In other species: horse , pig , sheep

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 236100 , 157170 , 142945 , 142946 , 609637 , 605934 , 610828 , 609408 , 610829 , 614226

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2020

Cross-species summary: Developmental failure of cleavage of the forebrain (prosencephalon); with a deficit in midline facial development, and with cyclopia (see MIA 000249) in the severe form.

History: As summarised by Yu et al. (2020), "In an effort to develop a breed of cats [Toyger] having similar phenotypes to a tiger, including a small rounded ear, a mixed breed cat derived from the Oriental cat breed was discovered to have small rounded ears and hence, was used as a foundation sire for a breeding program. Outcross and backcross breeding indicated the phenotype was autosomal recessive [Keating et al., 2016]. However, a magnetic resonance imaging (MRI) examination of a kitten with the desired ear phenotype, which had an accidental head injury from a fall, indicated the presence of congenital hydrocephalus. Additional MRIs of the breeding stock suggested cats with the ear phenotype had congenital brain malformations. These cats have small rounded ear pinnae and doming of the head . . . . This extended family of mixed-breed cats derived from the Oriental breed has been characterized clinically and histopathologically with forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts. . . . As a result of the potentially harmful impacts associated with the trait, the breeder promptly discontinued the breeding program".

Inheritance: Keating et al. (2016) provided evidence consistent with autosomal recessive inheritance.

Mapping: Yu et al. (2020): "Forty-three cats were genotyped on the Illumina Infinium Feline 63K iSelect DNA Array and used for analyses. Genome-wide association studies, including a sib-transmission disequilibrium test and a case-control association analysis, and homozygosity mapping, identified a critical region on cat chromosome A3."

Molecular basis: Yu et al. (2020): "Short-read whole genome sequencing was completed for a cat trio segregating with the syndrome. A homozygous 7 bp deletion in growth differentiation factor 7 (GDF7) (c.221_227delGCCGCGC [p.Arg74Profs]) was identified in affected cats, by comparison to the 99 Lives Cat variant dataset, validated using Sanger sequencing and genotyped by fragment analyses. . . . The variant segregated concordantly in an extended pedigree."

Clinical features: "Ventriculomegaly with frequent concomitant supratentorial interhemispheric, communicating ventricular type-1b cysts and multiple midline and callosal malformations were detected in all cats displaying neurologic signs" (Keating et al., 2016)

Prevalence: Yu et al. (2020): "This variant was not identified in 192 unaffected cats in the 99 Lives dataset."

Breed: Toyger.

Associated gene: