Whole exome sequencing reveals a biallelic frameshift mutation in GRXCR2 in hearing impairment in Cameroon

Abstract Background Hearing impairment (HI) genes are poorly studied in African populations. Methods We used whole exome sequencing (WES) to investigate pathogenic and likely pathogenic (PLP) variants in 10 individuals with HI, from four multiplex families from Cameroon, two of which were previously unresolved with a targeted gene enrichment (TGE) panel of 116 genes. In silico protein modelling, western blotting and live imaging of transfected HEK293 cells were performed to study protein structure and functions. Results All PLP variants previously identified with TGE were replicated. In one previously unresolved family, we found a homozygous frameshift PLP variant in GRXCR2 (OMIM: 615762), NM_001080516.1(GRXCR2):c.251delC p.(Ile85SerfsTer33), in two affected siblings; and additionally, in 1/80 unrelated individuals affected with non‐syndromic hearing impairment (NSHI). The GRXCR2‐c.251delC variant introduced a premature stop codon, leading to truncation and loss of a zinc‐finger domain. Fluorescence confocal microscopy tracked the wild‐type GRXCR2 protein to the cellular membrane, unlike the mutated GRXCR2 protein. Conclusion This study confirms GRXCR2 as a HI‐associated gene. GRXCR2 should be included to the currently available TGE panels for HI diagnosis.

Abstract licence: CC BY-NC

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