[Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations].

Objective: To analyze the phenotypic-genotypic characteristics of hereditary deafness caused by OTOA gene variations. Methods: Family histories, clinical phenotypes and gene variations of six pedigrees were analyzed, which were diagnosed with hearing loss caused by OTOA gene variations at the PLA General Hospital from September 2015 to January 2022. The sequence variations were verified by Sanger sequencing and the copy number variations were validated by multiplex ligation-dependent probe amplification (MLPA) in the family members. Results: The hearing loss phenotype caused by OTOA variations ranged from mild to moderate in the low frequencies, and from moderate to severe in the high frequencies in the probands, which came from six sporadic pedigrees, among which a proband was diagnosed as congenital deafness and five were diagnosed as postlingual deafness. One proband carried homozygous variations and five probands carried compound heterozygous variations in OTOA gene. Nine pathogenic variations (six copy number variations, two deletion variations and one missense variation) and two variations with uncertain significance in OTOA were identified in total, including six copy number variations and five single nucleotide variants, and three of the five single nucleotide variants were firstly reported [c.1265G>T(p.Gly422Val),c.1534delG(p.Ala513Leufs*11) and c.3292C>T(p.Gln1098fs*)]. Conclusions:OTOA gene variations can lead to autosomal recessive nonsyndromic hearing loss. In this study, the hearing loss caused by OTOA defects mostly presents as bilateral, symmetrical, and postlingual, and that of a few presents as congenital. The pathogenic variations of OTOA gene are mainly copy number variations followed by deletion variations and missense variations.目的： 分析OTOA基因变异导致的遗传性聋患者的表型及基因型特点。 方法： 对2015年9月至2022年1月在解放军总医院经二代测序诊断为OTOA基因变异致聋的6个家系进行病史、临床表型及基因变异分析，在家系内对发现的序列变异进行Sanger测序验证、对发现的拷贝数变异进行多重连接探针扩增技术（multiplex ligation-dependent probe amplification，MLPA）验证。 结果： 6个散发耳聋家系的先证者均表现为低频轻~中度感音神经性听力损失，高频中~重度感音神经性听力损失；其中1例为语前聋，5例为语后聋。6例先证者中1例携带OTOA基因纯合变异，5例携带OTOA基因复合杂合变异。共鉴定了OTOA基因9个致病性变异（分别是6个拷贝数变异、2个缺失变异和1个错义变异）和2个临床意义未明的错义变异；5个单核苷酸变异中有3个为未经报道的新变异［c.1265G>T（p.Gly422Val）、c.1534delG（p.Ala513Leufs*11）及c.3292C>T（p.Gln1098fs*）］。 结论：OTOA基因变异可导致常染色体隐性遗传非综合征型耳聋。本组病例中临床表型主要为语后发生的双耳对称性感音神经性听力损失，少数表现为语前先天性聋；其致病变异主要以拷贝数变异为主，其次为缺失变异和错义变异。.