In other species: dog

Possibly relevant human trait(s) and/or gene(s) (MIM number): 613456

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Co-Dominant

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2016

Species-specific description: As summarised by Lyons et al. (2016), "The Burmese is a cat breed with an extreme brachycephalic phenotype . . .. In the late 1970's, a male Burmese cat in the USA with a more brachycephalic head type became a highly popular sire and his lineage became known as the “Contemporary” Burmese . . . . The head type was found to be heritable, however, offspring from “Contemporary” style mating produced a craniofacial defect in 25% of offspring (Noden and Evans, 1986 and Sponenberg and Graf-Webster, 1986). The abnormality is characterized by agenesis of all derivatives of the medial nasal prominence; lateral duplication of most derivatives of the maxillary process; including the canine teeth and whiskers fields; telencephalic meningoencephalocele; and secondary ocular degeneration . . . . The midline facial defect is autosomal recessive, however, carriers of the mutation are more brachycephalic individuals than wildtype and were positively selected in the breed, thus the trait has also been described as co-dominant. Affected kittens were generally born live and require euthanasia as the condition is incompatible with life. The heterozygous cats became the hallmark phenotype of the “Contemporary” Burmese and the predominant winners at cat shows."

Mapping: Lyons et al. (2016) reported that "Family-based linkage analysis localized the trait to cat chromosome B4".

Markers: Bertolini et al. (2016) identified four ~1Mb regions of homozygosity peculiar to Persian cats (which are characterised by an extreme form of brachycephaly), one of which contains two genes "CHL1 and CNTN6 known to determine face shape modification in humans".

Molecular basis: Lyons et al (2016): "A long-term project that initiated with targeted linkage analysis, and, as domestic cat genomic resources improved, progressed to identity by descent mapping, homozygosity mapping and a genome-wide case-control association study (GWAS) suggests ALX1 as a major gene controlling craniofacial structure and the variant in ALX1 is associated with the Burmese brachycephaly and the craniofacial abnormality". "Sequence analysis identified a 12 bp in frame deletion in ALX1, c.496delCTCTCAGGACTG, which is 100% concordant with the craniofacial defect and not found in cats not related to the Contemporary Burmese."

Associated gene: