In other species: horse

Possibly relevant human trait(s) and/or gene(s) (MIM number): 612813

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive Lethal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2007

Species-specific name: Bulldog calf

History: As summarised by Cavanagh et al. (2007): "A form of dwarfism (known as bulldog dwarfism) . . . was clearly documented in Dexter cattle in the 19th century (Curran 1990), and its Mendelian inheritance was suspected and discussed as early as 1904 (Seligmann, 1904)." Seligmann's (1904) paper mentions that "the College of Surgeons possesses a complete skeleton of a typical [Dexter bulldog] calf . . . (Teratological Series, 183A)". The citation is actually to an interleaved addendum (A) to entry 183 on page 56 of Lownes and Masters' (1893) catalogue of specimens held by the Royal College of Surgeons. The interleaved addendum comprises an entry from the Royal College's 1894 annual report with hand-written notes. The specimen's catalogue ID in the Royal College of Surgeons' collection is RCSPC/T 16D.11, where it is listed as "Congenital Lethal Chondrodysplasia", having been donated by the Royal Veterinary College in 1894. Seligmann's (1904) paper includes 15 plates illustrating various aspects of Dexter bulldog calves.

Calves with this characteristic embryonic-lethal phenotype were described in the Jersey breed by Mead et al. (1946).

Molecular basis: After homozygosity mapping in candidate regions, mutation screening in the aggrecan (ACAN) gene "revealed a 4-bp insertion in exon 11 (2266-2267insGGCA) (called BD1 for diagnostic testing) and a second, rarer transition in exon 1 (-198C>T) (called BD2) that cosegregate with the disorder" (Cavanagh et al., 2007).

Cabrera et al. (2016) reported a still-born calf with "Grossly evident chondrodystrophic dwarfism with hydrocephalus, compatible with so-called bulldog calf malformation", the result of a mating between a miniature Scottish Highland bull and cow, each of which was shown to be heterozygous for the same BD1 mutation in ACAN reported by Cavanagh et al. (2007) as being causal of bulldog dwarfism in the Dexter breed.

Struck et al. (2018) reported a different likely causal variant (ACAN:c.5686insC; p.Val1898fsTer9), homozygosity for which results in a very similar type of dwarfism in the Miniature Zebu breed: the variant was "homozygous in the affected calf and heterozygous in its [Miniature Zebu] parents".

Clinical features: As summarised by Cavanagh et al. (2007): "Affected fetuses display extremely disproportionate dwarfism, a short vertebral column, marked micromelia, a large abdominal hernia, and a relatively large head with a retruded muzzle, cleft palate, and protruding tongue (Harper et al. 1998)"

Breeds: Dexter, Jersey, Miniature Highland.

Associated gene: