Morquio A Syndrome-Associated Mutations: A Review of Alterations in the GALNS Gene and a New Locus-Specific Database

• Published in: Human mutation Vol. 35; no. 11; pp. 1271 - 1279
• Main Authors: Morrone, Amelia, Caciotti, Anna, Atwood, Robert, Davidson, Kathryn, Du, Chaoyi, Francis-Lyon, Patricia, Harmatz, Paul, Mealiffe, Matthew, Mooney, Sean, Oron, Tal Ronnen, Ryles, April, Zawadzki, Karl A., Miller, Nicole
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.11.2014; Hindawi Limited; BlackWell Publishing Ltd
• Subjects: Alleles; Animals; Biomarkers; Chondroitinsulfatases - genetics; Databases, Nucleic Acid; Disease Models, Animal; GALNS; Gene Frequency; Genetic Association Studies; Genetic disorders; Genotype; Geography; Humans; Infant, Newborn; lysosomal storage disorder; Morquio A; MPS IVA; Mucopolysaccharidosis IV - diagnosis; Mucopolysaccharidosis IV - genetics; Mucopolysaccharidosis IV - therapy; mucopolysaccharidosis type IVA; Mutation; Mutation Update; Neonatal Screening; Phenotype; Quantitative Trait Loci; GALNS; MPS IVA; mucopolysaccharidosis type IVA; Morquio A; lysosomal storage disorder
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22635

ABSTRACT Morquio A syndrome (mucopolysaccharidosis IVA) is an autosomal recessive disorder that results from deficient activity of the enzyme N‐acetylgalactosamine‐6‐sulfatase (GALNS) due to alterations in the GALNS gene, which causes major skeletal and connective tissue abnormalities and effects on multiple organ systems. The GALNS alterations associated with Morquio A are numerous and heterogeneous, and new alterations are continuously identified. To aid detection and interpretation of GALNS alterations, from previously published research, we provide a comprehensive and up‐to‐date listing of 277 unique GALNS alterations associated with Morquio A identified from 1,091 published GALNS alleles. In agreement with previous findings, most reported GALNS alterations are missense changes and even the most frequent alterations are relatively uncommon. We found that 48% of patients are assessed as homozygous for a GALNS alteration, 39% are assessed as heterozygous for two identified GALNS alterations, and in 13% of patients only one GALNS alteration is detected. We report here the creation of a locus‐specific database for the GALNS gene (http://galns.mutdb.org/) that catalogs all reported alterations in GALNS to date. We highlight the challenges both in alteration detection and genotype–phenotype interpretation caused in part by the heterogeneity of GALNS alterations and provide recommendations for molecular testing of GALNS. The mutations in GALNS causing Morquio A syndrome are both extremely heterogeneous and feature a high proportion of rare alleles; consequently, the discovery of previously unpublished GALNS alterations from patients with Morquio A is a relatively common occurrence. From previously published data, we find 277 unique GALNS alterations associated with Morquio A. This up‐to‐date summary of known GALNS alterations and accompanying locus‐specific database will be a resource for the Morquio A community.