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

backgroundCongenital 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.

resultsAffected 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.

conclusionsWe 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.