Categories: Integument (skin) phene

Possibly relevant human trait(s) and/or gene(s) (MIM number): 615886 (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: 2014

Species-specific name: Hereditary Footpad Hyperkeratosis

Species-specific symbol: HFH

Mapping: By conducting a GWAS with the 173k illumina canine HD chip in each of two breeds (Kromfohrländer: 13 cases and 29 controls, with 77,903 informative SNPs; Irish Terrier: 10 cases and 21 controls, with 82,671 informative SNPs), Drögemüller et al. (2014) mapped this disorder to a single region on chromosome CFA5. Homozygosity mapping across the two breeds narrowed the candidate region to 611kb (CFA5: 40,521,040–41,131,739 CanFam 3.1 assembly), containing 13 genes.

Molecular basis: Comparison of sequence in the positional candidate region, from whole-genome sequencing of an affected Kromfohrländer at 23.5x coverage, with relevant sequence from 46 non-affected dogs from other breeds identified the causal mutation as "a missense variant (c.155G>C) in the FAM83G gene encoding a protein with largely unknown function. It is predicted to change an evolutionary conserved arginine into a proline residue (p.R52P)". The causality of this variant was confirmed by genotyping of this mutation in other affected and normal dogs.

In a proof-of-concept project to detect a likely causal mutation without GWAS, Sayyab et al. (2016) reported the first use of whole-genome sequencing of a family trio (affected offspring and its two non-affected parents) which enabled them to confirm the causal mutation reported by Drögemüller et al. (2014): "527 single nucleotide variants (SNVs) and 15 indels were found to be homozygous in the affected offspring and heterozygous in the parents. Using the computer software packages ANNOVAR and SIFT to functionally annotate coding sequence differences and to predict their functional effect, resulted in seven candidate variants located in six different genes. Of these, only FAM83G:c155G>C (p.R52P) was found to be concordant in eight additional cases and 16 healthy Kromfohrländer dogs."

Clinical features: As summarised by Drögemüller et al. (2014): "Hyperkeratosis of the foot pads is noticed by the owners of both breeds at 4–5 months of age and involves all footpads. With time horny protrusions appear on the rims of the footpads and the pad surface becomes hard and develops cracks . . . . Affected animals avoid walking on irregular surfaces and may go lame. The nails of affected dogs are very hard and seem to grow faster. We noticed a duller, less wiry, softer coat on an affected Kromfohrländer . . . . Similar clinical symptoms were noted on 5 HFH affected Irish Terriers."

Breeds: Irish Terrier, Kromfohrländer.

Associated gene: