In other species: dog , pig , sheep

Categories: Hearing / vestibular / ear phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 113500 (trait) , 606835 (trait) , 606071 (trait) , 156530 (trait) , 168400 (trait) , 181405 (trait) , 184095 (trait) , 600175 (trait) , 184252 (trait) , 605427 (gene) , 613719 (gene) , 613718 (trait) , 617383 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal incomplete dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2016

Species-specific name: Scottish fold, Scottish Fold osteochondrodysplasia (SFOCD), osteodystrophy

Species-specific description: This entry combines information about two phenes in cats: 'OMIA:000319-9685 : Ears folded (drop vs prick)' and 'OMIA:001315-9685 : Osteochondrodysplasia' as both are caused by the same mutation.

Inheritance: Data supporting incompletely penetrant autosomal dominant inheritance was reported by Todd (1972), Dyte and Turner (1973) and Takanosu et al. (2008).

Mapping: By conducting a case-control GWAS on "35 Scottish fold and 32 controls (17 Scottish Shorthair, 8 Selkirk Rex, 3 British Shorthair and 4 Persian)", each genotyped with the Illumina Infinium Feline 63K iSelect DNA chip (yielding 46,203 informative SNPs), Gandolfi et al. (2016) mapped this disorder to a region of chromosome FCAD3 from D3:24,380,099 bp to D3:25,202,262 bp.

Molecular basis: Of the 23 genes in the mapped region (see above), Gandolfi et al. (2016) identified the most likely candidate as TPRV4. mutations in which are "responsible for a spectrum of dominantly inherited human skeletal dysplasias" (see Possible human homologues above). Sequencing of the coding sequence of this gene in 2 affecteds and 3 controls, followed by direct sequencing in other cats revealed just one missense mutation (c.1024G>T; p.V342F) as the likely cause: "all 21 Scottish shorthair cats were homozygous for the wild-type allele, two Scottish fold cats were homozygous for the variant allele and 39 Scottish fold cats were heterozygous. A single Scottish fold cat tested homozygous wild-type". Further "Screening of 648 cats representing several breeds and domestic shorthair cats of unknown ear type demonstrated the c.1024G>T substitution was detected only in the Scottish fold breed and was absent in all other populations."

Clinical features: As summarised by Gandolfi et al. (2016), "Scottish fold cats, named for their unique ear shape, have a dominantly inherited osteochondrodysplasia involving malformation in the distal forelimbs, distal hindlimbs and tail, and progressive joint destruction." Rorden et al. (2021) "early work demonstrated that homozygous cats with two copies of this variant develop severe radiographic consequences. Subsequent breeding programs have mated heterozygous cats with straight-eared cats to ensure an equal mix of heterozygous (fold) and wild-type (nonfolded) offspring, in the hope of raising healthy cats. More recent radiological surveys suggest that these heterozygous cats may also have medical problems consisting of deformed distal extremities in the worst cases and accelerated onset of osteoarthritis. … Our aim was to determine if heterozygous cats exhibit radiological abnormalities…. Specifically, DNA and radiographs were acquired for 22 Scottish Fold cats. Four reviewers, blinded to the ear phenotype, assessed the lateral radiographs. … Although each reviewer, on average, gave a numerically worse 'severity score' to folded-ear cats relative to straight-ear cats, the images in heterozygous cats showed much milder radiological signs than previously published.”

Pathology: Gandolfi et al. (2016): "Preliminary histologic examinations suggested chondrocyte cell death in articular cartilage, and disturbed maturation of proliferative chondrocytes to hypertrophic chondrocytes in the growth plate [Malik et al., 1999]." Endochondral ossification of tail bones, carpal, metacarpal, tarsal and metatarsal bones are observed in affected animals. Joint inflammation results from the joint fusion, and exostoses (benign bone growths) may also occur (Rorden et al., 2020). [IT thanks DVM students Beverly Hwang and Grace Iacobbe for contributions to this entry in April 2022]

Breeds: Foldex (Cat) (VBO_0100099), Highland Fold (Cat) (VBO_0100112), Scottish Fold (Cat) (VBO_0100209), Scottish Fold Longhair (Cat) (VBO_0100210).
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: