Exome sequencing utility in defining the genetic landscape of hearing loss and novel-gene discovery in Iran

Hearing loss (HL) is one of the most common sensory defects affecting more than 466 million individuals worldwide. It is clinically and genetically heterogeneous with over 120 genes causing non-syndromic HL identified to date. Here, we performed exome sequencing (ES) on a cohort of Iranian families with no disease-causing variants in known deafness-associated genes after screening with a targeted gene panel. We identified likely causal variants in 20 out of 71 families screened. Fifteen families segregated variants in known deafness-associated genes. Eight families segregated variants in novel candidate genes for HL: DBH, TOP3A, COX18, USP31, TCF19, SCP2, TENM1, and CARMIL1. In the three of these families, intrafamilial locus heterogeneity was observed with variants in both known and novel candidate genes. In aggregate, we were able to identify the underlying genetic cause of HL in nearly 30 of our study cohort using ES. This study corroborates the observation that high-throughput DNA sequencing in populations with high rates of consanguineous marriages represents a more appropriate strategy to elucidate the genetic etiology of heterogeneous conditions such as HL. © 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Lt

Effect of inbreeding on intellectual disability revisited by trio sequencing

In outbred Western populations, most individuals with intellectual disability (ID) are sporadic cases, dominant de novo mutations (DNM) are frequent, and autosomal recessive ID (ARID) is very rare. Due to the high rate of parental consanguinity which raises the risk for ARID and other recessive disorders, the prevalence of ID is significantly higher in Near- and Middle-East countries. Indeed, homozygosity mapping and sequencing in consanguineous families have already identified a plethora of ARID genes, but due to the design of these studies, DNMs could not be systematically assessed, and the proportion of cases that are potentially preventable by avoiding consanguineous marriages or through carrier testing is hitherto unknown. This prompted us to perform whole exome sequencing in 100 sporadic ID patients from Iran and their healthy consanguineous parents. In 61 patients, we identified apparently causative changes in known ID genes. Of these, 44 were homozygous recessive and 17 dominant de novo mutations. Assuming that the DNM rate is stable, these results suggest that parental consanguinity raises the ID risk about 3.6-fold, and about 4.1-4.25-fold for children of first-cousin unions. These results do not rhyme with recent opinions that consanguinity-related health risks are generally small and have been 'overstated' in the past. This article is protected by copyright. All rights reserved