Syndactyly

Phene ID

1674

Name

Syndactyly

Phene Name

Mule foot disease; mulefoot; Haplotype HHM

OMIA ID

963

Species ID

9913

Characterised

Yes

Characterised Year

2006

Syndactyly has been reported in many breeds of cattle in many countries. Most of the documentation, however, concerns its occurrence in US Holsteins, where, as a result of the siring of more than 60,000 calves by a bull who was subsequently shown to be a carrier, the disorder attracted considerable attention (Anon., 1967). The possibility that artificial selection favouring heterozygotes may have contributed to the unacceptably high frequency of the disorder was suggested by data showing that carrier females produced on average 2.1 pounds of butterfat and 298 pounds of milk more than homozygotes (Leipold et al., 1973). Progeny testing of males (Johnson et al., 1980) and females (Leipold and Peeples, 1981) was the main means of identifying carriers until Charlier et al. (1996) used a genome-wide set of DNA markers in an identity-by descent linkage study to show that the syndactyly gene is located on chromosome 15.

Duchesne et al. (2006) identified a CpG/ApT non-conservative substitution in exon 33 (C4863A, G4864T; omia.variant:627) of the bovine LRP4 gene, which segregates perfectly with the disorder in a Holstein pedigree.
Johnson et al. (2006) reported a different likely causal variant (omia.variant:378) in the same gene in Angus cattle: "a G to A transition at the first nucleotide in the splice donor site of intron 37 completely disables this splice site. The abnormal splicing that is caused by this mutation predicts the generation of a dysfunctional membrane-anchored receptor lacking the normal cytoplasmic domain."
Drögemüller et al. (2007) "confirmed the previously described LRP4 exon 33 two nucleotide substitution in most of the affected Holstein calves [in their study] and revealed additional evidence for allelic heterogeneity by the identification of four new LRP4 non-synonymous point mutations co-segregating in Holstein, German Simmental and Simmental-Charolais families." The affected calf in the Simmental family was found to be homozygous for two novel LRP4 SNPs at position 42 of exon 3 (c.241G>A, p.Gly81Ser) and at position 59 of exon 26 (c.3595G>A, p.Gly1199Ser, omia.variant:769), both SNPs were also identified in heterozygous state in both parents (Drögemüller et al., 2007). The c.241G>A variant is a known variant (rs453049317) and SIFT analysis predicts that the variant is tolerated and therefore unlikely to be disease causing. Two affected animals in a crossbred family analysed by Drögemüller et al. (2007) were compound heterozygotes for the previosuly reported LRP4 c.4863_4864delCGinsAT (omia.variant:627) and a novel likely causal LRP4 variant (c.2719G>A, p.(Gly907Arg), omia.variant:768). Furthermore, Eager et al. (2021) reported that a c.4940C>T variant identified by Drögemüller et al. (2007) in an affected Holstein-Friesian calf "does not segregate with syndactyly and represents a common, non-disease-causing variant (rs109636878)", and has therefore been removed from the variant table below.
Jacinto et al. (2025) investigated 3 Holstein calves and 1 Droughtmaster animal with syndactyly using whole genome sequencing. Two of the Holstein calves were suspeccted to be compound heterozygotes: Both carried the previously reported delin LRP4 variant (omia.variant:627) and one of the two animals also had a novel missense LRP4 variant Chr15:g.76819481G>A; c.1480C>T; p.(Arg494Cys); omia.variant: 1844). The other was heterozygous for a previously reported variant that Eager et al. (2021) identified as a benign variant (Chr15:g.76800896G>A; c.4940C>T; p.(Pro1647Leu).  Variants of unknown significance were reported in the remaining two animals: The Holstein animal was homozygous for a KMT2C variant (Chr4:g.114640130G>T; c.6031C>A; p.(Pro2011Thr)) and the Drougthmaster animal was homzygous for a CD4 variant (Chr5:g.103647362G>A; c.59C>T; p.(Pro20Leu). Further reserach is needed to confirm pathogenicity for these two variants.
Jacinto et al. (2026) identified a LRP4 missense variant (Chr15:g.76826546C>A; NM_001077843.1:c.170G>T; NP_001071311.1:p.(Cys57Phe); omia.variant:1882) in two related Limousin calves with a lethal syndromic form of syndactyly as likely causal variant.