Antunes Larissa Nascimento, Dias Alex Marcel Moreira, Schiavo Beatriz Cetalle, Mendes Beatriz C A, Bertola Debora Romeo, Lezirovitz Karina, Mingroni-Netto Regina Célia
Centro de Pesquisas sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
Divisão de Educação e Reabilitação dos Distúrbios da Comunicação da Pontifícia Universidade Católica de São Paulo, São Paulo, Brazil.
Front Genet. 2024 Oct 21;15:1409306. doi: 10.3389/fgene.2024.1409306. eCollection 2024.
Hearing loss is a frequent sensory impairment type in humans, with about 50% of prelingual cases being attributed to genetic factors. Autosomal recessive hearing loss (ARHL) exhibits great locus heterogeneity and is responsible for 70%-80% of hereditary nonsyndromic cases.
A total of 90 unrelated Brazilian individuals were selected for having hearing loss of presumably autosomal recessive inheritance, either born from consanguineous marriages or belonging to families with two or more affected individuals in the sibship and most cases were of normal hearing parents. In all cases, common pathogenic variants in (c.35delG), [del(GJB6-D13S1830) and del(GJB6-D13S1854)] and (m.1555A>G) were discarded and most were previously assessed by complete Sanger sequencing of . Their genetic material was analyzed through next-generation sequencing, targeting 99 hearing loss-related genes and/or whole exome sequencing.
In 32 of the 90 probands (36,7%) causative variants were identified, with autosomal recessive inheritance confirmed in all, except for two cases due to dominant variants ( and ). Thirty-nine different causative variants were found in 24 different known hearing loss-associated genes, among which 10 variants are novel, indicating wide genetic heterogeneity in the sample, after exclusion of common pathogenic variants. Despite the genetic heterogeneity, some genes showed greater contribution: , , , , and .
The present results confirmed that next-generation sequencing is an effective tool for identifying causative variants in autosomal recessive hearing loss. To our knowledge, this is the first report of next-generation sequencing being applied to a large cohort of pedigrees with presumable autosomal recessive hearing loss in Brazil and South America.
听力损失是人类常见的感觉障碍类型，约50%的语前聋病例归因于遗传因素。常染色体隐性听力损失（ARHL）表现出高度的基因座异质性，占遗传性非综合征病例的70%-80%。
总共选择了90名无亲缘关系的巴西个体，他们患有可能为常染色体隐性遗传的听力损失，这些个体要么出生于近亲结婚家庭，要么属于同胞中有两个或更多受影响个体的家庭，且大多数病例的父母听力正常。在所有病例中，排除了（c.35delG）、[del(GJB6-D13S1830)和del(GJB6-D13S1854)]以及（m.1555A>G）中的常见致病变异，并且大多数先前已通过的完整桑格测序进行了评估。通过下一代测序分析他们的遗传物质，靶向99个与听力损失相关的基因和/或全外显子测序。
在90名先证者中的32名（36.7%）中鉴定出了致病变异，除了两例由显性变异（和）导致的病例外，所有病例均确认为常染色体隐性遗传。在24个不同的已知听力损失相关基因中发现了39种不同的致病变异，其中10种变异是新发现的，这表明在排除常见致病变异后，该样本中存在广泛的遗传异质性。尽管存在遗传异质性，但一些基因的贡献更大：、、、、和。
目前的结果证实，下一代测序是鉴定常染色体隐性听力损失致病变异的有效工具。据我们所知，这是巴西和南美将下一代测序应用于一大群可能患有常染色体隐性听力损失的家系的首次报告。
