Molecular basis of mucopolysaccharidosis IVA in a large cohort: genotype-phenotype correlations and reporting of 12 novel GALNS variants.

Mucopolysaccharidosis type IVA (MPS IVA) is an autosomal recessive lysosomal storage disorder caused by deficient activity of N-acetylgalactosamine-6-sulfatase (GALNS). In this single-center study, we analyzed the clinical and genetic characteristics of 82 pediatric MPS IVA patients, including 68 severe, 12 intermediate, and 2 mild cases. The most common clinical manifestations were pectus carinatum (72%), short stature (56%), and genu valgum (45%). All patients showed markedly reduced GALNS activity, although no significant difference was observed across phenotypic subgroups. Genetic analysis identified 66 distinct GALNS variants, 12 of which were novel. The c.953T>G (p.M318R) variant was the most frequent allele (24.7%). Based on integrated clinical, structural, and in silico assessments, p.M318R and p.R386C were linked to severe disease, whereas p.P499L was associated with mild phenotypes. Protein structure analysis revealed that all homozygous missense variants located in domain 1 correlated with severe presentations. Among patients carrying two missense variants, 85% (34/40) exhibited severe symptoms, and 70.6% (24/34) of these had at least one variant affecting buried residues. Notably, 85.7% (24/28) of patients with biallelic buried-residue missense variants were classified as severe. In summary, this study delineates the phenotypic spectrum of MPS IVA, expands its genotypic landscape, and provides a foundation for further genotype-phenotype investigations.