title: Optimizing the molecular diagnosis of GALNS: novel methods to define and characterize Morquio-A syndrome-associated mutations.
abstract: Morquio A syndrome (MPS IVA) is a systemic lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), encoded by the GALNS gene. We studied 37 MPS IV A patients and defined genotype-phenotype correlations based on clinical data, biochemical assays, molecular analyses, and in silico structural analyses of associated mutations. We found that standard sequencing procedures, albeit identifying 14 novel small GALNS genetic lesions, failed to characterize the second disease-causing mutation in the 16% of the patients' cohort. To address this drawback and uncover potential gross GALNS rearrangements, we developed molecular procedures (CNV [copy-number variation] assays, QF-PCRs [quantitative fluorescent-PCRs]), endorsed by CGH-arrays. Using this approach, we characterized two new large deletions and their corresponding breakpoints. Both deletions were heterozygous and included the first exon of the PIEZO1 gene, which is associated with dehydrated hereditary stomatocitosis, an autosomal-dominant syndrome. In addition, we characterized the new GALNS intronic lesion c.245-11C>G causing m-RNA defects, although identified outside the GT/AG splice pair. We estimated the occurrence of the disease in the Italian population to be approximately 1:300,000 live births and defined a molecular testing algorithm designed to help diagnosing MPS IVA and foreseeing disease progression.
authors.affiliation: Molecular and Cell Biology Laboratory, Paediatric Neurology Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, Florence, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caciotti
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Tonin
authors.forename: Miriam
authors.initials: M
authors.lastname: Rigoldi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Ferri
authors.forename: Serena
authors.initials: S
authors.lastname: Catarzi
authors.forename: Catia
authors.initials: C
authors.lastname: Cavicchi
authors.forename: Elena
authors.initials: E
authors.lastname: Procopio
authors.forename: Maria Alice
authors.initials: MA
authors.lastname: Donati
authors.forename: Anna
authors.initials: A
authors.lastname: Ficcadenti
authors.forename: Agata
authors.initials: A
authors.lastname: Fiumara
authors.forename: Rita
authors.initials: R
authors.lastname: Barone
authors.forename: Livia
authors.initials: L
authors.lastname: Garavelli
authors.forename: Maja Di
authors.initials: MD
authors.lastname: Rocco
authors.forename: Mirella
authors.initials: M
authors.lastname: Filocamo
authors.forename: Daniela
authors.initials: D
authors.lastname: Antuzzi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scarpa
authors.forename: Sean D
authors.initials: SD
authors.lastname: Mooney
authors.forename: Biao
authors.initials: B
authors.lastname: Li
authors.forename: Anastasia
authors.initials: A
authors.lastname: Skouma
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Bianca
authors.forename: Daniela
authors.initials: D
authors.lastname: Concolino
authors.forename: Rosario
authors.initials: R
authors.lastname: Casalone
authors.forename: Elena
authors.initials: E
authors.lastname: Monti
authors.forename: Marilena
authors.initials: M
authors.lastname: Pantaleo
authors.forename: Sabrina
authors.initials: S
authors.lastname: Giglio
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Rossella
authors.initials: R
authors.lastname: Parini
authors.forename: Amelia
authors.initials: A
authors.lastname: Morrone
mesh_terms: D000293:Adolescent; D000328:Adult; D002460:Cell Line; D002811:Chondroitinsulfatases / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005347:Fibroblasts; D006801:Humans; D008214:Lymphocytes; D008297:Male; D009085:Mucopolysaccharidosis IV / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D012867:Skin / Q000166:cytology; D055815:Young Adult
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D002811:Chondroitinsulfatases; C102295:GALNS protein, human
keywords: GALNS; MPSIVA; Morquio A; intellectual disability; submicroscopic deletions