Investigation of GALNS variants and genotype–phenotype correlations in a large cohort of patients with mucopolysaccharidosis type IVA

Abstract Mucopolysaccharidosis type IVA (MPS IVA) is a rare autosomal recessive disorder resulting from the deficiency of N ‐acetylgalactosamine‐6‐sulfate sulfatase (GALNS) caused by pathogenic variants in the GALNS gene. A systematic analysis for genotype–phenotype correlation is essential due to hundreds of variants generating different levels of residual GALNS activity and causing a wide degree of clinical manifestation effects. Here, we retrospectively analyzed clinical and genetic data of 108 unrelated patients with MPS IVA to investigate the variants spectrum of GALNS and assess their clinical effects. In this cohort, 82 patients were classified as severe, 14 as intermediate, and 12 as mild. One hundred and one GALNS variants were identified, of which 47 were novel. Most patients with at least one GALNS null variant were classified as severe phenotype (92%, 33/36). Missense variants mapped to different residues of GALNS protein resulted in different phenotypes in patients with MPS IVA. Ninety‐two percent of patients with two missense variants mapped to buried residues were classified as severe (92%, 24/26), while at least one missense variant mapped to surface residues was identified in patients with biallelic missense variants presenting intermediate MPS IVA (78%, 7/9) and presenting mild MPS IVA (86%, 6/7). Our study contributes to a better understanding of the molecular spectrum of GALNS variants and their clinical implications. Based on the data herein reported, we generated a systematic flowchart correlating the GALNS variants to assist in phenotype prediction and classification of patients with MPS IVA.