Novel and Recurrent MYO7A Mutations in Usher Syndrome Type 1 and Type 2

Usher syndrome (USH) is a group of disorders manifested as retinitis pigmentosa and bilateral sensorineural hearing loss, with or without vestibular dysfunction. Here, we recruited three Chinese families affected with autosomal recessive USH for detailed clinical evaluations and for mutation screening in the genes associated with inherited retinal diseases. Using targeted next-generation sequencing (NGS) approach, three new alleles and one known mutation in MYO7A gene were identified in the three families. In two families with USH type 1, novel homozygous frameshift variant p.Pro194Hisfs*13 and recurrent missense variant p.Thr165Met were demonstrated as the causative mutations respectively. Crystal structural analysis denoted that p.Thr165Met would very likely change the tertiary structure of the protein encoded by MYO7A. In another family affected with USH type 2, novel biallelic mutations in MYO7A, c.[1343+1G>A];[2837T>G] or p.[?];[Met946Arg], were identified with clinical significance. Because MYO7A, to our knowledge, has rarely been correlated with USH type 2, our findings therefore reveal distinguished clinical phenotypes associated with MYO7A. We also conclude that targeted NGS is an effective approach for genetic diagnosis for USH, which can further provide better understanding of genotype-phenotype relationship of the disease.乌谢尔综合征（Usher syndrome, USH）是一组以色素性视网膜炎和双侧感音神经性听力损失为特征，伴或不伴前庭功能障碍的遗传性疾病。本研究纳入3个罹患常染色体隐性遗传USH的中国家系，对其开展详尽的临床评估，并针对遗传性视网膜疾病相关基因进行突变筛查。采用靶向二代测序（targeted next-generation sequencing, NGS）技术，在3个家系的MYO7A基因中检出3个新等位基因及1个已知突变。在2个1型USH家系中，分别确认新发纯合移码变异p.Pro194Hisfs*13与复发性错义变异p.Thr165Met为致病突变。晶体结构分析显示，p.Thr165Met极有可能改变MYO7A编码蛋白的三级结构。在另一个罹患2型USH的家系中，检出MYO7A基因新发双等位基因突变c.[1343+1G>A];[2837T>G]，对应蛋白变异为p.[?];[Met946Arg]，该变异具有临床意义。据我们所知，此前MYO7A极少与2型USH相关联，本研究结果因此揭示了与MYO7A相关的独特临床表型。本研究同时证实，靶向NGS是一种有效的USH遗传诊断手段，可进一步深化对该疾病基因型-表型关联的认知。