In other species: indicine cattle (zebu)

Categories: Limbs / fins / digit / tail phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 275220 (trait) , 605420 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2012

Species-specific description: See also: 'OMIA:001009-9915 : Hemimelia, tibial in Bos indicus'

History: This disorder was first reported (in Galloways) in the UK by Young (1951) and in the USA and Germany by Ojo et a. (1974).

Mapping: Chromosome BTA15

Molecular basis: A deletion of around 45,694 bp including exon 1 of ALX4 (omia.variant:764) was reported in affected Shorthorns (Beever and Marron, 2012).
Brenig et al. (2015) reported a 20bp duplication in exon 2 of ALX4 in affected Galloways (omia.variant:763), which is predicted to cause a frameshift. Coordinates for the variant were reported as g.75154399_75154418dup in UMD3.1 and genomic coordinates were later updated to reflect improved annoation of the ALX4 gene in the reference genome (Brenig et al., 2024). 
Buitkamp et al. (2023) reported the 20-bp duplication in the ALX4 gene (called ALX4dup-LfL, initially listed in OMIA as omia.variant:1516) as being the likely cause of the case of tibial hemimelia in a white Galloway calf born in Germany. These authors noted that the likely causal variant reported by Brenig et al. (2015) (called ALX4dup-GAU) corresponds "exactly to the last 20 bp of exon 2, whereas the ALX4dup-LfL is shifted by 3 bp in the 5-prime direction". However, the correction by Brenig et al. (2024) identified that affected animals in both studies had the same variant. Both variants are now merged into one entry and omia.variant:1516 is redundant.

Control: In the 1970s, the Galloway Cattle Society in Great Britain instigated what became a text-book example of how to control an autosomal-recessive disorder for which there was (at that time) no blood-based genotype test (Nicholas, 1987). The control programme comprised: 1. Maintaining a register of carriers, i.e. bulls and cows that had produced at least one affected calf 2. An insurance scheme, in which the purchaser of a young bull at any official breed society sale was insured against that young bull throwing affected offspring within 21 months following the sale (9 months gestation and 12 months use). It was compulsory for all young bulls sold at official sales to be insured, the vendor being obliged to pay the premium. 3. Maintaining a test herd of known carrier cows, through which young bulls could be progeny-tested for this disorder. The effectiveness of this progeny-testing was enhanced by the use of early pregnancy termination, made feasible by the disorder being visible in 90-day embryos (Pollock et al., 1979).

Genetic testing: A DNA test for this disorder in Shorthorns was described in 2006 in a patent published in 2012 (Beever and Marron, 2012).

Breeds: Galloway (Cattle) (VBO_0000207), Shorthorn (Cattle) (VBO_0000375).
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: