Dataset Information

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

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.

SUBMITTER: Charng WL

PROVIDER: S-EPMC4950750 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Charng Wu-Lin WL Karaca Ender E Coban Akdemir Zeynep Z Gambin Tomasz T Atik Mehmed M MM Gu Shen S Posey Jennifer E JE Jhangiani Shalini N SN Muzny Donna M DM Doddapaneni Harsha H Hu Jianhong J Boerwinkle Eric E Gibbs Richard A RA Rosenfeld Jill A JA Cui Hong H Xia Fan F Manickam Kandamurugu K Yang Yaping Y Faqeih Eissa A EA Al Asmari Ali A Saleh Mohammed A M MA El-Hattab Ayman W AW Lupski James R JR

BMC medical genomics 20160719 1

<h4>Background</h4>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.<h4>Methods</h4>We performed WES in 31 mostly consanguineous Arab families and analyzed both single nucleotide and copy number variants (CN ...[more]

PMID: 27435318

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Project description:Consanguineous marriages have a prevalence rate of 24% in Turkey. These carry an increased risk of autosomal recessive genetic conditions, leading to severe disability or premature death, with a significant health and economic burden. A definitive molecular diagnosis could not be achieved in these children previously, as infrastructures and access to sophisticated diagnostic options were limited. We studied the cause of neurogenetic disease in 246 children from 190 consanguineous families recruited in three Turkish hospitals between 2016 and 2020. All patients underwent deep phenotyping and trio whole exome sequencing, and data were integrated in advanced international bioinformatics platforms. We detected causative variants in 119 known disease genes in 72% of families. Due to overlapping phenotypes 52% of the confirmed genetic diagnoses would have been missed on targeted diagnostic gene panels. Likely pathogenic variants in 27 novel genes in 14% of the families increased the diagnostic yield to 86%. Eighty-two per cent of causative variants (141/172) were homozygous, 11 of which were detected in genes previously only associated with autosomal dominant inheritance. Eight families carried two pathogenic variants in different disease genes. De novo (9.3%), X-linked recessive (5.2%) and compound heterozygous (3.5%) variants were less frequent compared to non-consanguineous populations. This cohort provided a unique opportunity to better understand the genetic characteristics of neurogenetic diseases in a consanguineous population. Contrary to what may be expected, causative variants were often not on the longest run of homozygosity and the diagnostic yield was lower in families with the highest degree of consanguinity, due to the high number of homozygous variants in these patients. Pathway analysis highlighted that protein synthesis/degradation defects and metabolic diseases are the most common pathways underlying paediatric neurogenetic disease. In our cohort 164 families (86%) received a diagnosis, enabling prevention of transmission and targeted treatments in 24 patients (10%). We generated an important body of genomic data with lasting impacts on the health and wellbeing of consanguineous families and economic benefit for the healthcare system in Turkey and elsewhere. We demonstrate that an untargeted next generation sequencing approach is far superior to a more targeted gene panel approach, and can be performed without specialized bioinformatics knowledge by clinicians using established pipelines in populations with high rates of consanguinity.

Dataset Information

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

Background

Methods

Results

Conclusions

Trial registration

Publications

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

Similar Datasets

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