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In some cases, the digits of the pelvic limbs can be variably affected, but otherwise, the pelvic limbs are generally spared. A GWAS performed with nine BAA affected Chihuahuas identified a significant association on chromosome 13, and homozygosity mapping delineated a 2.1\u00a0Mb chromosomal region containing the <jats:italic>RSPO2<\/jats:italic> gene. Loss of function variants of <jats:italic>RSPO2<\/jats:italic> in humans and cattle has been associated with the absence of all limbs. Six affected Chihuahuas were whole genome sequenced (WGS) and aligned to the CanFam4 assembly. SNVs, small indels, and structural variants within the critical interval that fitted a recessive model were investigated. Three SNVs (NC_049234.1:g.8891861C\u2009&gt;\u2009T; NC_049234.1:g.8974204C\u2009&gt;\u2009T and NC_049234.1:g.9789424G\u2009&gt;\u2009A) were homozygous in five cases and absent from 3,418 genetically diverse control genome sequences, except for one Small Poodle that was heterozygous. One SNV resided in RSPO2\u2019s second intron, while the two others were intergenic. The three candidate variants were genotyped in 7 additional cases and 100 control Chihuahuas. Twelve of 13 cases were homozygous for the mutant allele, and one case was heterozygous. Controls were either homozygous for the reference allele (97%) or heterozygous (3%). Our data should facilitate genetic testing of Chihuahuas to prevent the unintentional production of BAA affected dogs. Moreover, the identification of these variants enhances understanding of <jats:italic>RSPO2<\/jats:italic> gene function in limb development.<\/jats:p>","DOI":"10.1007\/s00335-025-10123-1","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T02:27:57Z","timestamp":1743128877000},"page":"746-760","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The RSPO2 gene is associated with bilateral anterior amelia in Chihuahuas"],"prefix":"10.1007","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8602-1993","authenticated-orcid":false,"given":"Lucie","family":"Chevallier","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marin","family":"Green","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6951-9524","authenticated-orcid":false,"given":"Julia","family":"Vo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8062-0028","authenticated-orcid":false,"given":"Karen","family":"Vernau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6596-5928","authenticated-orcid":false,"given":"Denis J.","family":"Marcellin-Little","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8155-0041","authenticated-orcid":false,"given":"Vidhya","family":"Jagannathan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0553-4880","authenticated-orcid":false,"given":"Tosso","family":"Leeb","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7614-7207","authenticated-orcid":false,"given":"Danika","family":"Bannasch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"issue":"2","key":"10123_CR1","first-page":"135","volume":"8","author":"S Aftimos","year":"1999","unstructured":"Aftimos S, Winship I (1999) A patient with VACTERL association, amelia and hemifacial microsomia. 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