Redfield Shelby E, Mauriac Stephanie A, Géléoc Gwenaëlle S, Shearer A Eliot
Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Boston, Massachusetts, USA.
Children's Rare Disease Collaborative, Department of Information Technology, Boston Children's Hospital, Boston, Massachusetts, USA.
Am J Med Genet C Semin Med Genet. 2025 Apr 18:e32142. doi: 10.1002/ajmg.c.32142.
Usher syndrome, the most common form of deaf-blindness, displays extensive genetic, allelic, and phenotypic heterogeneity. The dual sensory impairment associated with this autosomal recessive disorder makes Usher syndrome an important target for gene therapy, with dozens of published preclinical studies targeting multiple Usher syndrome genes and using multiple gene therapy strategies. Nine genes have been conclusively linked to Usher syndrome; however, data on the prevalence and contribution of specific genetic variants is lacking. Such information is essential to choosing a favorable target gene or therapeutic approach during clinical trial design. Here, we used large genomic databases to systematically evaluate the genomics of Usher syndrome. We ascertained pathogenic Usher syndrome variants from three clinical databases and determined the occurrence of these pathogenic Usher syndrome variants within: (1) a publicly available dataset including worldwide populations (GnomAD), (2) a cohort of 3888 children without hearing loss, and (3) 637 children with hearing loss. Results show significant variability in the frequency of Usher syndrome variants by gene and genetic ancestry. 1% of control subjects carry a pathogenic USH variant. Pathogenic variants in USH2A are the most prevalent, at 1 in 150 individuals (0.0062). Calculated general population prevalence for all Usher syndrome subtypes is 1 in ~29,000, indicating that 30,405 individuals in the United States and 721,769 individuals worldwide are affected. We estimate that 324 babies in the United States and 12,090 worldwide are born with Usher syndrome each year. We identify key targets for genetic therapy based on population-level prevalence including a focus on alternatives to gene replacement therapies, specifically for USH2A.
尤塞氏综合征是最常见的致聋致盲疾病，具有广泛的遗传、等位基因和表型异质性。这种常染色体隐性疾病所导致的双重感官障碍，使尤塞氏综合征成为基因治疗的重要靶点，已有数十项临床前研究针对多个尤塞氏综合征基因并采用了多种基因治疗策略。已有九个基因被明确与尤塞氏综合征相关联；然而，缺乏关于特定基因变异的患病率和贡献的数据。这些信息对于在临床试验设计过程中选择合适的靶基因或治疗方法至关重要。在此，我们使用大型基因组数据库系统地评估尤塞氏综合征的基因组学。我们从三个临床数据库中确定了致病性尤塞氏综合征变异，并确定了这些致病性尤塞氏综合征变异在以下情况中的出现频率：（1）一个包括全球人群的公开可用数据集（GnomAD），（2）一组3888名无听力损失的儿童，以及（3）637名有听力损失的儿童。结果显示，尤塞氏综合征变异的频率因基因和遗传血统而异。1%的对照受试者携带致病性USH变异。USH2A中的致病性变异最为普遍，每150人中就有1人（0.0062）。所有尤塞氏综合征亚型的计算得出的一般人群患病率约为1/29000，这表明美国有30405人、全球有721769人受此影响。我们估计，美国每年有324名婴儿、全球每年有12090名婴儿出生时患有尤塞氏综合征。我们基于人群水平的患病率确定了基因治疗的关键靶点，包括关注基因替代疗法的替代方案，特别是针对USH2A的替代方案。
