Abstract
BackgroundNeurodevelopment 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.MethodsWe 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.ResultsWe 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 %.ConclusionsMolecular 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 registrationNot applicable.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-016-0208-3) contains supplementary material, which is available to authorized users.
Highlights
Neurodevelopment is orchestrated by a wide range of genes, and the genetic causes of neurodevelopmental disorders are heterogeneous
The cohort was further clinically assigned into phenotypic subgroups including syndromic brain malformation, corpus callosum abnormalities, cortical dysgenesis, microcephaly, hindbrain malformation, white matter abnormalities, as well as syndromic and non-syndromic Delay/Intellectual Disability (DD/ID) (Fig. 1b and Additional file 1: Table S2)
Among the 31 cases, we found compound heterozygous variant alleles consisting of a SNV and a Copy Number Variants (CNV) in a novel candidate gene RPS6KC1 (Figure 2 and Additional file 1: Table S1) as well as a homozygous intragenic deletion in GRID2 (Additional file 2: Figure S3)
Summary
Neurodevelopment is orchestrated by a wide range of genes, and the genetic causes of neurodevelopmental disorders are heterogeneous. Neurodevelopmental disorders reflect the biology and underlying complexity of nervous system developmental processes, its constituent cellular and anatomical structure, and neurophysiological functions. The study of developmental brain disorders is further challenged by the high degree of genetic heterogeneity observed, even within clinically well-defined disorders, such as pontocerebellar hypoplasia [4]. These observations underscore both the necessity for and power of comprehensive molecular studies in this field [5]. The study of Mendelian phenotypes, including neurodevelopmental disorders, provides perhaps the most direct route to identify the link between gene function and resultant phenotype, and a foundation for investigating the underlying biology [7]
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