Variants in CIB2 cause DFNB48 and not USH1J

Abstract

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.

Preferential Binding of Mg2+ Over Ca2+ to CIB2 Triggers an Allosteric Switch Impaired in Usher Syndrome Type 1J

“…In this work, we present a thorough characterization of two variants of human CIB2, namely the WT form and the E64D mutant associated with USH1J. It should be reported that a recent study disqualified CIB2 as a USH1J-related gene, however the E64D variant was found to be associated with autosomal recessive non-syndromic hearing loss (Booth et al, 2018 ). Our biochemical and biophysical study highlights a number of clear structural and functional differences with CIB1, which may thus pose the molecular basis for understanding the malfunctioning of CIB2 in USH1J and possibly other genetic diseases causing hearing loss.…”

GJB2 and GJB6 Genetic Variant Curation in an Argentinean Non-Syndromic Hearing-Impaired Cohort

“…Furthermore, patients with GJB 2 genetic variants present excellent outcomes in speech perception/production skills after cochlear implantation [ 35 , 36 , 37 ]. Therefore, correct interpretation of the phenotypic consequences of genetic variants is crucial in genetic diagnosis, since discrepancies in sequence variant interpretation and classification has been reported to lead to serious impact in patient health maintenance [ 38 , 39 , 40 ]. Thus, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) has developed guidelines for clinical interpretation of genetic variants [ 41 ].…”

Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy

“…The p.E64D missense mutation that is thought to cause USH1J is only two amino acids away from the p.R66W missense mutation that is exclusively linked to non-syndromic deafness (Seco et al, 2016). In addition, none of the 13 patients in a multi-ethnic cohort (Booth et al, 2018) had an abnormal retinal phenotype, regardless of the mutation type, even null alleles. Lastly, while a retinal phenotype is rarely evident in mouse models of any USH type, many do exhibit some vestibular dysfunction, unlike CIB2 knockout mice (Giese et al, 2017;Michel et al, 2017).…”