Possibly relevant human trait(s) and/or gene(s) (MIM number): 603434 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2020

History: "An autosomal recessive, neurodevelopmental abnormality spontaneously arose in a domestic cat closed breeding colony at Auburn University that was established to study lysosomal storage diseases" (Graff et al., 2020)

Mapping: Graff et al. (2020): "To identify the underlying genetic cause of cerebral dysgenesis, we initially carried out whole genome sequencing (WGS) and RNA-seq-based genotyping of eight affected animals and six obligate carriers. ... Applying zygosity-based filtering criteria under the model of complete penetrance of an autosomal recessive trait, we identified all variants that were homozygous in eight affected animals and heterozygous in the six obligate carriers, and observed a cluster of variants that was significantly enriched (p = 0.006, chi-square vs. random genome-wide distribution) in a 5 Mb region towards the end of chromosome F1. ... To confirm and further fine-map the region, we carried out amplicon-based genotype-by-sequencing on an additional 91 cats."

Molecular basis: Graff et al. (2020) "report that a loss of function variant in PEA15 (XM_023247767.1:c.176delA, XP_023103535.1:p.(Asn59fs), felCat9 chrF1:66768323 GT -> G) is likely responsible for a form of cerebral dysgenesis in the domestic cat, characterized by microcephaly and polymicrogyria."

Clinical features: Graff et al. (2020): "Animals with cerebral dysgenesis exhibit spastic tetraparesis and ataxia first apparent around 3–4 weeks of age as they begin to walk. As the animals grow, spasticity and ataxia partially resolve, stabilizing by 6–9 months of age. At approximately 1.5 years, affected cats develop sensory abnormalities and often become aggressive. Sensory abnormalities manifest as stargazing and fly-biting: staring into empty space, and attacking or biting with no stimulus present, respectively. Aggressive behaviors were often erratic, unpredictable and included unprovoked attacks on long-term cage mates and caretakers. Some affected animals had seizures, although abnormal baseline EEG tracings were not observed. There were no deviations from reference intervals in complete blood count, serum biochemistry or urinalysis of affected cats, indicating that apart from the severe neurologic changes there was no additional systemic disease."

Pathology: Graff et al. (2020): "At necropsy, affected juvenile and adult cats exhibited generalized microcephaly and polymicrogyria with focal lissencephaly and regional gyral variability .... The most severely affected areas (frontoparietal) often had a cobblestone appearance. The average brain weight of affected cats was 4.3 grams per kilogram of body weight, while for unaffected and carrier cats average brain weight was 7.8 grams per kilogram, indicating a 45% decrease in brain mass ... . In contrast to the significant abnormalities in the cerebral cortex, the size and structure of the cerebellum was normal with no vermal or hemispheric hypoplasia, dysplasia or agenesis. ... Brains from affected cats aged 1–8 months were evaluated histologically in comparison to aged-matched controls ... . Overall, affected cats exhibited variable thinning of the cerebral cortex, especially in dorsal and lateral regions, and disorganization of cortical layers. In severely affected areas, cortical neurons were present in an undulating laminar band reminiscent of gyri, but sulci were largely absent and gyral folds were irregular in size, location, distribution, and orientation. White matter of the corona radiata and internal capsule was markedly decreased in volume, but the corpus callosum was generally spared. Basal nuclei appeared normally organized, as did olfactory tubercles, olfaction tracts and thalamus, although all areas were smaller than age-matched controls. Recapitulating the impressions garnered at necropsy, the cerebellum was normally organized with all layers including an age-appropriate external granule layer in cats younger than 3–4 months."

Associated gene: