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COL4A6 – X-linked Nonsyndromic Hearing Loss

The type IV collagen gene COL4A6 has been implicated in X-linked nonsyndromic hearing loss. Three unrelated hemizygous male probands in three families, including two individuals described here, harbor rare COL4A6 variants c.3269G>C (p.Gly1090Ala) and the splice-site variant c.951+1G>T, inherited from asymptomatic carrier mothers, consistent with X-linked recessive inheritance (PMID:33840813). The missense p.Gly1090Ala remains a variant of uncertain significance, whereas c.951+1G>T results in skipping of exon 15 in an in vitro minigene splicing assay, indicating a deleterious splicing defect (PMID:33840813).

Functional studies in Col4a6 knockout mice reveal normal auditory brainstem responses and cochlear morphology, distinguishing simple loss of gene expression from the human hearing loss phenotype and supporting a dominant-negative mechanism for pathogenic COL4A6 variants (PMID:33848312). Taken together, genetic evidence remains limited with minimal family segregation, but functional data are moderate, implicating COL4A6 in X-linked nonsyndromic hearing loss. Key Take-home: Rare COL4A6 splice and missense variants with demonstrated splicing defects should be considered in the genetic work-up of X-linked sensorineural hearing loss.

References

  • European journal of human genetics • 2022 • Confirmation of COL4A6 variants in X-linked nonsyndromic hearing loss and its clinical implications. PMID:33840813
  • PloS one • 2021 • Lack of collagen α6(IV) chain in mice does not cause severe-to-profound hearing loss or cochlear malformation, a distinct phenotype from nonsyndromic hearing loss with COL4A6 missense mutation PMID:33848312

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Three unrelated hemizygous probands with rare COL4A6 variants segregating in carrier mothers and minimal additional segregation ([PMID:33840813]).

Genetic Evidence

Limited

Identification of one missense and one splice-site variant in three probands across three families with X-linked inheritance and no extensive segregation.

Functional Evidence

Moderate

In vitro minigene assay shows exon 15 skipping due to c.951+1G>T ([PMID:33840813]); knockout mouse model lacks hearing phenotype, supporting a dominant-negative mechanism ([PMID:33848312]).