Batissoco Ana Carla, Pedroso-Campos Vinicius, Pardono Eliete, Sampaio-Silva Juliana, Sonoda Cindy Yukimi, Vieira-Silva Gleiciele Alice, da Silva de Oliveira Longati Estefany Uchoa, Mariano Diego, Hoshino Ana Cristina Hiromi, Tsuji Robinson Koji, Jesus-Santos Rafaela, Abath-Neto Osório, Bento Ricardo Ferreira, Oiticica Jeanne, Lezirovitz Karina
Laboratório de Otorrinolaringologia/LIM 32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
ENT Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil.
Hum Genet. 2022 Apr;141(3-4):519-538. doi: 10.1007/s00439-021-02372-2. Epub 2021 Oct 1.
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.
听力损失是最常见的感官缺陷之一，影响着全球5.5%的人口，并对健康和社会生活产生重大影响。它主要归因于遗传因素，但其相对贡献反映了地理区域的社会经济发展。涉及数百个耳聋基因的极端遗传异质性给分子诊断带来了挑战。在此，我们报告了对来自巴西所有地区的542名听力受损受试者进行的调查，以寻找遗传病因。在12.9%的受试者中鉴定出双等位基因GJB2/GJB6致病变体（在北部地区发现的频率最低，为7.7%），0.4%的受试者携带GJB2显性变体，0.6%的受试者具有m.1555A > G变体（一种与氨基糖苷类相关的变体）。此外，根据临床表现和推定的遗传模式，对选定的先证者进行的其他基因筛查在2.4%的受试者中鉴定出致病变体。分别在10.8%和3.5%的先证者中诊断出耳部畸形和听神经病。在3.8%的语前/语期病例中，临床诊断为瓦登伯革氏综合征，在71.4%的病例中，这些诊断通过揭示的致病变体得到证实；其中七个是新发现的，包括一个拷贝数变异。所有这些基因筛查策略在16.2%的病例中发现了致病变体。基于分子诊断中的致病变体和系谱分析，在约50%的病例中发现了可能的遗传病因。本研究强调了GJB2/GJB6作为巴西所有地区听力损失病因的相关性，以及对未选择样本进行筛查以估计频率的重要性。此外，当无法进行全面筛查时，可以通过选择先证者进行特定筛查来加强分子诊断。
