Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate

Wu-Lin Charng , Ender Karaca , Zeynep Coban Akdemir , Tomasz Gambin , Mehmed M. Atik , Shen Gu , Jennifer E. Posey , Shalini N. Jhangiani , Donna M. Muzny , Harsha Doddapaneni , Jianhong Hu , Eric Boerwinkle , Richard A. Gibbs , Jill A. Rosenfeld , Hong Cui , Fan Xia , Kandamurugu Manickam , Yaping Yang , Eissa A. Faqeih , Ali Al Asmari , Mohammed A. M. Saleh , Ayman W. El-Hattab , James R. Lupski


Background Neurodevelopment is orchestrated by a wide range of genes, and the genetic causes of neurodevelopmental disorders are thus heterogeneous. We applied whole exome sequencing (WES) for molecular diagnosis and in silico analysis to identify novel disease gene candidates in a cohort from Saudi Arabia with primarily Mendelian neurologic diseases. Methods We performed WES in 31 mostly consanguineous Arab families and analyzed both single nucleotide and copy number variants (CNVs) from WES data. Interaction/expression network and pathway analyses, as well as paralog studies were utilized to investigate potential pathogenicity and disease association of novel candidate genes. Additional cases for candidate genes were identified through the clinical WES database at Baylor Miraca Genetics Laboratories and GeneMatcher. Results We found known pathogenic or novel variants in known disease genes with phenotypic expansion in 6 families, disease-associated CNVs in 2 families, and 12 novel disease gene candidates in 11 families, including KIF5B, GRM7, FOXP4, MLLT1, and KDM2B. Overall, a potential molecular diagnosis was provided by variants in known disease genes in 17 families (54.8 %) and by novel candidate disease genes in an additional 11 families, making the potential molecular diagnostic rate ~90 %. Conclusions Molecular diagnostic rate from WES is improved by exome-predicted CNVs. Novel candidate disease gene discovery is facilitated by paralog studies and through the use of informatics tools and available databases to identify additional evidence for pathogenicity.
Author Wu-Lin Charng
Wu-Lin Charng,,
, Ender Karaca
Ender Karaca,,
, Zeynep Coban Akdemir
Zeynep Coban Akdemir,,
, Tomasz Gambin II - [Department of Molecular and Human Genetics (DMHG) [Baylor College of Medicine (BCM)]]
Tomasz Gambin,,
- The Institute of Computer Science
- Department of Molecular and Human Genetics
, Mehmed M. Atik
Mehmed M. Atik,,
, Shen Gu
Shen Gu,,
, Jennifer E. Posey
Jennifer E. Posey,,
, Shalini N. Jhangiani
Shalini N. Jhangiani,,
, Donna M. Muzny
Donna M. Muzny,,
, Harsha Doddapaneni
Harsha Doddapaneni,,
et al.`
Journal seriesBMC Medical Genomics, ISSN 1755-8794
Issue year2016
Publication size in sheets0.65
Keywords in EnglishWhole exome sequencing (WES) – Copy Number Variants (CNV) – Neurodevelopment – Developmental Delay/Intellectual Disability (DD/ID) – GRM7
URL https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-016-0208-3
Languageen angielski
LicenseJournal (articles only); author's original; Uznanie Autorstwa (CC-BY); after publication
Score (nominal)35
ScoreMinisterial score = 30.0, 27-03-2017, ArticleFromJournal
Ministerial score (2013-2016) = 35.0, 27-03-2017, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 2.848 (2) - 2016=3.238 (5)
Citation count*15 (2018-07-20)
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