In other species: domestic cat , pig , taurine cattle , rabbit

Categories: Digestive / alimentary phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 600155 (trait) , 277580 (trait) , 600501 (trait) , 131244 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1998

Cross-species summary: Also known as Hirschsprung disease. A disorder in which the large intestine (caecum, colon and sometimes the rectum) undergoes a large dilation and fills with faecal mass. Associated with incomplete migration of nerve cells to the intestine during embryonic development, resulting in lack of peristalsis and hence a build-up of faecal material.

Species-specific name: Overo lethal white foal syndrome; frame overo spotting

Species-specific symbol: OLWFS

Species-specific description: As with white spotting, the Overo coat-colour pattern is characterised by pigment spreading down both sides from the dorsal midline, giving way to lack of pigment (i.e. white) primarily on the ventral surfaces. Unfortunately, homozygosity for the Overo allele results in white or nearly white foals which die within a few days of birth: the so-called lethal white foal sysndrome (LWFS). The cause of death is intestinal obstruction resulting from a lack of nerve cells in the distal portion of the large intestine (aganglionic megacolon), which is thought to be due to a fault in the proliferation and/or migration of nerve stem cells from the neural crest of the developing embryo.

Inheritance: The Overo coat colour is dominant to normal solid colour, but lethal white foal syndrome (LWFS) is recessive (i.e. the only horses to show this disorder are homozygotes for the Overo allele).

Molecular basis: Noting that mutations in the genes for endothelin 3 (EDN3) or its receptor (EDNRB) are responsible for similar disorders in humans and rodents, Santschi et al. (1998), from the University of Minnesota, sequenced cDNA from 22 affected foals, their parents, and some solid-colour normal controls, all registered with the American Paint Horse Association. There was no variation in the EDN3 gene, but a di-nucleotide substitution (TC>AG) at nucleotides 353-354 of the gene for EDNRB, resulting in an Ile118Lys amino-acid substitution, segregates perfectly with LWFS, thereby providing a molecular explanation for the disorder in American Paint horses. In quick succession, two other research groups reported similar findings: Metallinos et al. (1998), from the University of California, found the same mutation in other US horses; and Yang et al. (1998) found the same mutation causing the same disorder in Australian horses. Interestingly, both American studies found that some non-overo horses are carriers, suggesting that the mutation has incomplete penetrance.

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

Prevalence: Badial et al. (2018) "developed and validated a high-resolution melting (HRM) genotyping assay to detect the OLWFS causative mutation, and . . . also determined the frequency of heterozygotes among American Paint horses in Brazil. . . . The overall estimated frequency of heterozygotes was 21.6%; however, this frequency increased to 89.5% when considering only overo horses".

Associated gene: