title: A De Novo Nonsense Mutation in MAGEL2 in a Patient Initially Diagnosed as Opitz-C: Similarities Between Schaaf-Yang and Opitz-C Syndromes.
abstract: Opitz trigonocephaly C syndrome (OTCS) is a rare genetic disorder characterized by craniofacial anomalies, variable intellectual and psychomotor disability, and variable cardiac defects with a high mortality rate. Different patterns of inheritance and genetic heterogeneity are known in this syndrome. Whole exome and genome sequencing of a 19-year-old girl (P7), initially diagnosed with OTCS, revealed a de novo nonsense mutation, p.Q638*, in the MAGEL2 gene. MAGEL2 is an imprinted, maternally silenced, gene located at 15q11-13, within the Prader-Willi region. Patient P7 carried the mutation in the paternal chromosome. Recently, mutations in MAGEL2 have been described in Schaaf-Yang syndrome (SHFYNG) and in severe arthrogryposis. Patient P7 bears resemblances with SHFYNG cases but has other findings not described in this syndrome and common in OTCS. We sequenced MAGEL2 in nine additional OTCS patients and no mutations were found. This study provides the first clear molecular genetic basis for an OTCS case, indicates that there is overlap between OTCS and SHFYNG syndromes, and confirms that OTCS is genetically heterogeneous. Genes encoding MAGEL2 partners, either in the retrograde transport or in the ubiquitination-deubiquitination complexes, are promising candidates as OTCS disease-causing genes.
authors.affiliation: Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, Barcelona, Spain.|CIBERER, Barcelona, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Urreizti
authors.affiliation: Department of Clinical and Molecular Genetics and Rare Diseases Unit, Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Cueto-Gonzalez
authors.affiliation: Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, Barcelona, Spain.
authors.forename: Héctor
authors.initials: H
authors.lastname: Franco-Valls
authors.affiliation: Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, Barcelona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Mort-Farre
authors.affiliation: Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, Barcelona, Spain.|CIBERER, Barcelona, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Roca-Ayats
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, and Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Ponomarenko
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, and Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Luca
authors.initials: L
authors.lastname: Cozzuto
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, and Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Company
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, and Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Mattia
authors.initials: M
authors.lastname: Bosio
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, and Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ossowski
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, and Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Magda
authors.initials: M
authors.lastname: Montfort
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, and Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.affiliation: CIBERER, Barcelona, Spain.|Department of Clinical and Molecular Genetics and Rare Diseases Unit, Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: Eduardo F
authors.initials: EF
authors.lastname: Tizzano
authors.affiliation: Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, Barcelona, Spain.|CIBERER, Barcelona, Spain.
authors.forename: Bru
authors.initials: B
authors.lastname: Cormand
authors.affiliation: Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, Barcelona, Spain.|CIBERER, Barcelona, Spain.
authors.forename: Lluïsa
authors.initials: L
authors.lastname: Vilageliu
authors.affiliation: Pediatrics Medical Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Opitz
authors.affiliation: Istituto di Medicina Genomica, Università Cattolica Sacro Cuore, Policlínico A Gemelli, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Neri
authors.affiliation: Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, Barcelona, Spain.|CIBERER, Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Grinberg
authors.affiliation: Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, Barcelona, Spain.|CIBERER, Barcelona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Balcells
mesh_terms: D000328:Adult; D003398:Craniosynostoses / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins
chemical_list: D011506:Proteins; C510822:MAGEL2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins