A novel HEXA frameshift mutation identified in Angus cattle with GM2 gangliosidosis

Gangliosidoses are inherited lysosomal storage disorders characterised by neuronal accumulation of gangliosides. While GM1 gangliosidosis has been reported in cattle, GM2 gangliosidosis has yet to be. We investigated a herd of Angus cattle with progressive neurological signs, including blindness, ataxia and lethargy. Histopathology revealed widespread neuronal vacuolation, and electron microscopy identified laminated cytoplasmic bodies consistent with ganglioside accumulation. Whole-genome sequencing of an affected calf identified a homozygous frameshift variant in the HEXA gene (NC_037337.1:g.19269480_19269481delinsGGAGT, NM_001075164.2: c.(834_835delinsACTCC)), absent from 18 control genomes and 1842 individuals in the 1000 Bull Genomes Project. The variant was confirmed in homozygous form in all four affected animals by Sanger sequencing and meets multiple criteria for pathogenicity. These findings support a diagnosis of GM2 gangliosidosis type I, representing the first report in cattle and enabling development of a diagnostic test for carrier screening and herd management.