Whole exome sequencing of Saudi Hydrocephalus

Hydrocephalus is a highly heterogeneous multifactorial disease that arises from genetic and environmental factors. Familial genetic studies of hydrocephalus have elucidated four robustly associated Hydrocephalus associated loci. This study aims to identify potential genetic causation in up to 48 Saudi Arabian families with 51 cases of Hydrocephalus, with or without Spina Bifida and DWS, using family-based rare variant association analysis of whole exome sequencing. Accordingly, we performed whole exome sequencing in 143 individuals across 48 families where at least one offspring was affected with Hydrocephalus (n=27), with hydrocephalus with Spina Bifida (n= 21) and with Dandy Walker Syndrome (n=3) also evident in 24 of the cases. No pathogenic or putative pathogenic single-nucleotide variants were evident in the four known Hydrocephalus loci in our subjects. However, after examining 73 known Hydrocephalus genes previously identified from literature and identified 3 potentially impactful variants from the cohort. Using a gene panel comprising variants in known Neural tube defects loci, we identified a total of 1,024 potentially deleterious variants, of which 797 were missense variants and 191 were frameshift variants, 36 were stop gain/loss variants. A small portion of our family pedigree analyses yielded putative genetic signals which may be responsible for Hydrocephaly elated phenotypes, however the low diagnostic yield may be due to lack of capture of genetic variants in the exonic regions i.e. structural variants may only be evident from whole genome sequencing, or the etiology in some of the cases may be due to non-genetic factors.