title: Solving a case of allelic dropout in the GNPTAB gene: implications in the molecular diagnosis of mucolipidosis type III alpha/beta.
abstract: While being well known that the diagnosis of many genetic disorders relies on a combination of clinical suspicion and confirmatory genetic testing, not rarely, however, genetic testing needs much perseverance and cunning strategies to identify the causative mutation(s). Here we present a case of a thorny molecular diagnosis of mucolipidosis type III alpha/beta, which is an autosomal recessive lysosomal storage disorder, caused by a defect in the GNPTAB gene that codes for the α/β-subunits of the GlcNAc-1-phosphotransferase. We used both cDNA and gDNA analyses to characterize a mucolipidosis type III alpha/beta patient whose clinical diagnosis was already confirmed biochemically. In a first stage only one causal mutation was identified in heterozygosity, the already described missense mutation c.1196C>T(p.S399F), both at cDNA and gDNA levels. Only after conducting inhibition of nonsense-mediated mRNA decay (NMD) assays and after the utilization of another pair of primers the second mutation, the c.3503_3504delTC deletion, was identified. Our findings illustrate that allelic dropout due to the presence of polymorphisms and/or of mutations that trigger the NMD pathway can cause difficulties in current molecular diagnosis tests.
authors.forename: Maria Francisca
authors.initials: MF
authors.lastname: Coutinho
authors.forename: Marisa
authors.initials: M
authors.lastname: Encarnação
authors.forename: Francisco
authors.initials: F
authors.lastname: Laranjeira
authors.forename: Lúcia
authors.initials: L
authors.lastname: Lacerda
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Prata
authors.forename: Sandra
authors.initials: S
authors.lastname: Alves
mesh_terms: D000483:Alleles; D002675:Child, Preschool; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D009081:Mucolipidoses / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics*
chemical_list: D017855:Transferases (Other Substituted Phosphate Groups); C511050:GNPTAB protein, human