Categories: Craniofacial phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 619136 (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: 2016

Cross-species summary: See also OMIA 000236 : Craniomandibular osteopathy, generic

Inheritance: Padgett and Mostosky (1965) concluded autosomal recessive inheritance in the West Highland White terrier breed. Hytönen et al. (2016) reported that "The determination of the exact mode of inheritance in dogs [in West Highland White Terriers, Cairn Terriers and Scottish Terriers] is not straightforward due to the nature of the leaky splice variant and mild self-limiting phenotype that may remain unobserved and prevent retrospective diagnosis. We found some dogs that were homozygous for the variant but had no reported clinical signs. However, we observed a considerable level of the wild-type SLC37A2 transcript in homozygous dogs in the peripheral blood due to the splicing leakage, suggesting that the leaky expression is sufficient to avoid a clinical phenotype in some cases. We also found several heterozygous dogs that had developed CMO. We found that heterozygous dogs had lower levels of wild-type SLC37A2 transcript compared to the unaffected dogs with individual variation of expression between dogs. This result suggested a dominant disease with incomplete penetrance that could help to explain the reported differences in the severity and duration of CMO among the affected dogs, although alternative models of inheritance cannot be completely ruled out yet."

Molecular basis: Hytönen et al. (2016) reported that a likely causal variant in West Highland White Terriers, Cairn Terriers and Scottish Terriers is a splicing variant "c.1332C>T in exon 15 of SLC37A2 . . . The mutant T allele eliminates a potential binding site for the splicing factor ASF/SF-2". Letko et al. (2020) discovered a likely causal variant for this disorder: "in a Basset Hound, a heterozygous most likely pathogenic splice site variant was found in SLC37A2 (c.1446+1G>A), predicted to lead to exon skipping as shown before in SLC37A2‐associated canine CMO of Terriers."

Breeds: Basset Hound (Dog) (VBO_0200126), Cairn Terrier (Dog) (VBO_0200267), Scottish Terrier (Dog) (VBO_0201198), West Highland White Terrier (Dog) (VBO_0201415).
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: