title: A girl with incomplete Prader-Willi syndrome and negative MS-PCR, found to have mosaic maternal UPD-15 at SNP array.
abstract: The Prader-Willi syndrome (PWS) is caused by lack of expression of paternal allele of the 15q11.2-q13 region, due to deletions at paternal 15q11.2-q13 (<70%), maternal uniparental disomy of chromosome 15 (mat-UPD 15) (30%) or imprinting defects (1%). Hyperphagia, intellectual disabilities/behavioral disorders, neonatal hypotonia, and hypogonadism are cardinal features for PWS. Methylation sensitive PCR (MS-PCR) of the SNRPN locus, which assesses the presence of both the unmethylated (paternal) and the methylated (maternal) allele of 15q11.2-q13, is considered a sensitive reference technique for PWS diagnosis regardless of genetic subtype. We describe a 17-year-old girl with severe obesity, short stature, and intellectual disability, without hypogonadism and history of neonatal hypotonia, who was suspected to have an incomplete PWS. The MS-PCR showed a normal pattern with similar maternal and paternal electrophoretic bands. Afterwards, a SNP array showed the presence of iso-UPD 15, that is, UPD15 with two copies of the same chromosome 15, in about 50% of cells, suggesting a diagnosis of partial PWS due to mosaic maternal iso-UPD15 arisen as rescue of a post-fertilization error. A quantitative methylation analysis confirmed the presence of mosaic UPD15 in about 50% of cells. We propose that complete clinical criteria for PWS and MS-PCR should not be considered sensitive in suspecting and diagnosing partial PWS due to mosaic UPD15. In contrast, clinical suspicion based on less restrictive criteria followed by SNP array is a more powerful approach to diagnose atypical PWS due to UPD15 mosaicism.
authors.affiliation: Pediatric Diabetes and Metabolic Disorders Unit, University Hospital of Verona, Verona, Italy.
authors.forename: Anita
authors.initials: A
authors.lastname: Morandi
authors.affiliation: CNRS UMR 8199, Pasteur Institute of Lille, Lille, France.|Lille 2 University, Lille, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.affiliation: CNRS UMR 8199, Pasteur Institute of Lille, Lille, France.|Lille 2 University, Lille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lobbens
authors.affiliation: Clinic of Child and Adolescent Neuropsychiatry, Second University of Naples, Naples, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Carotenuto
authors.affiliation: Department of Pediatrics, Second University of Naples, Naples, Italy.
authors.forename: Emanuele Miraglia
authors.initials: EM
authors.lastname: Del Giudice
authors.affiliation: CNRS UMR 8199, Pasteur Institute of Lille, Lille, France.|Genetic of Common Disease, Imperial College London, London, UK.
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.affiliation: Pediatric Diabetes and Metabolic Disorders Unit, University Hospital of Verona, Verona, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Maffeis
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004587:Electrophoresis, Agar Gel; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009030:Mosaicism; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011218:Prader-Willi Syndrome / Q000235:genetics*; D024182:Uniparental Disomy / Q000235:genetics*; D055517:snRNP Core Proteins / Q000235:genetics
chemical_list: D055517:snRNP Core Proteins
keywords: SNP array; mosaic; prader willi syndrome