Whole exome sequencing reveals pathogenic variants inMYO3A,MYO15AandCOL9A3and differential frequencies in ancestral alleles in hearing impairment genes among individuals from Cameroon

Abstract

There is scarcity of known gene variants of Hearing Impairment (HI) in African populations. This knowledge deficit is ultimately affecting the development of genetic diagnoses. We used whole exome sequencing to investigate gene variants, pathways of interactive genes, and the fractions of ancestral over derived alleles for 159 HI genes, among 18 Cameroonian patients with non-syndromic HI (NSHI), and 129 ethnically matched controls. Pathogenic and likely pathogenic (PLP) variants were found in MYO3A, MYO15A and COL9A3, with a resolution rate of 50% (9/18 patients). The study identified significant genetic differentiation in novel population specific gene variants at FOXD4L2, DHRS2L6, RPL3L and VTN, between HI patients and controls. These gene variants are found in functional/co-expressed interactive networks with other known HI associated genes; and in the same pathways with VTN being a hub protein, i.e. focal adhesion pathway and regulation of the actin cytoskeleton (p values < 0.05). The results suggest that these novel population specific gene variants are possible modifiers of the HI phenotypes. We found a high proportion of ancestral allele vs derived at low HI patients-specific minor allele frequency in range of 0.0 to 0.1. The results showed a relatively low pick up rate of PLP variants in known genes in this group of Cameroonian patients with NSHI. In addition, findings may signal an evolutionary enrichment of some variants of HI genes in patients, as the result of polygenic adaptation, and suggest the possibility of multigenic influence on the phenotype of congenital HI, which deserves further investigations.

Exome sequencing of families from Ghana reveals known and candidate hearing impairment genes

“…Recent WES data from a Cameroonian study identified variants in MYO15A in 22.2% of hearing-impaired cases of putative genetic origin; with three variants identified in multiplex families and one variant detected in a simplex family. These data suggest that MYO 15A may be the most common gene underlying HI in Cameroon 52 . A review on MYO15A has shown that the majority of studies reported novel variants 48 , which is consistent with our study.…”

Hearing loss in Africa: current genetic profile

“…The study suggested that a large majority of African countries are still to be investigated. The few available data using next-generation sequencing reveals expected genetic and allelic heterogeneity, and a high proportion of variants not previously reported (Bakhchane et al 2015b;Ben-Rebeh et al 2016;Oluwole et al 2021;Wonkam et al 2021b), that will definitively contribute to improving the disease-gene pair curation, globally. Moreover, there is evidence that novel HI genes will be discovered in Africa, based on the much lower pick-up rate when exploring patients with target genes panels (Lebeko et al 2015;Yan et al 2016).…”

Population-scale analysis of common and rare genetic variation associated with hearing loss in adults

“…Mutations in COL9A3 , which is highly expressed in the ear, have been implicated in the autosomal recessive Stickler syndrome, in which hearing loss is prominent 22 , and tentatively in non-syndromic hearing loss 23,24 . High-throughput mouse knockout characterization from the International Mouse Phenotyping Consortium (IMPC) indicates that Col9a3 -null mice also have hearing loss 25 . TMPRSS3 is a type II membrane serine protease that localizes to the endoplasmic reticulum and plasma membranes, and is expressed in hair cells and supporting cells in the organ of Corti, the spiral ganglion, and the stria vascularis in the ear 26–28 .…”

“…Top variants at two other novel loci were missense changes and thus also implicate specific genes: in COL9A3 (Arg103Trp; MAF = 0.066) and TMPRSS3 (Ala90Thr; MAF = 0.055). Mutations in COL9A3 , which is highly expressed in the ear, have been implicated in the autosomal recessive Stickler syndrome, in which hearing loss is prominent 23 , and tentatively in non-syndromic hearing loss 24,25 . High-throughput mouse knockout characterization from the International Mouse Phenotyping Consortium (IMPC) indicates that Col9a3 -null mice also have hearing loss 26 .…”