Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 604418 (gene) , 129500 (trait)

Single-gene trait/disorder: yes

Mode of inheritance: Probably autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2026

Inheritance: Rietmann et al. (2026) reported a single affected dog that was born out of unaffected parents. The presumed causal variant was the result of a de novo mutation event and the affected dog was heterozygous at this variant. This suggested autosomal dominant inheritance, although transmission to the next generation was not reported.

Molecular basis: Rietmann et al. (2026) sequenced the whole genome of an affected Labrador Retriever. Comparison of the whole genome sequencing data to 1664 unaffected control dogs revealed 12 private protein changing variants. Only one of them resided in one of 68 known functional candidate genes that were considered. This was a private de novo heterozygous missense variant in the GJB6 gene, which was not present in the parents, XP_038429444.1:p.(Arg75Trp). GJB6 encodes gap junction protein beta 6, also known as connexin 30. Variants in the human GJB6 gene were shown to cause either isolated deafness or Clouston syndrome, which is an ectodermal dysplasia characterized by palmoplantar hyperkeratosis, nail dystrophy, fine and brittle hair. Clouston syndrome may or may not be accompanied by deafness. The homologous human variant, p.Arg75Trp had been reported as pathogenic in a Chinese family segregating non-syndromic hearing loss.
GJB6 and GJB2 are neighbouring genes with co-regulated expression. GJB2 is essential for auditory function. Deafness in GJB6-mutant patients may be due to regulatory effects on GJB2 expression. A Gjb6 knockout mouse strain that preserved Gjb2 expression had normal hearing (Boulay et al., 2013).

Clinical features: Rietmann et al. (2026) reported "At approximately 18 months old, the patient was presented to a veterinarian due to an abnormal growth on one of her outer toes. Upon further examination by a veterinarian, excessive skin growth was observed present on all four paw pads and most of the digital pads to some degree."
Rietmann et al. (2026) also reported "At age approximately 16 months, the owner noticed a decreased or inappropriate reaction to commands or verbal clues and expressed suspicion that the patient may have deafness or impaired hearing function. No further investigation was pursued and to this date no clear diagnosis was made."

Pathology: "Histological examination revealed a stratum corneum expanded by diffuse moderate to severe orthokeratotic and occasional mild parakeratotic hyperkeratosis arranged in spires or villous-like projections. The epidermis was mildly hyperplastic, and there were small numbers of perivascular lymphocytes, plasma cells, and mast cells in the superficial dermis." (Rietmann et al. 2026).

Breed: Labrador Retriever (Dog) (VBO_0200800).
Breeds in which the phene or likely causal variants have been documented. If a likely causal variant has been documented, see variant-specific breed information in the variant table. (Breed information may be incomplete).

Associated gene: