HOMER2 – DFNA68 Nonsyndromic Hearing Loss

HOMER2 encodes a stereociliary scaffolding protein critical for normal auditory transduction in cochlear hair cells. Heterozygous pathogenic variants in HOMER2 cause autosomal dominant nonsyndromic hearing loss type 68 (DFNA68 Nonsyndromic Hearing Loss), characterized by progressive sensorineural hearing impairment.

The first family-level evidence emerged from a Chinese pedigree harboring a missense variant c.554G>C (p.Arg185Pro) and a frameshift insertion c.840_841insC (p.Glu281ArgfsTer22), both segregating with early-onset hearing loss under an autosomal dominant pattern (PMID:30047143). A subsequent Spanish family exhibited a novel truncating deletion c.832_836delCCTCA (p.Pro278AlafsTer10) within the coiled-coil domain essential for HOMER2 multimerization, cosegregating with progressive moderate-to-profound hearing loss (PMID:33809266).

In 2023, a Sicilian kindred demonstrated segregation of a nonstop variant converting the stop codon into tryptophan (predicted p.Ter355Trpext10), escaping non-stop decay and extending the protein by ten residues; affected individuals spanned three generations (PMID:37173411). To date, at least four unrelated probands across four families illustrate the autosomal dominant inheritance and multi-generational segregation of HOMER2 variants.

The variant spectrum includes two missense substitutions, multiple truncating alleles (frameshift and deletion), and a nonstop extension, collectively disrupting the CDC42 binding and coiled-coil domains essential for protein multimerization. A representative variant is c.832_836delCCTCA (p.Pro278AlafsTer10), illustrating a loss-of-function mechanism through premature truncation.

Functional assays support a dominant-negative or haploinsufficiency mechanism: in vivo zebrafish models expressing the nonstop variant recapitulate auditory deficits, and cellular studies of frameshift mutants reveal decreased protein stability, impaired multimerization, and altered subcellular distribution compared with wild-type HOMER2 (PMID:37173411; PMID:33809266). These data converge on disrupted stereociliary scaffolding as the pathogenic basis.

Collectively, genetic segregation in four families, a spectrum of functionally deleterious variants, and concordant experimental models establish a strong ClinGen gene–disease association for HOMER2 and DFNA68. Key Take-home: HOMER2 should be included in diagnostic gene panels for autosomal dominant progressive hearing loss, with validated pathogenic variants and functional assays guiding variant interpretation.

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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