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Am J Hum Genet. 2015 Oct 1;97(4):616-20. doi: 10.1016/j.ajhg.2015.08.010. Epub 2015 Sep 10.

Truncating Mutations of MAGEL2, a Gene within the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis.

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UMR-1169, INSERM and University of Paris South, Le Kremlin Bicêtre, 94276, France.
Medical Genetic Unit, South University Hospital, St Pierre-La Réunion, 97448, France.
Reference Center of Developmental Anomalies and Malformations, University Hospital of Nice, Nice, 06000, France.
Centro Nacional de Análisis Genómico, Barcelona, 080028, Spain.
Service de Biochimie Métabolique and UMR 1127-7225, Hôpitaux Universitaires Pitié-Salpêtrière, Paris, 75651, France.
Pathology Laboratory and NeoVasc Region-INSERM Team ERI28, Institute of Research for Innovation in Biomedicine, University of Rouen, Rouen, 76031, France.
UMR-1169, INSERM and University of Paris South, Le Kremlin Bicêtre, 94276, France. Electronic address:


Arthrogryposis multiplex congenita (AMC) is characterized by the presence of multiple joint contractures resulting from reduced or absent fetal movement. Here, we report two unrelated families affected by lethal AMC. By genetic mapping and whole-exome sequencing in a multiplex family, a heterozygous truncating MAGEL2 mutation leading to frameshift and a premature stop codon (c.1996delC, p.Gln666Serfs∗36) and inherited from the father was identified in the probands. In another family, a distinct heterozygous truncating mutation leading to frameshift (c.2118delT, p.Leu708Trpfs∗7) and occurring de novo on the paternal allele of MAGEL2 was identified in the affected individual. In both families, RNA analysis identified the mutated paternal MAGEL2 transcripts only in affected individuals. MAGEL2 is one of the paternally expressed genes within the Prader-Willi syndrome (PWS) locus. PWS is associated with, to varying extents, reduced fetal mobility, severe infantile hypotonia, childhood-onset obesity, hypogonadism, and intellectual disability. MAGEL2 mutations have been recently reported in affected individuals with features resembling PWS and called Schaaf-Yang syndrome. Here, we show that paternal MAGEL2 mutations are also responsible for lethal AMC, recapitulating the clinical spectrum of PWS and suggesting that MAGEL2 is a PWS-determining gene.

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