Chiang Yu-tingPEI-HSUAN LINLo, Ming-YuMing-YuLoHSIN-LIN CHENLee, Chen-YuChen-YuLeeTsai, Cheng-YuCheng-YuTsaiLin, Yin-HungYin-HungLinTsai, Shih-FengShih-FengTsaiTIEN-CHEN LIUHsu, Chuan-JenChuan-JenHsuPEI-LUNG CHENJacob Shujui HsuCHEN-CHI WU2023-11-082023-11-082023-09-0715251578https://scholars.lib.ntu.edu.tw/handle/123456789/637008Recessive variants in GJB2 are the most important genetic cause of sensorineural hearing impairment (SNHI) worldwide. Phenotypes vary significantly in GJB2-related SNHI, even in patients with identical variants. For instance, patients homozygous for the GJB2 p.V37I variant, which is highly prevalent in the Asian populations, usually present with mild-to-moderate SNHI; yet severe-to-profound SNHI is occasionally observed in approximately 10% of p.V37I homozygotes. To investigate the genomic underpinnings of the phenotypic variability, we performed next-generation sequencing of GJB2 and other deafness genes in 63 p.V37I homozygotes with extreme phenotypic severities. We identified additional pathogenic variants of other deafness genes in 5 of the 35 patients with severe-to-profound SNHI. Furthermore, we conducted case-control association analyses for 30 unrelated p.V37I homozygotes with severe-to-profound SNHI against 28 p.V37I homozygotes with mild-to-moderate SNHI, and 120 population controls from the Taiwan Biobank. We found that the severe-to-profound group had a higher frequency of the crystallin lambda 1 (CRYL1) variant (rs14236), located upstream of GJB2, than the mild-to-moderate and Taiwan Biobank groups. Our results demonstrated that pathogenic variants in other deafness genes and a possible modifier, the CRYL1 rs14236 variant, may contribute to phenotypic variability in GJB2-realted SNHI, highlighting the importance of comprehensive genomic surveys to delineate the genotype-phenotype correlations.en[SDGs]SDG3journal article10.1016/j.jmoldx.2023.07.005376838902-s2.0-85173212455https://api.elsevier.com/content/abstract/scopus_id/85173212455