Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Charng, Wu-Lin; Karaca, Ender; Coban Akdemir, Zeynep; Gambin, Tomasz; Atik, Mehmed; Gu, Shen; Posey, Jennifer; Jhangiani, Shalini; Muzny, Donna; Doddapaneni, Harsha; Hu, Jianhong; Boerwinkle, Eric; Gibbs, Richard; Rosenfeld, Jill; Cui, Hong; Xia, Fan; Manickam, Kandamurugu; Yang, Yaping; Faqeih, Eissa; Al Asmari, Ali; Saleh, Mohammed; El-Hattab, Ayman; Lupski, James
• Is Part Of: BMC medical genomics. Volume 9:Issue 1(2016)
• Page Start: 1
• Page End: 14
• Publication Date: 2016-12
• Subjects: Whole exome sequencing (WES) -- Copy Number Variants (CNV) -- Neurodevelopment -- Developmental Delay/Intellectual Disability (DD/ID) -- GRM7; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1186/s12920-016-0208-3
• Languages: English
• ISSNs: 1755-8794

Abstract

Abstract 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 andin 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, includingKIF5B, GRM7, FOXP4, MLLT1, andKDM2B . 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. Trial registration Not applicable.