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Optimizing the Molecular Diagnosis of GALNS : Novel Methods to Define and Characterize M orquio—A Syndrome‐Associated Mutations
Author(s) -
Caciotti Anna,
Tonin Rodolfo,
Rigoldi Miriam,
Ferri Lorenzo,
Catarzi Serena,
Cavicchi Catia,
Procopio Elena,
Donati Maria Alice,
Ficcadenti Anna,
Fiumara Agata,
Barone Rita,
Garavelli Livia,
Rocco Maja Di,
Filocamo Mirella,
Antuzzi Daniela,
Scarpa Maurizio,
Mooney Sean D.,
Li Biao,
Skouma Anastasia,
Bianca Sebastiano,
Concolino Daniela,
Casalone Rosario,
Monti Elena,
Pantaleo Marilena,
Giglio Sabrina,
Guerrini Renzo,
Parini Rossella,
Morrone Amelia
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22751
Subject(s) - biology , genetics , exon , mutation , gene , population , structural variation , in silico , copy number variation , phenotype , medicine , genome , environmental health
M orquio 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 ‐ PCR s [quantitative fluorescent‐ PCR s]), 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.245‐11 C > G causing m‐ RNA defects, although identified outside the GT / AG splice pair. We estimated the occurrence of the disease in the I talian 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.