Molecular and genetic characterization of a large Brazilian cohort presenting hearing loss.

Hearing loss is one of the most common sensory defects, affecting 5.5% of the worldwide population and significantly impacting health and social life. It is mainly attributed to genetic causes, but their relative contribution reflects the geographical region's socio-economic development. Extreme genetic heterogeneity with hundreds of deafness genes involved poses challenges for molecular diagnosis. Here we report the investigation of 542 hearing-impaired subjects from all Brazilian regions to search for genetic causes. Biallelic GJB2/GJB6 causative variants were identified in 12.9% (the lowest frequency was found in the Northern region, 7.7%), 0.4% carried GJB2 dominant variants, and 0.6% had the m.1555A > G variant (one aminoglycoside-related). In addition, other genetic screenings, employed in selected probands according to clinical presentation and presumptive inheritance patterns, identified causative variants in 2.4%. Ear malformations and auditory neuropathy were diagnosed in 10.8% and 3.5% of probands, respectively. In 3.8% of prelingual/perilingual cases, Waardenburg syndrome was clinically diagnosed, and in 71.4%, these diagnoses were confirmed with pathogenic variants revealed; seven out of them were novel, including one CNV. All these genetic screening strategies revealed causative variants in 16.2% of the cases. Based on causative variants in the molecular diagnosis and genealogy analyses, a probable genetic etiology was found in ~ 50% of the cases. The present study highlights the relevance of GJB2/GJB6 as a cause of hearing loss in all Brazilian regions and the importance of screening unselected samples for estimating frequencies. Moreover, when a comprehensive screening is not available, molecular diagnosis can be enhanced by selecting probands for specific screenings.

New Insights into the Identity of the DFNA58 Gene.

Hearing loss is the most common sensory deficit, affecting 466 million people worldwide. The vast and diverse genes involved reflect the complexity of auditory physiology, which requires the use of animal models in order to gain a fuller understanding. Among the loci with a yet-to-be validated gene is the DFNA58, in which ~200 Kb genomic duplication, including three protein-coding genes (PLEK, CNRIP1, and PPP3R1's exon1), was found to segregate with autosomal dominant hearing loss. Through whole genome sequencing, the duplication was found to be in tandem and inserted in an intergenic region, without the disruption of the topological domains. Reanalysis of transcriptomes data studies (zebrafish and mouse), and RT-qPCR analysis of adult zebrafish target organs, in order to access their orthologues expression, highlighted promising results with Cnrip1a, corroborated by zebrafish in situ hybridization and immunofluorescence. Mouse data also suggested Cnrip1 as the best candidate for a relevant role in auditory physiology, and its importance in hearing seems to have remained conserved but the cell type exerting its function might have changed, from hair cells to spiral ganglion neurons.