid" sort="Jazayeri, Omid" uniqKey="Jazayeri O" first="Omid" last="Jazayeri">Omid Jazayeri</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Dijk Bos, Krista K" sort="Van Dijk Bos, Krista K" uniqKey="Van Dijk Bos K" first="Krista K." last="Van Dijk-Bos">Krista K. Van Dijk-Bos</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Johansson, Lennart F" sort="Johansson, Lennart F" uniqKey="Johansson L" first="Lennart F." last="Johansson">Lennart F. Johansson</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff3">Department of Genetics, University of Groningen, University Medical Centre Groningen, Genomics Coordination Centre, Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, Genomics Coordination Centre, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Essen, Anthonie J" sort="Van Essen, Anthonie J" uniqKey="Van Essen A" first="Anthonie J." last="Van Essen">Anthonie J. Van Essen</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Verheij, Johanna B G M" sort="Verheij, Johanna B G M" uniqKey="Verheij J" first="Johanna B. G. M." last="Verheij">Johanna B. G. M. Verheij</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Veenstra Knol, Hermine E" sort="Veenstra Knol, Hermine E" uniqKey="Veenstra Knol H" first="Hermine E." last="Veenstra-Knol">Hermine E. Veenstra-Knol</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Redeker, Egbert J W" sort="Redeker, Egbert J W" uniqKey="Redeker E" first="Egbert J. W." last="Redeker">Egbert J. W. Redeker</name>
<affiliation wicri:level="1"><nlm:aff id="Aff2">Department of Clinical Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Clinical Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mannens, Marcel M A M" sort="Mannens, Marcel M A M" uniqKey="Mannens M" first="Marcel M. A. M." last="Mannens">Marcel M. A. M. Mannens</name>
<affiliation wicri:level="1"><nlm:aff id="Aff2">Department of Clinical Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Clinical Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Swertz, Morris A" sort="Swertz, Morris A" uniqKey="Swertz M" first="Morris A." last="Swertz">Morris A. Swertz</name>
<affiliation wicri:level="1"><nlm:aff id="Aff3">Department of Genetics, University of Groningen, University Medical Centre Groningen, Genomics Coordination Centre, Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, Genomics Coordination Centre, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Alizadeh, Behrooz Z" sort="Alizadeh, Behrooz Z" uniqKey="Alizadeh B" first="Behrooz Z." last="Alizadeh">Behrooz Z. Alizadeh</name>
<affiliation wicri:level="1"><nlm:aff id="Aff4">Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Ravenswaaij Arts, Conny M A" sort="Van Ravenswaaij Arts, Conny M A" uniqKey="Van Ravenswaaij Arts C" first="Conny M. A." last="Van Ravenswaaij-Arts">Conny M. A. Van Ravenswaaij-Arts</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sinke, Richard J" sort="Sinke, Richard J" uniqKey="Sinke R" first="Richard J." last="Sinke">Richard J. Sinke</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sikkema Raddatz, Birgit" sort="Sikkema Raddatz, Birgit" uniqKey="Sikkema Raddatz B" first="Birgit" last="Sikkema-Raddatz">Birgit Sikkema-Raddatz</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">26846091</idno>
<idno type="pmc">4743197</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743197</idno>
<idno type="RBID">PMC:4743197</idno>
<idno type="doi">10.1186/s12920-016-0167-8</idno>
<date when="2016">2016</date>
<idno type="wicri:Area/Pmc/Corpus">000C66</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000C66</idno>
<idno type="wicri:Area/Pmc/Curation">000C65</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000C65</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly</title>
<author><name sortKey="Rump, Patrick" sort="Rump, Patrick" uniqKey="Rump P" first="Patrick" last="Rump">Patrick Rump</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Jazayeri, Omid" sort="Jazayeri, Omid" uniqKey="Jazayeri O" first="Omid" last="Jazayeri">Omid Jazayeri</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Dijk Bos, Krista K" sort="Van Dijk Bos, Krista K" uniqKey="Van Dijk Bos K" first="Krista K." last="Van Dijk-Bos">Krista K. Van Dijk-Bos</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Johansson, Lennart F" sort="Johansson, Lennart F" uniqKey="Johansson L" first="Lennart F." last="Johansson">Lennart F. Johansson</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff3">Department of Genetics, University of Groningen, University Medical Centre Groningen, Genomics Coordination Centre, Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, Genomics Coordination Centre, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Essen, Anthonie J" sort="Van Essen, Anthonie J" uniqKey="Van Essen A" first="Anthonie J." last="Van Essen">Anthonie J. Van Essen</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Verheij, Johanna B G M" sort="Verheij, Johanna B G M" uniqKey="Verheij J" first="Johanna B. G. M." last="Verheij">Johanna B. G. M. Verheij</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Veenstra Knol, Hermine E" sort="Veenstra Knol, Hermine E" uniqKey="Veenstra Knol H" first="Hermine E." last="Veenstra-Knol">Hermine E. Veenstra-Knol</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Redeker, Egbert J W" sort="Redeker, Egbert J W" uniqKey="Redeker E" first="Egbert J. W." last="Redeker">Egbert J. W. Redeker</name>
<affiliation wicri:level="1"><nlm:aff id="Aff2">Department of Clinical Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Clinical Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mannens, Marcel M A M" sort="Mannens, Marcel M A M" uniqKey="Mannens M" first="Marcel M. A. M." last="Mannens">Marcel M. A. M. Mannens</name>
<affiliation wicri:level="1"><nlm:aff id="Aff2">Department of Clinical Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Clinical Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Swertz, Morris A" sort="Swertz, Morris A" uniqKey="Swertz M" first="Morris A." last="Swertz">Morris A. Swertz</name>
<affiliation wicri:level="1"><nlm:aff id="Aff3">Department of Genetics, University of Groningen, University Medical Centre Groningen, Genomics Coordination Centre, Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, Genomics Coordination Centre, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Alizadeh, Behrooz Z" sort="Alizadeh, Behrooz Z" uniqKey="Alizadeh B" first="Behrooz Z." last="Alizadeh">Behrooz Z. Alizadeh</name>
<affiliation wicri:level="1"><nlm:aff id="Aff4">Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Van Ravenswaaij Arts, Conny M A" sort="Van Ravenswaaij Arts, Conny M A" uniqKey="Van Ravenswaaij Arts C" first="Conny M. A." last="Van Ravenswaaij-Arts">Conny M. A. Van Ravenswaaij-Arts</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sinke, Richard J" sort="Sinke, Richard J" uniqKey="Sinke R" first="Richard J." last="Sinke">Richard J. Sinke</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sikkema Raddatz, Birgit" sort="Sikkema Raddatz, Birgit" uniqKey="Sikkema Raddatz B" first="Birgit" last="Sikkema-Raddatz">Birgit Sikkema-Raddatz</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">BMC Medical Genomics</title>
<idno type="eISSN">1755-8794</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>Clinical and genetic heterogeneity in monogenetic disorders represents a major diagnostic challenge. Although the presence of particular clinical features may aid in identifying a specific cause in some cases, the majority of patients remain undiagnosed.</p>
<p>Here, we investigated the utility of whole-exome sequencing as a diagnostic approach for establishing a molecular diagnosis in a highly heterogeneous group of patients with varied intellectual disability and microcephaly.</p>
</sec>
<sec><title>Methods</title>
<p>Whole-exome sequencing was performed in 38 patients, including three sib-pairs, in addition to or in parallel with genetic analyses that were performed during the diagnostic work-up of the study participants.</p>
</sec>
<sec><title>Results</title>
<p>In ten out of these 35 families (29 %), we found mutations in genes already known to be related to a disorder in which microcephaly is a main feature. Two unrelated patients had mutations in the <italic>ASPM</italic>
gene. In seven other patients we found mutations in <italic>RAB3GAP1</italic>
, <italic>RNASEH2B, KIF11</italic>
, <italic>ERCC8</italic>
, <italic>CASK</italic>
, <italic>DYRK1A</italic>
and <italic>BRCA2</italic>
. In one of the sib-pairs, mutations were found in the <italic>RTTN</italic>
gene. Mutations were present in seven out of our ten families with an established etiological diagnosis with recessive inheritance.</p>
</sec>
<sec><title>Conclusions</title>
<p>We demonstrate that whole-exome sequencing is a powerful tool for the diagnostic evaluation of patients with highly heterogeneous neurodevelopmental disorders such as intellectual disability with microcephaly. Our results confirm that autosomal recessive disorders are highly prevalent among patients with microcephaly.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (doi:10.1186/s12920-016-0167-8) contains supplementary material, which is available to authorized users.</p>
</sec>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Woods, Cg" uniqKey="Woods C">CG Woods</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Prasad, An" uniqKey="Prasad A">AN Prasad</name>
</author>
<author><name sortKey="Bunzeluk, K" uniqKey="Bunzeluk K">K Bunzeluk</name>
</author>
<author><name sortKey="Prasad, C" uniqKey="Prasad C">C Prasad</name>
</author>
<author><name sortKey="Chodirker, Bn" uniqKey="Chodirker B">BN Chodirker</name>
</author>
<author><name sortKey="Magnus, Kg" uniqKey="Magnus K">KG Magnus</name>
</author>
<author><name sortKey="Greenberg, Cr" uniqKey="Greenberg C">CR Greenberg</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Piro, E" uniqKey="Piro E">E Piro</name>
</author>
<author><name sortKey="Antona, V" uniqKey="Antona V">V Antona</name>
</author>
<author><name sortKey="Consiglio, V" uniqKey="Consiglio V">V Consiglio</name>
</author>
<author><name sortKey="Ballacchino, A" uniqKey="Ballacchino A">A Ballacchino</name>
</author>
<author><name sortKey="Graziano, F" uniqKey="Graziano F">F Graziano</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Cooper, Gm" uniqKey="Cooper G">GM Cooper</name>
</author>
<author><name sortKey="Coe, Bp" uniqKey="Coe B">BP Coe</name>
</author>
<author><name sortKey="Girirajan, S" uniqKey="Girirajan S">S Girirajan</name>
</author>
<author><name sortKey="Rosenfeld, Ja" uniqKey="Rosenfeld J">JA Rosenfeld</name>
</author>
<author><name sortKey="Vu, Th" uniqKey="Vu T">TH Vu</name>
</author>
<author><name sortKey="Baker, C" uniqKey="Baker C">C Baker</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hagen, M" uniqKey="Hagen M">M Hagen</name>
</author>
<author><name sortKey="Pivarcsi, M" uniqKey="Pivarcsi M">M Pivarcsi</name>
</author>
<author><name sortKey="Liebe, J" uniqKey="Liebe J">J Liebe</name>
</author>
<author><name sortKey="Bernuth, H" uniqKey="Bernuth H">H Bernuth</name>
</author>
<author><name sortKey="Didonato, N" uniqKey="Didonato N">N Didonato</name>
</author>
<author><name sortKey="Hennermann, Jb" uniqKey="Hennermann J">JB Hennermann</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Alcantara, D" uniqKey="Alcantara D">D Alcantara</name>
</author>
<author><name sortKey="O Riscoll, M" uniqKey="O Riscoll M">M O’Driscoll</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Dixon Salazar, Tj" uniqKey="Dixon Salazar T">TJ Dixon-Salazar</name>
</author>
<author><name sortKey="Silhavy, Jl" uniqKey="Silhavy J">JL Silhavy</name>
</author>
<author><name sortKey="Udpa, N" uniqKey="Udpa N">N Udpa</name>
</author>
<author><name sortKey="Schroth, J" uniqKey="Schroth J">J Schroth</name>
</author>
<author><name sortKey="Bielas, S" uniqKey="Bielas S">S Bielas</name>
</author>
<author><name sortKey="Schaffer, Ae" uniqKey="Schaffer A">AE Schaffer</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Dyment, Da" uniqKey="Dyment D">DA Dyment</name>
</author>
<author><name sortKey="Sawyer, Sl" uniqKey="Sawyer S">SL Sawyer</name>
</author>
<author><name sortKey="Chardon, Jw" uniqKey="Chardon J">JW Chardon</name>
</author>
<author><name sortKey="Boycott, Km" uniqKey="Boycott K">KM Boycott</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rabbani, B" uniqKey="Rabbani B">B Rabbani</name>
</author>
<author><name sortKey="Mahdieh, N" uniqKey="Mahdieh N">N Mahdieh</name>
</author>
<author><name sortKey="Hosomichi, K" uniqKey="Hosomichi K">K Hosomichi</name>
</author>
<author><name sortKey="Nakaoka, H" uniqKey="Nakaoka H">H Nakaoka</name>
</author>
<author><name sortKey="Inoue, I" uniqKey="Inoue I">I Inoue</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Abecasis, G" uniqKey="Abecasis G">G Abecasis</name>
</author>
<author><name sortKey="Altshuler, D" uniqKey="Altshuler D">D Altshuler</name>
</author>
<author><name sortKey="Auton, A" uniqKey="Auton A">A Auton</name>
</author>
<author><name sortKey="Brooks, Ld" uniqKey="Brooks L">LD Brooks</name>
</author>
<author><name sortKey="Durbin Rm, Gra" uniqKey="Durbin Rm G">GRA Durbin RM</name>
</author>
<author><name sortKey="Hurles, Me" uniqKey="Hurles M">ME Hurles</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Li, H" uniqKey="Li H">H Li</name>
</author>
<author><name sortKey="Durbin, R" uniqKey="Durbin R">R Durbin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mckenna, A" uniqKey="Mckenna A">A McKenna</name>
</author>
<author><name sortKey="Hanna, M" uniqKey="Hanna M">M Hanna</name>
</author>
<author><name sortKey="Banks, E" uniqKey="Banks E">E Banks</name>
</author>
<author><name sortKey="Sivachenko, A" uniqKey="Sivachenko A">A Sivachenko</name>
</author>
<author><name sortKey="Cibulskis, K" uniqKey="Cibulskis K">K Cibulskis</name>
</author>
<author><name sortKey="Kernytsky, A" uniqKey="Kernytsky A">A Kernytsky</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Ye, K" uniqKey="Ye K">K Ye</name>
</author>
<author><name sortKey="Schulz, Mh" uniqKey="Schulz M">MH Schulz</name>
</author>
<author><name sortKey="Long, Q" uniqKey="Long Q">Q Long</name>
</author>
<author><name sortKey="Apweiler, R" uniqKey="Apweiler R">R Apweiler</name>
</author>
<author><name sortKey="Ning, Z" uniqKey="Ning Z">Z Ning</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Cingolani, P" uniqKey="Cingolani P">P Cingolani</name>
</author>
<author><name sortKey="Platts, A" uniqKey="Platts A">A Platts</name>
</author>
<author><name sortKey="Wang, L" uniqKey="Wang L">L Wang</name>
</author>
<author><name sortKey="Coon, M" uniqKey="Coon M">M Coon</name>
</author>
<author><name sortKey="Nguyen, T" uniqKey="Nguyen T">T Nguyen</name>
</author>
<author><name sortKey="Wang, L" uniqKey="Wang L">L Wang</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Byelas, H" uniqKey="Byelas H">H Byelas</name>
</author>
<author><name sortKey="Dijkstra, M" uniqKey="Dijkstra M">M Dijkstra</name>
</author>
<author><name sortKey="Neerincx, Pb" uniqKey="Neerincx P">PB Neerincx</name>
</author>
<author><name sortKey="Van Dijk, F" uniqKey="Van Dijk F">F Van Dijk</name>
</author>
<author><name sortKey="Kanterakis, A" uniqKey="Kanterakis A">A Kanterakis</name>
</author>
<author><name sortKey="Deelen, P" uniqKey="Deelen P">P Deelen</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Francioli, Lc" uniqKey="Francioli L">LC Francioli</name>
</author>
<author><name sortKey="Menelaou, A" uniqKey="Menelaou A">A Menelaou</name>
</author>
<author><name sortKey="Pulit, Sl" uniqKey="Pulit S">SL Pulit</name>
</author>
<author><name sortKey="Van Dijk, F" uniqKey="Van Dijk F">F van Dijk</name>
</author>
<author><name sortKey="Palamara, Pf" uniqKey="Palamara P">PF Palamara</name>
</author>
<author><name sortKey="Elbers, Cc" uniqKey="Elbers C">CC Elbers</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct></biblStruct>
<biblStruct></biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Crow, Yj" uniqKey="Crow Y">YJ Crow</name>
</author>
<author><name sortKey="Leitch, A" uniqKey="Leitch A">A Leitch</name>
</author>
<author><name sortKey="Hayward, Be" uniqKey="Hayward B">BE Hayward</name>
</author>
<author><name sortKey="Garner, A" uniqKey="Garner A">A Garner</name>
</author>
<author><name sortKey="Parmar, R" uniqKey="Parmar R">R Parmar</name>
</author>
<author><name sortKey="Griffith, E" uniqKey="Griffith E">E Griffith</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Passemard, S" uniqKey="Passemard S">S Passemard</name>
</author>
<author><name sortKey="Titomanlio, L" uniqKey="Titomanlio L">L Titomanlio</name>
</author>
<author><name sortKey="Elmaleh, M" uniqKey="Elmaleh M">M Elmaleh</name>
</author>
<author><name sortKey="Afenjar, A" uniqKey="Afenjar A">A Afenjar</name>
</author>
<author><name sortKey="Alessandri, J L" uniqKey="Alessandri J">J-L Alessandri</name>
</author>
<author><name sortKey="Andria, G" uniqKey="Andria G">G Andria</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Aligianis, Ia" uniqKey="Aligianis I">IA Aligianis</name>
</author>
<author><name sortKey="Johnson, Ca" uniqKey="Johnson C">CA Johnson</name>
</author>
<author><name sortKey="Gissen, P" uniqKey="Gissen P">P Gissen</name>
</author>
<author><name sortKey="Chen, D" uniqKey="Chen D">D Chen</name>
</author>
<author><name sortKey="Hampshire, D" uniqKey="Hampshire D">D Hampshire</name>
</author>
<author><name sortKey="Hoffmann, K" uniqKey="Hoffmann K">K Hoffmann</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Alter, Bp" uniqKey="Alter B">BP Alter</name>
</author>
<author><name sortKey="Rosenberg, Ps" uniqKey="Rosenberg P">PS Rosenberg</name>
</author>
<author><name sortKey="Brody, Lc" uniqKey="Brody L">LC Brody</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Yang, Y" uniqKey="Yang Y">Y Yang</name>
</author>
<author><name sortKey="Muzny, Dm" uniqKey="Muzny D">DM Muzny</name>
</author>
<author><name sortKey="Reid, Jg" uniqKey="Reid J">JG Reid</name>
</author>
<author><name sortKey="Bainbridge, Mn" uniqKey="Bainbridge M">MN Bainbridge</name>
</author>
<author><name sortKey="Willis, A" uniqKey="Willis A">A Willis</name>
</author>
<author><name sortKey="Ward, Pa" uniqKey="Ward P">PA Ward</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Neveling, K" uniqKey="Neveling K">K Neveling</name>
</author>
<author><name sortKey="Feenstra, I" uniqKey="Feenstra I">I Feenstra</name>
</author>
<author><name sortKey="Gilissen, C" uniqKey="Gilissen C">C Gilissen</name>
</author>
<author><name sortKey="Hoefsloot, Lh" uniqKey="Hoefsloot L">LH Hoefsloot</name>
</author>
<author><name sortKey="Kamsteeg, E J" uniqKey="Kamsteeg E">E-J Kamsteeg</name>
</author>
<author><name sortKey="Mensenkamp, Ar" uniqKey="Mensenkamp A">AR Mensenkamp</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fahiminiya, S" uniqKey="Fahiminiya S">S Fahiminiya</name>
</author>
<author><name sortKey="Almuriekhi, M" uniqKey="Almuriekhi M">M Almuriekhi</name>
</author>
<author><name sortKey="Nawaz, Z" uniqKey="Nawaz Z">Z Nawaz</name>
</author>
<author><name sortKey="Staffa, A" uniqKey="Staffa A">A Staffa</name>
</author>
<author><name sortKey="Lepage, P" uniqKey="Lepage P">P Lepage</name>
</author>
<author><name sortKey="Ali, R" uniqKey="Ali R">R Ali</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Nicholas, Ak" uniqKey="Nicholas A">AK Nicholas</name>
</author>
<author><name sortKey="Swanson, Ea" uniqKey="Swanson E">EA Swanson</name>
</author>
<author><name sortKey="Cox, Jj" uniqKey="Cox J">JJ Cox</name>
</author>
<author><name sortKey="Karbani, G" uniqKey="Karbani G">G Karbani</name>
</author>
<author><name sortKey="Malik, S" uniqKey="Malik S">S Malik</name>
</author>
<author><name sortKey="Springell, K" uniqKey="Springell K">K Springell</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ostergaard, P" uniqKey="Ostergaard P">P Ostergaard</name>
</author>
<author><name sortKey="Simpson, Ma" uniqKey="Simpson M">MA Simpson</name>
</author>
<author><name sortKey="Mendola, A" uniqKey="Mendola A">A Mendola</name>
</author>
<author><name sortKey="Vasudevan, P" uniqKey="Vasudevan P">P Vasudevan</name>
</author>
<author><name sortKey="Connell, Fc" uniqKey="Connell F">FC Connell</name>
</author>
<author><name sortKey="Van Impel, A" uniqKey="Van Impel A">A van Impel</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kheradmand Kia, S" uniqKey="Kheradmand Kia S">S Kheradmand Kia</name>
</author>
<author><name sortKey="Verbeek, E" uniqKey="Verbeek E">E Verbeek</name>
</author>
<author><name sortKey="Engelen, E" uniqKey="Engelen E">E Engelen</name>
</author>
<author><name sortKey="Schot, R" uniqKey="Schot R">R Schot</name>
</author>
<author><name sortKey="Poot, Ra" uniqKey="Poot R">RA Poot</name>
</author>
<author><name sortKey="De Coo, If" uniqKey="De Coo I">IF de Coo</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Barkovich, Aj" uniqKey="Barkovich A">AJ Barkovich</name>
</author>
<author><name sortKey="Guerrini, R" uniqKey="Guerrini R">R Guerrini</name>
</author>
<author><name sortKey="Kuzniecky, Ri" uniqKey="Kuzniecky R">RI Kuzniecky</name>
</author>
<author><name sortKey="Jackson, Gd" uniqKey="Jackson G">GD Jackson</name>
</author>
<author><name sortKey="Dobyns, Wb" uniqKey="Dobyns W">WB Dobyns</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Laugel, V" uniqKey="Laugel V">V Laugel</name>
</author>
<author><name sortKey="Dalloz, C" uniqKey="Dalloz C">C Dalloz</name>
</author>
<author><name sortKey="Durand, M" uniqKey="Durand M">M Durand</name>
</author>
<author><name sortKey="Sauvanaud, F" uniqKey="Sauvanaud F">F Sauvanaud</name>
</author>
<author><name sortKey="Kristensen, U" uniqKey="Kristensen U">U Kristensen</name>
</author>
<author><name sortKey="Vincent, M C" uniqKey="Vincent M">M-C Vincent</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Najm, J" uniqKey="Najm J">J Najm</name>
</author>
<author><name sortKey="Horn, D" uniqKey="Horn D">D Horn</name>
</author>
<author><name sortKey="Wimplinger, I" uniqKey="Wimplinger I">I Wimplinger</name>
</author>
<author><name sortKey="Golden, Ja" uniqKey="Golden J">JA Golden</name>
</author>
<author><name sortKey="Chizhikov, Vv" uniqKey="Chizhikov V">VV Chizhikov</name>
</author>
<author><name sortKey="Sudi, J" uniqKey="Sudi J">J Sudi</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hackett, A" uniqKey="Hackett A">A Hackett</name>
</author>
<author><name sortKey="Tarpey, Ps" uniqKey="Tarpey P">PS Tarpey</name>
</author>
<author><name sortKey="Licata, A" uniqKey="Licata A">A Licata</name>
</author>
<author><name sortKey="Cox, J" uniqKey="Cox J">J Cox</name>
</author>
<author><name sortKey="Whibley, A" uniqKey="Whibley A">A Whibley</name>
</author>
<author><name sortKey="Boyle, J" uniqKey="Boyle J">J Boyle</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Moog, U" uniqKey="Moog U">U Moog</name>
</author>
<author><name sortKey="Kutsche, K" uniqKey="Kutsche K">K Kutsche</name>
</author>
<author><name sortKey="Kortum, F" uniqKey="Kortum F">F Kortüm</name>
</author>
<author><name sortKey="Chilian, B" uniqKey="Chilian B">B Chilian</name>
</author>
<author><name sortKey="Bierhals, T" uniqKey="Bierhals T">T Bierhals</name>
</author>
<author><name sortKey="Apeshiotis, N" uniqKey="Apeshiotis N">N Apeshiotis</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="O Oak, Bj" uniqKey="O Oak B">BJ O’Roak</name>
</author>
<author><name sortKey="Vives, L" uniqKey="Vives L">L Vives</name>
</author>
<author><name sortKey="Fu, W" uniqKey="Fu W">W Fu</name>
</author>
<author><name sortKey="Egertson, Jd" uniqKey="Egertson J">JD Egertson</name>
</author>
<author><name sortKey="Stanaway, Ib" uniqKey="Stanaway I">IB Stanaway</name>
</author>
<author><name sortKey="Phelps, Ig" uniqKey="Phelps I">IG Phelps</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Van Bon, B" uniqKey="Van Bon B">B Van Bon</name>
</author>
<author><name sortKey="Hoischen, A" uniqKey="Hoischen A">A Hoischen</name>
</author>
<author><name sortKey="Hehir Kwa, J" uniqKey="Hehir Kwa J">J Hehir-Kwa</name>
</author>
<author><name sortKey="De Brouwer, A" uniqKey="De Brouwer A">A de Brouwer</name>
</author>
<author><name sortKey="Ruivenkamp, C" uniqKey="Ruivenkamp C">C Ruivenkamp</name>
</author>
<author><name sortKey="Gijsbers, A" uniqKey="Gijsbers A">A Gijsbers</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Howlett, Ng" uniqKey="Howlett N">NG Howlett</name>
</author>
<author><name sortKey="Taniguchi, T" uniqKey="Taniguchi T">T Taniguchi</name>
</author>
<author><name sortKey="Olson, S" uniqKey="Olson S">S Olson</name>
</author>
<author><name sortKey="Cox, B" uniqKey="Cox B">B Cox</name>
</author>
<author><name sortKey="Waisfisz, Q" uniqKey="Waisfisz Q">Q Waisfisz</name>
</author>
<author><name sortKey="De Die Smulders, C" uniqKey="De Die Smulders C">C de Die-Smulders</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Tea, M Km" uniqKey="Tea M">M-KM Tea</name>
</author>
<author><name sortKey="Kroiss, R" uniqKey="Kroiss R">R Kroiss</name>
</author>
<author><name sortKey="Muhr, D" uniqKey="Muhr D">D Muhr</name>
</author>
<author><name sortKey="Fuerhauser Rappaport, C" uniqKey="Fuerhauser Rappaport C">C Fuerhauser-Rappaport</name>
</author>
<author><name sortKey="Oefner, P" uniqKey="Oefner P">P Oefner</name>
</author>
<author><name sortKey="Wagner, Tm" uniqKey="Wagner T">TM Wagner</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Firth, Hv" uniqKey="Firth H">HV Firth</name>
</author>
<author><name sortKey="Hurst, Ja" uniqKey="Hurst J">JA Hurst</name>
</author>
<author><name sortKey="Hall, Jg" uniqKey="Hall J">JG Hall</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Veltman, Ja" uniqKey="Veltman J">JA Veltman</name>
</author>
<author><name sortKey="Brunner, Hg" uniqKey="Brunner H">HG Brunner</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="De Ligt, J" uniqKey="De Ligt J">J De Ligt</name>
</author>
<author><name sortKey="Willemsen, Mh" uniqKey="Willemsen M">MH Willemsen</name>
</author>
<author><name sortKey="Van Bon, Bw" uniqKey="Van Bon B">BW van Bon</name>
</author>
<author><name sortKey="Kleefstra, T" uniqKey="Kleefstra T">T Kleefstra</name>
</author>
<author><name sortKey="Yntema, Hg" uniqKey="Yntema H">HG Yntema</name>
</author>
<author><name sortKey="Kroes, T" uniqKey="Kroes T">T Kroes</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">BMC Med Genomics</journal-id>
<journal-id journal-id-type="iso-abbrev">BMC Med Genomics</journal-id>
<journal-title-group><journal-title>BMC Medical Genomics</journal-title>
</journal-title-group>
<issn pub-type="epub">1755-8794</issn>
<publisher><publisher-name>BioMed Central</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26846091</article-id>
<article-id pub-id-type="pmc">4743197</article-id>
<article-id pub-id-type="publisher-id">167</article-id>
<article-id pub-id-type="doi">10.1186/s12920-016-0167-8</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Rump</surname>
<given-names>Patrick</given-names>
</name>
<address><email>p.rump@umcg.nl</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jazayeri</surname>
<given-names>Omid</given-names>
</name>
<address><email>o.jazayeri@umcg.nl</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>van Dijk-Bos</surname>
<given-names>Krista K.</given-names>
</name>
<address><email>k.k.dijk@umcg.nl</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Johansson</surname>
<given-names>Lennart F.</given-names>
</name>
<address><email>l.johansson@umcg.nl</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>van Essen</surname>
<given-names>Anthonie J.</given-names>
</name>
<address><email>a.j.van.essen@umcg.nl</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Verheij</surname>
<given-names>Johanna B. G. M.</given-names>
</name>
<address><email>j.b.g.m.verheij@umcg.nl</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Veenstra-Knol</surname>
<given-names>Hermine E.</given-names>
</name>
<address><email>h.e.veenstra-knol@umcg.nl</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Redeker</surname>
<given-names>Egbert J. W.</given-names>
</name>
<address><email>e.j.w.redeker@amc.uva.nl</email>
</address>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mannens</surname>
<given-names>Marcel M. A. M.</given-names>
</name>
<address><email>m.a.mannens@amc.uva.nl</email>
</address>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Swertz</surname>
<given-names>Morris A.</given-names>
</name>
<address><email>m.a.swertz@gmail.com</email>
</address>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alizadeh</surname>
<given-names>Behrooz Z.</given-names>
</name>
<address><email>b.z.alizadeh@umcg.nl</email>
</address>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>van Ravenswaaij-Arts</surname>
<given-names>Conny M. A.</given-names>
</name>
<address><email>c.m.a.van.ravenswaaij@umcg.nl</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sinke</surname>
<given-names>Richard J.</given-names>
</name>
<address><email>r.j.sinke@umcg.nl</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Sikkema-Raddatz</surname>
<given-names>Birgit</given-names>
</name>
<address><phone>+31-50-3617229</phone>
<email>b.sikkema01@umcg.nl</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<aff id="Aff1"><label>1</label>
Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands</aff>
<aff id="Aff2"><label>2</label>
Department of Clinical Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands</aff>
<aff id="Aff3"><label>3</label>
Department of Genetics, University of Groningen, University Medical Centre Groningen, Genomics Coordination Centre, Groningen, The Netherlands</aff>
<aff id="Aff4"><label>4</label>
Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands</aff>
</contrib-group>
<pub-date pub-type="epub"><day>4</day>
<month>2</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>4</day>
<month>2</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="collection"><year>2016</year>
</pub-date>
<volume>9</volume>
<elocation-id>7</elocation-id>
<history><date date-type="received"><day>10</day>
<month>7</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>25</day>
<month>1</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>© Rump et al. 2016</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>
) applies to the data made available in this article, unless otherwise stated.</license-p>
</license>
</permissions>
<abstract id="Abs1"><sec><title>Background</title>
<p>Clinical and genetic heterogeneity in monogenetic disorders represents a major diagnostic challenge. Although the presence of particular clinical features may aid in identifying a specific cause in some cases, the majority of patients remain undiagnosed.</p>
<p>Here, we investigated the utility of whole-exome sequencing as a diagnostic approach for establishing a molecular diagnosis in a highly heterogeneous group of patients with varied intellectual disability and microcephaly.</p>
</sec>
<sec><title>Methods</title>
<p>Whole-exome sequencing was performed in 38 patients, including three sib-pairs, in addition to or in parallel with genetic analyses that were performed during the diagnostic work-up of the study participants.</p>
</sec>
<sec><title>Results</title>
<p>In ten out of these 35 families (29 %), we found mutations in genes already known to be related to a disorder in which microcephaly is a main feature. Two unrelated patients had mutations in the <italic>ASPM</italic>
gene. In seven other patients we found mutations in <italic>RAB3GAP1</italic>
, <italic>RNASEH2B, KIF11</italic>
, <italic>ERCC8</italic>
, <italic>CASK</italic>
, <italic>DYRK1A</italic>
and <italic>BRCA2</italic>
. In one of the sib-pairs, mutations were found in the <italic>RTTN</italic>
gene. Mutations were present in seven out of our ten families with an established etiological diagnosis with recessive inheritance.</p>
</sec>
<sec><title>Conclusions</title>
<p>We demonstrate that whole-exome sequencing is a powerful tool for the diagnostic evaluation of patients with highly heterogeneous neurodevelopmental disorders such as intellectual disability with microcephaly. Our results confirm that autosomal recessive disorders are highly prevalent among patients with microcephaly.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (doi:10.1186/s12920-016-0167-8) contains supplementary material, which is available to authorized users.</p>
</sec>
</abstract>
<kwd-group xml:lang="en"><title>Keywords</title>
<kwd>Autosomal recessive inheritance</kwd>
<kwd><italic>ASPM</italic>
</kwd>
<kwd><italic>BRCA2</italic>
</kwd>
<kwd><italic>CASK</italic>
</kwd>
<kwd><italic>DYRK1A</italic>
</kwd>
<kwd><italic>ERCC8</italic>
</kwd>
<kwd><italic>KIF11</italic>
</kwd>
<kwd>Microcephaly</kwd>
<kwd><italic>RAB3GAP1 RNASEH2B</italic>
</kwd>
<kwd><italic>RTTN</italic>
</kwd>
<kwd>Whole-exome sequencing</kwd>
</kwd-group>
<funding-group><award-group><funding-source><institution>grant from the University Medical Centre Groningen (Doelmatigheidsfonds).</institution>
</funding-source>
</award-group>
</funding-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2016</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/LymphedemaV1/Data/Pmc/Curation
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000C65 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Curation/biblio.hfd -nk 000C65 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Sante |area= LymphedemaV1 |flux= Pmc |étape= Curation |type= RBID |clé= PMC:4743197 |texte= Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Curation/RBID.i -Sk "pubmed:26846091" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Curation/biblio.hfd \ | NlmPubMed2Wicri -a LymphedemaV1
This area was generated with Dilib version V0.6.31. |