Abstract
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.
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Acknowledgements
The authors thank São Paulo Research Foundation (FAPESP, São Paulo, Brazil; Processes 2014/13071-6, 2018/03433-9), and Brazilian National Council for Scientific and Technological Development (CNPq, Brasília, Brazil; Process 573920/2008-7) for financial support, and all the patients that participated in this study and all the health care professionals that evaluated and assisted the patients enrolled in this study. We also thank Dr. Mingroni-Netto for giving us positive controls of some deafness gene variants screening, Dr. Silvia Souza Costa for performing the array CGH, and MSc William Torres for performing Exome Sequencing in two Waardenburg patients. We are also really grateful to Dr. Veronique Pingault’s team (Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, Université de Paris, Paris, France) for performing MLPA analysis to validate one case of MITF deletion.
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São Paulo Research Foundation (FAPESP, São Paulo, Brazil; Processes 2014/13071-6, 2018/03433-9), and Brazilian National Council for Scientific and Technological Development (CNPq, Brasília, Brazil; Process 573920/2008-7).
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Design research: ACB, EP, KL, VPC, JSS, CS, GAVS, EUSOL, and RJS; computational analyses: DM, KL, and ACB; clinical diagnosis and genetic counseling: KL, EP, ACHH, RKT, OAN, and JO; conducted review and editing ACB, KL, and ACB; provided funding acquisition, project administration, and resources: KL, JO, and RFB; wrote the paper: ACB and KL.
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Batissoco, A.C., Pedroso-Campos, V., Pardono, E. et al. Molecular and genetic characterization of a large Brazilian cohort presenting hearing loss. Hum Genet 141, 519–538 (2022). https://doi.org/10.1007/s00439-021-02372-2
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DOI: https://doi.org/10.1007/s00439-021-02372-2