Categories: Limbs / fins / digit / tail phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 615682 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2015

Species-specific name: Also known as Hoof Wall Separation Disease

Species-specific symbol: HWSD

Inheritance: All ponies homozygous for this allele were affected by HWSD suggesting complete penetrance. However, affected ponies have varying levels of disease form mild to severe, indicating variable expressivity. No potential genetic modifiers were found in this study. Heterozygosity for this allele was not a cause for disease (Finno et al., 2015). (FN thanks Daniel J. Schmidt, who provided the basis of this contribution, working under the supervision of Professor Ernie Bailey; 16 April 2020)

Mapping: By conducting a GWAS on 15 affected and 17 non-affected Connemara ponies, each genotyped with the Illumina SNP70 Genotyping Beadchip (yielding 51,453 informative SNPs), Finno et al. (2015) mapped this disorder to a 1.7Mb region on horse chromosome ECA8: 79,936,024–81,676,900 bp; UCSC assembly equCab2.

Molecular basis: Whole-genome next-generation sequencing was conducted on 4 Connemara Ponies (2 cases, 2 control). The variants in the candidate region (see Mapping section above) were evaluated in a larger sample of Connemara Ponies, and a non-synonymous variant within the gene SERPINB11 was identified as the most likely cause of the trait, namely g.83600643_83600644insC (updated to Equcab 3.0) which introduces a frameshift resulting in a premature stop codon (Finno et al., 2015). This variant was homozygous in 23 affected horses and heterozygous in 27 obligate carriers. Evaluation of mRNA levels at the proximal hoof capsule of 8 Connemara ponies (4 cases, 4 controls) showed that SERPINB11 expression was significantly reduced in the affected ponies. (Finno et al., 2015) (FN thanks Daniel J. Schmidt, who provided the basis of this contribution, working under the supervision of Professor Ernie Bailey; 16 April 2020)

Clinical features: Hoof Wall Separation Disease (HWSD) is a disease that affects the Connemara Pony, a breed known for their strong, hearty hooves. HWSD is classified primarily by its clinical signs of a receding dorsal hoof wall and secondary solar proliferation. This disease differs from other causes of separation (e.g. White Line Disease, Abscessation, etc.) because the sole and white line both appear healthy, with the exception of the proliferative sole. (FN thanks Daniel J. Schmidt, who provided the basis of this contribution, working under the supervision of Professor Ernie Bailey; 16 April 2020)

Prevalence: "Within the entire 423-Connemara-pony data set, allele frequency was 18.7% and a total of 96 ponies were heterozygous for the SERPINB11 insertion. The heterozygous animals are all phenotypically unaffected by HWSD. Within a 324-pony subset of individuals unrelated to the affected animals, carrier frequency for the variant is 14.8%." The variant was not found among 169 horses of other unspecified breeds (Finno et al., 2015). (FN thanks Daniel J. Schmidt, who provided the basis of this contribution, working under the supervision of Professor Ernie Bailey; 16 April 2020)

Breed: Connemara Pony (Horse) (VBO_0000937).
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: