Truncating mutations of MAGEL2 cause autism and Prader-Willi Syndrome-like phenotypes. C. P. Schaaf1, 2, M. L. Gonzalez-Garay3, F. Xia1, L. Potocki1, K. W. Gripp4, B. Zhang1, B. A. Peters5, M. A. McElwain5, R. Drmanac5, A. L. Beaudet1, C. T. Caskey1, Y. Yang1 1) Department of Molecular & Human Genetics, Baylor College Med, Houston, TX; 2) Jan and Dan Duncan Neurological Research Institute, Texas Childrens Hospital, Houston, TX; 3) The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas, Health Science Center at Houston, Houston, TX; 4) Division of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, DE; 5) Complete Genomics, Inc., Mountain View, CA.

   Prader-Willi Syndrome is caused by the absence of paternally expressed, maternally silenced genes at 15q11-q13. We report four individuals with truncating mutations on the paternal allele of MAGEL2, a gene within the Prader-Willi syndrome (PWS) domain. The first case was ascertained by whole genome trio analysis for PWS features. Three additional patients were identified in a cohort of 400 cases submitted for clinical whole exome sequencing to a clinical laboratory. The phenotypes of the four probands ranged from meeting criteria for PWS to some features of PWS, but autism spectrum disorders (ASDs) were present in all four probands. The reported MAGEL2 mutations are de novo in three cases, and not inherited from the mother in one case (father unavailable). Using two different methodologies, we show that the mutations are on the paternal allele of the MAGEL2 gene in all four cases, and therefore probably pathogenic. First, we performed long fragment analysis in conjunction with parental SNP genotypes in proximity to the mutated locus. Second, we digested genomic DNA with the methylation-sensitive restriction enzyme SmaI, followed by long-range PCR and Sanger sequencing. As the unmethylated (paternal) allele is digested by SmaI, only the maternal allele is amplified in the subsequent PCR, and all sequencing reads reflect the sequence of the maternal MAGEL2 allele. In summary, our findings suggest MAGEL2 is a novel gene causing complex ASDs, and lack of a functional MAGEL2 copy can contribute to several aspects of the PWS phenotype.

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