Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University and Institute of Otorhinolaryngology, Sun Yat-sen University, Guangzhou, China.
Mol Genet Genomic Med. 2022 Apr;10(4):e1887. doi: 10.1002/mgg3.1887. Epub 2022 Feb 1.
Many hearing-impaired patients carry mutations in rare or novel genes undetected in regular genetic hot regions/genes screening.
We collected clinical and genetic data from subjects with hearing loss who visited our department for genetic counseling. Next-generation sequencing was conducted after 154 deafness-related genes were captured using a designed genes panels in 14 unrelated families (37 participants). The results were filtered and assessed with in silico tools, in combination with pedigree mapping.
Ten mutations in regular deafness genes (GJB2, SLC26A4) and uncommon genes (OTOF, MYO7A, MYO15A, and KARS) were detected, which constituted 57.2% of yielded rate. In particular, two patients with nonsyndromic deafness carried biallelic KARS mutations. In addition, we identified an unreported digenic mutational inheritance in GRP98/USH2A genes in a proband with isolated hearing loss. Functional analyses and molecular modeling suggested the damaging consequence of these variants on encoded proteins. According to the variant pathogenicity guidelines, the 17 identified variants in total were classified as "pathogenic" or "likely pathogenic."
The candidate mutations in deafness genes were suggested to be co-segregated in at least 57.2% of the studied pedigrees. This is the new report of rare/novel mutations causing inherited hearing loss in Chinese.
许多听力受损患者携带在常规遗传热点区域/基因筛查中未检测到的罕见或新型基因的突变。
我们收集了在我们科室进行遗传咨询的听力损失患者的临床和遗传数据。在 14 个无关家庭（37 名参与者）中，使用设计的基因面板捕获 154 个与耳聋相关的基因后，进行了下一代测序。使用计算机工具进行过滤和评估，并结合系谱图谱进行评估。
在常规耳聋基因（GJB2、SLC26A4）和罕见基因（OTOF、MYO7A、MYO15A 和 KARS）中检测到 10 个突变，占检出率的 57.2%。特别是，两名非综合征性耳聋患者携带双等位基因 KARS 突变。此外，我们在一名孤立性听力损失的先证者中发现了 GRP98/USH2A 基因的未报道的双基因突变遗传。功能分析和分子建模表明这些变体对编码蛋白的破坏性后果。根据变体致病性指南，总共鉴定出的 17 个变体被归类为“致病性”或“可能致病性”。
候选耳聋基因中的突变至少在 57.2%的研究家系中被认为是共分离的。这是中国关于罕见/新型突变导致遗传性听力损失的新报告。
