HOMER2 – Nonsyndromic Genetic Hearing Loss

HOMER2 encodes a stereociliary scaffolding protein essential for hair-cell function. Heterozygous variants in HOMER2 cause autosomal dominant nonsyndromic hearing loss (DFNA68), characterized by early-onset, moderate-to-profound progressive sensorineural impairment. Based on multiple segregation studies and functional data, the gene–disease association is classified as Strong.

Genetic evidence includes five distinct heterozygous coding variants identified in five unrelated families: three frameshift/deletion mutations (c.840dupC (p.Met281HisfsTer9), c.832_836delCCTCA (p.Pro278AlafsTer10), c.592_597delACCACA (p.Thr198HisfsTer15)), two missense substitutions (c.554G>C (p.Arg185Pro), c.188>T (p.Ile63Thr)), and one nonstop variant (c.1064>G (p.*355TrpextTer10)). These variants cluster in the coiled-coil CDC42-binding domain critical for protein multimerization (PMID:30047143, PMID:33809266, PMID:37173411).

Segregation analysis demonstrates co-segregation of these heterozygous variants with hearing impairment across at least three multi-generation families, encompassing six additional affected relatives, supporting autosomal dominant inheritance.

Functional assays of frameshift mutants reveal decreased HOMER2 protein stability, reduced multimerization capability, and aberrant subcellular distribution in transfected cells compared with wild-type HOMER2 (PMID:30047143, PMID:33809266).

In vivo, a zebrafish model expressing the nonstop c.1064>G variant exhibits defective auditory evoked responses and altered swim behavior, recapitulating the human hearing-loss phenotype and confirming haploinsufficiency as the likely mechanism (PMID:37173411).

In summary, multiple unrelated families with autosomal dominant segregation, robust functional concordance in cell and animal models, and a clear mechanistic link support a Strong clinical validity for HOMER2 in DFNA68 nonsyndromic hearing loss. This evidence underpins accurate molecular diagnosis, genetic counseling, and the exploration of therapeutic modulation of HOMER2 multimerization.

References

• Genes | 2021 | A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family. PMID:33809266
• Clinical Genetics | 2018 | Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non-syndromic deafness. PMID:30047143
• European Journal of Human Genetics | 2023 | Identification and in vivo functional investigation of a HOMER2 nonstop variant causing hearing loss. PMID:37173411

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