Molecular basis of mucopolysaccharidosis IVA (Morquio A syndrome): A review and classification of GALNS gene variants and reporting of 68 novel variants

Hum Mutat 2021 Aug 13. doi: 10.1002/humu.24270.

PMID: 34387910

Alessandra Zanetti, Francesca D'Avanzo, Moeenaldeen AlSayed

Highlights: Mutation updates are essential for the correct molecular diagnoses, genetic counseling, prenatal and preimplantation diagnosis, and disease management.

Abstract

Objective: Mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene cause Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome), a rare autosomal recessive lysosomal storage disease. All reported GALNS gene variants were gathered, evaluated, and consistently summarized, thereby updating the prior mutation review (published in 2014). In addition, seven reference laboratories in Europe, the Middle East, Latin America, Asia, and the United States reported novel variants.

Methods: All of the data was examined for common alleles, geographic distribution, level of homozygosity, and genotype-phenotype correlation. Furthermore, as proposed by ACMG, variants were categorized according to their pathogenicity.

Results: We gathered 446 unique variants from 1190 individuals, including those previously published, of which 68 were novel (including newborn screening positive subjects). Missense was the most common kind of variant (65.0%), followed by nonsense (8.1%), splicing (7.2%), small frameshift deletions(del)/insertions(ins) (7.0%), intronic (4.0%), and large del/ins and complex rearrangements (4.0%). (3.8%). Half of the subjects (50.4%) were homozygous, 37.1% were compound heterozygous, and 10.7% had only one variant. In silico analysis was used to assess the pathogenicity of the novel variants. ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) was used to make all variants publicly available.

Conclusion: For accurate molecular diagnoses, genetic counseling, prenatal and preimplantation diagnosis, and disease treatment, mutation updates are required.

Keywords: GALNS, MPS IVA, Morquio A syndrome, N-acetylgalactosamine-6-sulfate, lysosomal storage disorder, mucopolysaccharidosis IVA