Variants in CIB2 cause DFNB48 and not USH1J

The mutational spectrum of CIB2 includes missense, nonsense, splice‐site, frameshift and copy number variants. Regardless of variant‐type, location or combination, all pathogenic variants in CIB2 in our multi‐ethnic cohort resulted in non‐syndromic deafness. The genetic, mutational and phenotypic spectrum of deafness‐causing genes shows great diversity and pleiotropy. The best examples are the group of genes, which when mutated can either cause non‐syndromic hearing loss (NSHL) or the most common dual sensory impairment, Usher syndrome (USH). Variants in the CIB2 gene have been previously reported to cause hearing loss at the DFNB48 locus and deaf‐blindness at the USH1J locus. In this study, we characterize the phenotypic spectrum in a multiethnic cohort with autosomal recessive non‐syndromic hearing loss (ARNSHL) due to variants in the CIB2 gene. Of the 6 families we ascertained, 3 segregated novel loss‐of‐function (LOF) variants, 2 families segregated missense variants (1 novel) and 1 family segregated a previously reported pathogenic variant in trans with a frameshift variant. This report is the first to show that biallelic LOF variants in CIB2 cause ARNSHL and not USH. In the era of precision medicine, providing the correct diagnosis (NSHL vs USH) is essential for patient care as it impacts potential intervention and prevention options for patients. Here, we provide evidence disqualifying CIB2 as an USH‐causing gene.