An inherited SLC25A12-related recessive form of congenital porencephaly in Limousin cattle

Background: Congenital abnormalities in cattle, which include lesions in the central nervous system, usually occur sporadically. Porencephaly, a condition characterised by the presence of cystic fluid-filled cavities within brain tissue, is often virus-induced, but rare inherited forms have been identified in other species. Thirty-four calves affected by porencephaly were reported in Limousin cattle in Great Britain and 16 underwent clinicopathological investigation. We aimed to: (1) characterize the disorder phenotype, (2) investigate its possible genetic cause, and (3) determine the frequency of the identified variant across Limousin populations. Results: Affected calves presented blindness and stupor from birth and were unable to suckle without assistance. Brain examination revealed a bilateral symmetrical cavity in the cerebral cortex (porencephaly). Some of the affected calves also showed evidence of ongoing degeneration of the cerebellar cortex, typified by focal, spindle-shaped swellings found on the proximal axons of Purkinje cells (known as ’torpedoes’) within the inner granular layer and intra-myelinic phagocytes in the white matter of the cerebellar folia (cerebellar abiotrophy). After PCR-based exclusion of common teratogenic viruses, monogenic recessive inheritance was hypothesized based on pedigree analysis. Whole-genome mapping and sequencing approaches identified a unique homozygous genome region of 1.2 Mb on chromosome 2 with a private homozygous missense variant in SLC25A12 (NM_001101194.2: c.1742G > A; NP_001094664.1:p.(Arg581Gln)) in three cases. This variant was absent in > 5,000 control genomes. The affected gene encodes a calcium-binding mitochondrial carrier protein and is a known candidate for neurogenetic disorders. Genotyping confirmed recessive inheritance in the random study cohort of British Limousins, with the SLC25A12 variant having an allele frequency close to 0% in the studied French and Swiss Limousin populations. Conclusions: We report the first SLC25A12-related neurodevelopmental disorder in a domestic animal species and assume that the identified pathogenic variant impairs the normal function of the SLC25A12 protein. Thereby, this study provides a new spontaneous large animal model for similar human conditions. The identified allele should be considered in cattle breeding programs to prevent risk matings. Since several neurogenetic disorders share a morphology with virus-induced congenital malformations, diagnostic virus testing should always be considered for aborted, stillborn or live-born calves with porencephaly, alongside a possible genetic aetiology.