Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non-syndromic deafness.

Abstract

Hearing loss is one of the most common sensory disorders worldwide, and about half of all occurrences are attributable to genetic factors. Here, we have identified a novel pathogenic variant in HOMER2 in a Chinese family with autosomal dominant, non-syndromic hearing loss. This is the second family reported globally with hearing loss caused by a variant in HOMER2. The pathogenic variant c.840_841insC in HOMER2 (NM_199330), segregating with the hearing-loss phenotype in the family, leads to a premature stop codon producing a truncated protein. The coiled-coil domain in the C-terminal of HOMER2 protein is essential for protein multimerization and HOMER2-CDC42 interaction. We compared the phenotypes in the two families and found that hearing impairment in this Chinese family was more severe. Furthermore, we found that the ability of this insertion mutant type HOMER2 (HOMER2MU ) to multimerize decreased more significantly than wild-type HOMER2 (HOMER2WT ) and the reported c.554G>C (NM_004839) mutant HOMER2. HOMER2MU protein tended to be distributed in a diffuse manner, whereas HOMER2WT and the reported mutant HOMER2 tended to cluster together. Our research provides a validating second family for variants in HOMER2 causing non-syndromic sensorineural hearing loss. HOMER2 homo-/hetero-multimerization might be the first step in exerting its normal function.