Targeted Sequencing of HEXA Gene Shows Missense Substitution (p.Arg499His) in a Large Pakistani Family with Tay-Sachs Disease

Tay-Sachs disease or GM2 gangliosidosis, is caused by a deficiency of beta-hexosaminidase A (HEXA), resulting in lysosomal accumulation of GM2 ganglioside. However, deficiencies or reduced activities of HEXA and HEXB result in Sandhoff disease. The patients manifest with the macular cherry-red spots due to lipid-laden ganglion cells, hypotonia, low muscle tone, intractable seizures, developmental arrest, blindness, and neurological deterioration. The aim of this study was to identify the TSD-causing variant in a large Pakistani family showing typical symptoms of Tay-Sachs disease. Here, we studied a large Pakistani family with six TSD patients for the identification of the pathogenic variant by targeted DNA sequencing. As a result, we identified a missense substitution (p.Arg499His) in exon 13 of HEXA that was completely cosegregated among affected and normal individuals. In conclusion, we identified a missense substitution (p.Arg499His) in HEXA gene in a large consanguineous Pakistani family and further enriched the mutational spectrum of HEXA through Pakistani patients for the early diagnosis of the disease.