In other species: chicken , tammar wallaby , dog , domestic cat , pig , sheep , Swainson's hawk

Categories: Limbs / fins / digit / tail phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 212780 (trait) , 186100 (trait) , 186200 (trait) , 186300 (trait) , 604270 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2006

Cross-species summary: Fusion of the claws (cleats or digits). Occurs in one, two, three or (rarely) four legs.

Species-specific name: Mule foot disease; mulefoot; Haplotype HHM

Species-specific symbol: MFD; SY; HHM

Species-specific description: 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.

Mapping: Charlier et al. (1996) conducted a genome scan with 213 microsatellite markers genotyped on just 12 syndactylous (mule foot) animals and on a DNA pool of 10 unrelated non-affected animals from the same breed. Identity-by-descent mapping ("searching for shared homozygous haplotypes among affected individuals") identified a single region on each three chromosomes as being significant. Genotyping an additional 29 animals from the same pedigree, followed by a conventional linkage analysis, mapped the disorder to the telomeric end of chromosome BTA15. In the course of their large-scale study of BovineSNP50 BeadChip haplotypes that are common but never homozygous, VanRaden et al. (2011) mapped this disorder to BTA15 at 76-82Mb (UMD 3.0 genome assembly), consistent with the results of Charlier et al. (1996).

Molecular basis: Duchesne et al. (2006) identified a CpG/ApT non-conservative substitution in exon 33 (C4863A, G4864T) of the bovine LRP4 gene, which segregates perfectly with the disorder in a Holstein pedigree. Johnson et al. (2006) reported a different mutation 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), 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. 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.

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Breeds: Angus (Cattle) (VBO_0000104), Holstein Friesian (Cattle) (VBO_0000239), Simmental (Cattle) (VBO_0000380), Simmental Charolais Cross.
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: