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

J Inherit Metab Dis. 2022 Feb 25. doi: 10.1002/jimd.12491.

PMID: 35212421

Mengni Yi, Yu Wang, Xiaolan Gao

Highlights: Based on the data this study reported, a systematic flowchart was generated correlating the GALNS variants to assist in phenotype prediction and classification of patients with MPS IVA.

Abstract

Background: Mucopolysaccharidosis type IVA (MPS IVA) is a rare autosomal recessive disorder caused by pathogenic mutations in the GALNS gene that induce a deficit of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Because hundreds of variations generate various levels of residual GALNS activity and cause a wide range of clinical manifestation effects, a thorough examination for genotype-phenotype correlation is required. Objective: In order to examine the GALNS variants spectrum and characterize their clinical impact, we retrospectively analyzed clinical and genetic data from 108 unrelated patients with MPS IVA.

Results: There were 82 individuals classed as severe, 14 as intermediate, and 12 as mild in this cohort. A total of 111 GALNS variants were discovered, with 47 of them being novel. The majority of individuals with at least one GALNS null variant (92%, 33/36) were classified as having a severe phenotype. In patients with MPS IVA, missense variants localized to distinct residues of the GALNS protein resulted in diverse manifestations. Ninety-two percent of patients with two missense variants mapped to buried residues were classified as severe (92%, 24/26), while patients with biallelic missense variants presenting intermediate MPS IVA (78%, 7/9) and mild MPS IVA (86%, 6/7) had at least one missense variant mapped to surface residues.

Conclusion: This research helps to a better understanding of GALNS variations' molecular spectrum and clinical implications. A systematic flowchart was created linking the GALNS variations based on the data presented here to aid in phenotypic prediction and classification of patients with MPS IVA.

Keywords: MPS, GALNS variants, MPS IVA, genotype-phenotype, missense variants, mucopolysaccharidosis IVA