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Review
. 2021 Nov;42(11):1384-1398.
doi: 10.1002/humu.24270. Epub 2021 Aug 23.

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

Alessandra Zanetti  1   2 , Francesca D'Avanzo  1   2 , Moeenaldeen AlSayed  3 , Ana Carolina Brusius-Facchin  4 , Yin-Hsiu Chien  5 , Roberto Giugliani  6 , Emanuela Izzo  7 , David C Kasper  8 , Hsiang-Yu Lin  9 , Shuan-Pei Lin  9 , Laura Pollard  10 , Akashdeep Singh  7 , Rodolfo Tonin  11   12 , Tim Wood  10 , Amelia Morrone  11   12 , Rosella Tomanin  1   2
Affiliations
Review

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

Alessandra Zanetti et al. Hum Mutat. 2021 Nov.

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.

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

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Conflict of interest statement

Moeenaldeen AlSayed has received honorarium and travel reimbursement from BioMarin Pharmaceutical Inc., Shire, and Sanofi Genzyme. Yin‐Hsiu Chien is on the advisory board of Amicus and Sanofi, has received consulting fees from Amicus and Sanofi, has conducted research for Sanofi, and has received honoraria from Biogen, BioMarin Pharmaceutical Inc., Novartis, Sanofi, and Takeda. Roberto Giugliani has been an investigator, consultant, and/or speaker for Abeona, Allevex, Amicus, BioMarin Pharmaceutical Inc., Chiesi, Denali, Idorsia, Inventiva, JCR, Lysogene, Novartis, PassageBio, PTC, RegenxBio, Sanofi‐Genzyme, Sigilon, Sobi, Takeda, and Ultragenyx. Emanuela Izzo and Akashdeep Singh are employees of BioMarin Pharmaceutical Inc. David C. Kasper is an employee of ARCHIMED Life Science GmbH and is a stockholder in ARCHIMED Life Science GmbH. Hsiang‐Yu Lin has been an investigator, consultant, and/or speaker for BioMarin Pharmaceutical Inc., Sanofi‐Genzyme, and Takeda. Shuan‐Pei Lin is on the advisory board of HOS and Shire and has received honoraria from Sanofi Genzyme. Tim Wood is on the advisory board of Amicus‐Fabry. Amelia Morrone has been an investigator, consultant, and/or speaker for BioMarin Pharmaceutical Inc., Sanofi‐Genzyme, and Takeda. The remaining authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Distribution of subjects' zygosity. Percentage distribution of zygosity of the collected genotypes (n = 1190). “Other” refers to subjects in which >2 variants were described
Figure 2
Figure 2
Distribution of unique variant types (n = 446)
Figure 3
Figure 3
Schematic representation of the distribution of exonic variants in the GALNS protein. Exonic variants, excluding large deletions, insertions, and complex rearrangements, are represented in a schematic of the GALNS protein (522 amino acids). Missense variants are reported at the top of the figure and the remaining exonic variants at the bottom. “Lollipop” lengths represent variant frequency
Figure 4
Figure 4
Distribution of reported GALNS alleles by continent
Figure 5
Figure 5
Most common alleles† for the 10 most frequent nationalities/ethnic backgrounds reported. †Alleles registered ≥5 times are reported. “Others” are variants reported <5 times. Numbers related to “others” are shown within parentheses. Total allele numbers include those alleles for which originating countries/ethnographic origins were available/reported. Total number of unique variants is shown after the semicolon on the x‐axis. Middle East includes Saudi Arabia, Iraq, Iran, and Oman. NCBI reference sequences: NM_000512.5 for the GALNS gene and NP_000503.1 for the GALNS protein
See this image and copyright information in PMC

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