Objective: To perform the phenotype and genetic analysis on two families with moderate sensorineural hearing impairment and determine the cause of deafness. Methods: The phenotype and genetic analysis was performed on the two hearing impairment pedigrees coming to Chinese PLA General Hospital from January 2014 to August 2020. DNA samples of the proband from family 1 and the parents from family 2 were collected and tested through next generation sequencing on all deafness genes, and Sanger sequencing was performed to verify the mutation sites. The reported pathogenic variants of the otogelin-like (OTOGL) gene, the autosomal recessive inherited deafness genes that cause moderate sensorineural hearing loss and the clinical manifestations of the deafness genes that have the similar expression location as the OTOGL gene were summarized and analyzed. Results: The pathogenic variants in the families were compound heterozygous variants in the OTOGL gene c.2773C>T/c.2826C>G (p.Arg925*/p.Tyr942*) and c.4455G>A/c.875C>G (Trp1485*/p.Ser292*), respectively. c.2773C>T was an already reported pathogenic variant causing hearing impairment in the literature, while c.2826C>G, c.4455G>A and c.875C>G were novel reported variant sites. The above four variants were classified as pathogenic variants according to the variant interpretation standards and guideline of the Amercian College of Medical Genetics and Genomics. Conclusions: Pathogenic variants in OTOGL gene is an important genetic factor leading to moderate sensorineural hearing loss. The newly discovered variant sites c.2826C>G, c.4455G>A and c.875C>G enrich the variant spectrum of OTOGL gene. The results of the current study provide a basis for genetic counseling of the related families and a new target for the treatment of hereditary hearing loss in the future.
目的： 对两个中度感音神经性耳聋小家系行表型及遗传学分析，明确其致聋病因。 方法： 对2014年1月至2020年8月间就诊于解放军总医院的两个耳聋小家系进行表型及遗传学分析。对家系1先证者及家系2先证者父母的DNA样本行所有已知耳聋基因二代测序，并对变异位点在家系成员中进行Sanger测序验证。对已报道的耳胶样蛋白（OTOGL）基因致病变异位点、导致中度感音神经性耳聋的常染色体隐性遗传性耳聋基因和与OTOGL基因具有相同表达定位的耳聋基因的临床表型进行分析和总结。 结果： 两个耳聋家系先证者（均为男性患儿）的致病变异分别为OTOGL基因c.2773C>T/c.2826C>G（p.Arg925*/p.Tyr942*）和c.4455G>A/c.875C>G（p.Trp1485*/p.Ser292*）复合杂合变异，其中c.2773C>T为文献已报道的致聋变异位点，c.2826C>G、c.4455G>A和c.875C>G为新发现的变异位点，根据美国医学遗传学与基因组学学会（ACMG）制定的变异解读标准，上述4个变异位点分类均为致病变异。 结论： OTOGL基因变异是导致中度感音神经性聋的重要遗传因素，本研究新发现的c.2826C>G、c.4455G>A和c.875C>G变异位点丰富了该基因的基因变异谱，为耳聋家系的遗传咨询提供了依据，并为遗传性耳聋的治疗提供了新的靶点。.
Keywords: Genetic testing; Hearing loss, sensorineural; OTOGL gene; Pathogenic variants.