Revisiting disease genes based on whole-exome sequencing in consanguineous populations

Abstract

Assigning a causal role for genes in disease states is one of the most significant medical applications of human genetics research. The requirement for at least two different pathogenic alleles in the same gene in individuals with a similar phenotype to assign a causal link has not always been fully adhered to, and we now know that even two alleles may not necessarily constitute sufficient evidence. Autozygosity is a rich source of natural "knockout" events by virtue of rendering ancestral loss-of-function (LOF) variants homozygous. In this study, we exploit this phenomenon by examining 523 exomes enriched for autozygosity to call into question previously published disease links for several genes based on the identification of confirmed homozygous LOF variants in the absence of the purported diseases. This study highlights an additional advantage of consanguineous populations in the quest to improve the medical annotation of the human genome.

Confirming the candidacy ofTHOC6in the etiology of intellectual disability

“…Highly consanguineous populations provide a rich source of homozygous alleles that can both support and challenge previously reported disease links, as we have shown for a number of genes [Alazami et al, ; Alkuraya et al, ; Shamia et al, ]. A report in 2013 has proposed that THOC6 is a morbid gene based on a single missense mutation in patients who displayed developmental delay and intellectual disability [Beaulieu et al, ].…”

Revisiting the morbid genome of Mendelian disorders

“…However, we show in this study that our population can also improve the specificity of the morbid genome map of human Mendelian diseases [19]. Not only do we demonstrate that many variants in question represent Arab-enriched variants, but we also take advantage of autozygosity to show that their presence in homozygosity does not lead to the reported phenotype, thus establishing two key lines of evidence in support of their likely benign nature.…”

Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

“…Intellectual disability (ID), the most common clinical presentation, is a serious neurodevelopmental disorder characterized by significant limitations in intellectual functioning and adaptive behavior, having an age of onset before 18 (reviewed by Schalock and Luckasson 2015). ID is relatively common with a prevalence that can reach 3.6 % (Delobel-Ayoub et al 2015) with a higher frequency expected in inbred populations (Shamia et al 2015;Iqbal and van Bokhoven 2014). The advances in Intellectual Disability gene discovery have identified many causative genes, but about half of cases do not have a known etiology (Ellison et al 2013).…”