In other species: taurine cattle

Categories: Skeleton phene (incl. short stature & teeth) , 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: Probably autosomal recessive

Disease-related: yes

Key variant known: no

Year key variant first reported: 2025

Key variant is published: no

Cross-species summary: Renamed from 'Tetradysmelia' to 'Amelia, RSPO2-related' [15/04/2025]
This phene includes entries relating to tetradysmelia (severe reduction of all limb parts distal of the scapula and the pelvic girdle) and bilateral anterior amelia (BAA) (congenital absence of thoracic limbs) due to variants in the RSPO2 gene. This phene may be similar to 'limbless' in chicken (OMIA 000602-9031).

Species-specific name: Bilateral anterior amelia (BAA)

Species-specific symbol: BAA

Mapping: Chevallier et al. (2025): "A GWAS performed with nine [bilateral anterior amelia] BAA affected Chihuahuas identified a significant association on chromosome 13, and homozygosity mapping delineated a 2.1 Mb chromosomal region containing the RSPO2 gene."

Molecular basis: Chevallier et al. (2025): "Six affected Chihuahuas were whole genome sequenced (WGS) and aligned to the CanFam4 assembly. ... Whole genome sequencing identified three single nucleotide variants [NC_049234.1:g.8891861C > T; NC_049234.1:g.8974204C > T and NC_049234.1:g.9789424G > A] associated with the phenotype. Homozygosity for the variants was observed in 12 out of 13 affected dogs, suggesting an autosomal recessive mode of inheritance, though a semi-dominant mode of inheritance cannot be excluded. No structural variants were detected within the interval, but a gap present in all available canine genome assemblies—located in the first intron of RSPO2—may harbor the causative variant." ... The authors conclude "The variants identified in this study may disrupt RSPO2 expression by altering transcriptional regulation. ... Alternatively, the causative variant may reside in the uncovered genomic gap within RSPO2′s first intron. That region, characterized by repetitive elements and structural complexity, could harbor regulatory elements essential for forelimb-specific gene expression."

Clinical features: Chevallier et al. (2025): "All the [13 affected] the dogs ... were Chihuahua-like (n = 6) or mixed-breed Chihuahuas (n = 7) born with no forelimbs ... . They all had a scapula on both sides and presented a residual fragment of the humerus engaged in the glenoid cavity that varied in length ... . All of them were missing all bones distal to the humerus."

Breed: Chihuahua (Dog) (VBO_0200338).
Breeds in which the phene or likely causal variants have been documented. If a likely causal variant has been documented, see variant-specific breed information in the variant table. (Breed information may be incomplete).

Associated gene: