Categories: Vision / eye phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 212550 (trait) , 606326 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant with incomplete penetrance

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2019

Species-specific name: Congenital eye malformation; microphthalmos

Inheritance: Hug et al. (2019): "All cases traced back to the same male ancestor, but had quite diverse maternal lineages . . . . Seven out of 28 recorded puppies were affected and males and females were affected in equal proportions. As we could not identify any common ancestors in the maternal lines of the cases, we hypothesized an autosomal dominant inheritance with incomplete penetrance as the most likely mode of inheritance."

Molecular basis: By comparing the genome sequence of one affected Golden Retriever with the sequence of 601 control genomes, Hug et al. (2019) identified a "heterozygous private nonsense variant, c.487C>T . . . in the SIX6 gene. This variant is predicted to truncate about a third of the open reading frame, p.(Gln163*) . . . We hypothesize that the residual amount of functional SIX6 protein likely to be expressed in heterozygous dogs is sufficient to explain the observed incomplete penetrance and the varying severity of the eye defects in the affected dogs."

Prevalence: Hug et al. (2019): "All three available cases were heterozygous. Five additional close relatives including the common sire were also heterozygous, but did not show any obvious eye phenotypes. The variant was absent from the 464 unrelated Golden Retrievers and 17 non-affected siblings of the cases."

Breed: Golden Retriever (Dog) (VBO_0200610).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: