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

TitleExome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate.
Publication TypeJournal Article
Year of Publication2016
AuthorsCharng, W-L, Karaca, E, Akdemir, ZCoban, Gambin, T, Atik, MM, Gu, S, Posey, JE, Jhangiani, SN, Muzny, DM, Doddapaneni, H, Hu, J, Boerwinkle, E, Gibbs, RA, Rosenfeld, JA, Cui, H, Xia, F, Manickam, K, Yang, Y, Faqeih, EA, Asmari, AAl, Saleh, MAM, El-Hattab, AW, Lupski, JR
JournalBMC Med Genomics
Volume9
Issue1
Pagination42
Date Published2016 07 19
ISSN1755-8794
KeywordsArabs, Cohort Studies, Consanguinity, Data Mining, Databases, Genetic, DNA Copy Number Variations, Exome, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Molecular Diagnostic Techniques, Nervous System Diseases, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Sequence Analysis, DNA
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 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.

TRIAL REGISTRATION: Not applicable.

DOI10.1186/s12920-016-0208-3
Alternate JournalBMC Med Genomics
PubMed ID27435318
PubMed Central IDPMC4950750
Grant ListR01 NS058529 / NS / NINDS NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States