Categories: Limbs / fins / digit / tail phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 618021 (trait) , 610575 (gene) , 618022 (trait)

Links to relevant human diseases in MONDO:

• MONDO:0060732: tetraamelia syndrome 2

Single-gene trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2020

Cross-species summary: Tetradysmelia refers to the severe reduction of all limb parts distal of the scapula and the pelvic girdle. This phene may be similar to 'limbless' in chicken (OMIA 000602-9031).

History: In the 1990s, a Holstein Friesian bull was mated to five of his daughters using an embryo transfer program to produce a backcross family. Off 24 offspring, 6 stillborn calves lacked all four limbs (Kühn et al., 1998; Becker et al., 2020). Analysis of candidate genes EN1 and FGF10 did not identify likely causative variants (Kühn et al., 1999 & 2002).

Mapping: Applying a homozygosity mapping approach, Becker et al. (2020) identified a shared region of homozygosity of 10.54 Mb on chromosome 14 ranging from 52.42 to 62.96 Mb in the three genotyped affected animals that was not present in the dams and unaffected siblings.

Molecular basis: Becker et al. (2020) "detected a 50-kb deletion in the targeted chromosomal region that was in the heterozygous state in the cases’ sire" in whole genome sequencing data and "confirmed that this detected deletion segregated perfectly within the family with tetradysmelia. The deletion spanned three exons of the bovine R-spondin 2 (RSPO2) gene, which encode three domains of the respective protein."

Clinical features: Affected calves were aborted or stillborn and presented with severe limb malformations of all limbs: distal parts of the fore and hindlimbs were completely missing in most affected animals, while one affected animal had partly developed limbs. One affected animal "lacked the symphyseal fusion of the rostral ends of the mandibulae and" and one animal "showed a mild brachygnathia superior." (Becker et al., 2020).

Prevalence: Only six affected calves have been reported (Becker et al., 2020).

Breed: Holstein Friesian (Cattle) (VBO_0000239).
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: