Clinical and Molecular Characterization of Pakistani Mucopolysaccharidosis Families with SGSH and GALNS Deficiencies

Background: Mucopolysaccharidoses (MPS) are rare lysosomal storage disorders caused by deficiencies in glycosaminoglycan (GAG)-degrading enzymes, leading to progressive multisystem involvement. Methods: We evaluated two unrelated consanguineous Pakistani families, each with three individuals showing features consistent with MPS. Affected individuals in Family 1 presented with developmental regression, severe cognitive impairment, behavioral abnormalities and facial dysmorphisms. The affected individuals in Family 2 showed classical skeletal dysplasia consistent with Morquio syndrome. Whole-exome sequencing (WES), segregation analysis, and in silico protein modeling were performed to identify and characterize pathogenic gene variants. Results: Analysis of WES data revealed a homozygous missense variant in the SGSH gene [c.548G>A (p.Cys183Tyr)] in the three cases of Family 1 and a homozygous splice-site variant in the GALNS gene (c.423-1G>A) in the cases of Family 2. The SGSH variant, located within the sulfatase catalytic domain and classified as likely pathogenic (ACMG), is consistent with the Sanfilippo A phenotype and represents the first clinical characterization of this allele. Regarding Family 2, we identified the GALNS mutation as a recurrent pathogenic founder allele previously reported in individuals of South Asian descent. Structural modeling of SGSH p.Cys183Tyr predicted disruption of a conserved cysteine residue and altered protein stability, likely supporting its deleterious effect. Conclusions: This study expands the spectrum of MPS-associated variants in Pakistan. The findings underscore the importance of genomic diagnostics for enabling early detection, accurate classification, and genetic counseling in populations with high consanguinity.