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

Abstract

Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is a rare autosomal recessive lysosomal storage disorder caused by mutations in the N‐acetylgalactosamine‐6‐sulfatase (GALNS) gene. We collected, analyzed, and uniformly summarized all published GALNS gene variants, thus updating the previous mutation review (published in 2014). In addition, new variants were communicated by seven reference laboratories in Europe, the Middle East, Latin America, Asia, and the United States. All data were analyzed to determine common alleles, geographic distribution, level of homozygosity, and genotype‐phenotype correlation. Moreover, variants were classified according to their pathogenicity as suggested by ACMG. Including those previously published, we assembled 446 unique variants, among which 68 were novel, from 1190 subjects (including newborn screening positive subjects). Variants' distribution was missense (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 (3.8%). Half (50.4%) of the subjects were homozygous, 37.1% were compound heterozygous, and 10.7% had only one variant detected. The novel variants underwent in silico analysis to evaluate their pathogenicity. All variants were submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) to make them publicly available. Mutation updates are essential for the correct molecular diagnoses, genetic counseling, prenatal and preimplantation diagnosis, and disease management.

A novel splicing variant in GALNS in mucopolysaccharidosis IVA and the necessity of re‐evaluating primer sequences

“…WGS revealed a heterozygous c.1019G > A (p.(Gly340Asp)) variant that was not detected in initial Sanger sequencing. c.1019G > A variant was previously reported in a total of 23 alleles in MPS IVA patients according to a recent review article by Zanetti et al (Chien et al, 2020;Cozma et al, 2015;He et al, 2013;Tomatsu et al, 2004;Tüysüz et al, 2019;Wang et al, 2010;Zanetti et al, 2021). We classified the variant as pathogenic according to the 2015 ACMG/AMP guidelines (PM2+PM3_strong+PP3+PP4) (Richards et al, 2015).…”

“…To date, insufficient evidence is available to classify the pathogenicity of GALNS variants that 58% of variants are classified as VUS according to the 2015 ACMG/AMP classification (Zanetti et al., 2021). In our institution, 12% (4/33) of the observed variants were classified as VUS.…”

“…Molecular analysis can confirm the diagnosis of MPS IVA and is essential for genetic counseling (Morrone et al., 2014). However, a significant number of GLANS gene variants are classified as “of uncertain significance,” which could be attributable to the high genetic heterogeneity of variants in the GALNS gene and the lack of robust functional evidence for most variants (Zanetti et al., 2021). Here we present the case of a Korean boy with clinical and biochemical features clearly indicative of MPS IVA who was molecularly diagnosed by RNA sequencing of a novel intronic variant and discovery of a pathogenic variant on WGS that was missed on initial Sanger sequencing due to allele dropout (ADO) caused by a common benign variant in the primer binding site.…”

Characterization of a novel exonic deletion in the GALNS gene causing Morquio A syndrome

“…Deletions in addition to duplications and other complex rearrangements are not commonly reported in the literature, which could be due to under detection of these variant types [ 10 ]. The deletion characterized in this report was included in the recent review by Zanetti et al 2021 [ 11 ].…”

Delivery and assessment of a CRISPR/nCas9-based genome editing system on in vitro models of mucopolysaccharidoses IVA assisted by magnetite-based nanoparticles

“…Mucopolysaccharidosis IVA (MPS IVA, Morquio syndrome A, OMIM #253000) is a rare genetic disease caused by impaired N -acetylgalactosamine-6-sulfatase (GALNS, E.C.3.1.6.4) activity, which led to the lysosomal accumulation of keratan sulfate (KS) and chondroitin 6-sulfate (C6S) 1 , 2 . Under impaired GALNS activity, among many others, several pathological signal pathways related to oxidative stress 3 , 4 and inflammation 5 – 7 might take place.…”