Mucopolysaccharidosis type VI (MPS VI) and molecular analysis: Review and classification of published variants in the ARSB gene

Abstract

Maroteaux-Lamy syndrome (MPS VI) is an autosomal recessive lysosomal storage disorder caused by pathogenic ARSB gene variants, commonly diagnosed through clinical findings and deficiency of the arylsulfatase B (ASB) enzyme. Detection of ARSB pathogenic variants can independently confirm diagnosis and render genetic counseling possible. In this review, we collect and summarize 908 alleles (201 distinct variants, including 3 polymorphisms previously considered as disease-causing variants) from 478 individuals diagnosed with MPS VI, identified from literature and public databases. Each variant is further analyzed for clinical classification according to American College of Medical Genetics and Genomics (ACMG) guidelines. Results highlight the heterogeneity of ARSB alleles, with most unique variants (59.5%) identified as missense and 31.7% of unique alleles appearing once. Only 18% of distinct variants were previously recorded in public databases with supporting evidence and clinical significance. ACMG recommends publishing clinical and biochemical data that accurately characterize pathogenicity of new variants in association with reporting specific alleles. Variants analyzed were sent to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), and MPS VI locus-specific database (http://mps6-database.org) where they will be available. High clinical suspicion coupled with diagnostic testing for deficient ASB activity and timely submission and classification of ARSB variants with biochemical and clinical data in public databases is essential for timely diagnosis of MPS VI.

Keywords: ARSB; ASB; MPS VI; arylsulfatase B; databases; lysosomal storage disorder; variants.

Figure 1

Unique non‐polymorphic ARSB variants classified by mutation type, most common being missense and small deletion (N = 198 variants)

Figure 2

ARSB gene structure including coding variants reported >5 times Location of selected MPS VI variants in the human ARSB gene and ASB peptide. Exons are represented by grey boxes; cDNA coordinates are indicated within the exons. ASB protein domains are color coded as shown by legend. Individual variants are color coded by mutation type

Figure 3

Most common alleles for the 10 most frequent nationalities/ethnic backgrounds reported. The number of times an allele was encountered in a population is shown in parentheses. In grey other variants, reported less or equal to 5 times

Figure 4

ASB structure and variants of special interest Three‐dimensional structure of mature human ASB protein overlaid with variants of interest. The enzyme active site pocket is indicated by colored space‐filling models