A De Novo Nonsense Mutation in MAGEL2 in a Patient Initially Diagnosed as Opitz-C: Similarities Between Schaaf-Yang and Opitz-C Syndromes

• Published in: Scientific reports Vol. 7; no. 1; p. 44138
• Main Authors: Urreizti, Roser, Cueto-Gonzalez, Anna Maria, Franco-Valls, Héctor, Mort-Farre, Sílvia, Roca-Ayats, Neus, Ponomarenko, Julia, Cozzuto, Luca, Company, Carlos, Bosio, Mattia, Ossowski, Stephan, Montfort, Magda, Hecht, Jochen, Tizzano, Eduardo F., Cormand, Bru, Vilageliu, Lluïsa, Opitz, John M., Neri, Giovanni, Grinberg, Daniel, Balcells, Susana
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-03-2017; Nature Publishing Group
• Subjects: 45/77; 692/4017; 692/699/375/366; Arthrogryposis; Biologia molecular; Chromosome 15; Developmental neurobiology; Genes; Genetic disorders; Genomes; Heart diseases; Heredity; Heterogeneity; Humanities and Social Sciences; MAGEL2 gene; Molecular biology; multidisciplinary; Mutation; Neurobiologia del desenvolupament; Nonsense mutation; Opitz syndrome; Prader-Willi syndrome; Retrograde transport; Science; Ubiquitination
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep44138

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.