Ngiwsara L.Dhachpramuk D.Sawangareetrakul P.Vongphit S.Pacharn P.Svasti J.Vatanavicharn N.Mahidol University2025-04-082025-04-082025-01-01Annals of Human Genetics (2025)00034800https://repository.li.mahidol.ac.th/handle/123456789/109375ABSTRACT: Galactosialidosis (GS) is a rare lysosomal storage disease (LSD) with variable onset caused by a defect in protective protein/cathepsin A (PPCA) encoded by the CTSA gene. The late-infantile onset is characterized by developmental delay, visceromegaly, coarse facies, and cherry-red macula. We report cases of late-infantile GS in a Thai-Lahu family, with affected members initially presenting with recurrent infections due to T-cell defects. The clinical features of LSD and cherry-red macula led us to perform lysosomal enzyme assays, which showed undetectable activity of PPCA. A novel homozygous missense CTSA variant (NM_000308.4): c.1307A > G (p.Gln436Arg) was identified in affected individuals. In vitro functional analysis suggested that the variant may impair the dimerization process of PPCA, potentially disrupting proper protein maturation or function and leading to significantly reduced PPCA activity. Exome sequencing did not reveal any variants in other genes associated with primary immunodeficiencies. To date, our cases represent the first reported patients with GS and T-cell defects. Our study broadened the clinical and genotype spectrum of this rare disease.Biochemistry, Genetics and Molecular BiologyMedicineArticleSCOPUS10.1111/ahg.125952-s2.0-10500143380414691809