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Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism


Prader-Willi syndrome (PWS) 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 PWS domain. The first subject was ascertained by whole-genome sequencing analysis for PWS features. Three additional subjects were identified by reviewing the results of exome sequencing of 1,248 cases in a clinical laboratory. All four subjects had autism spectrum disorder (ASD), intellectual disability and a varying degree of clinical and behavioral features of PWS. These findings suggest that MAGEL2 is a new gene causing complex ASD and that MAGEL2 loss of function can contribute to several aspects of the PWS phenotype.

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Figure 1: Truncating mutations on the paternal allele of MAGEL2.

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We are indebted to the patients and their families for their willingness to participate in our research study. We thank P. Zimmerman and E. Austin for clinical assistance. C.P.S. is generously supported by the Joan and Stanford Alexander family. C.P.S. is a recipient of a Clinical Scientist Development Award from the Doris Duke Charitable Foundation. M.L.G.-G. and C.T.C. are generously supported by the Cullen Foundation for Higher Education and the Houston Foundation. A.L.B. is supported by US National Institutes of Health grant HD037283.

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Authors and Affiliations



M.L.G.-G. and M.A.M. performed whole-genome sequencing and phase determination on subject 1. M.L.G.-G., M.A.M., B.A.P., R.D. and C.T.C. designed and analyzed the experiments for subject 1. F.X. and Y.Y. performed whole-exome sequencing and phase determination on subjects 2–4. C.P.S., F.X., Y.Y., B.Z., A.L.B. and Y.Y. designed and analyzed the experiments for subjects 2–4. L.P. and K.W.G. contributed subjects and provided detailed physical examinations. C.P.S. conceived the overall study, coordinated enrollment, supervised the experiments, wrote the manuscript and generated the figures and tables. All authors participated in the discussion and interpretation of data and results, and all participated in editing and revising the manuscript.

Corresponding authors

Correspondence to Christian P Schaaf or Manuel L Gonzalez-Garay.

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Competing interests

C.P.S., A.L.B., C.T.C. and Y.Y. are faculty members of the Department of Molecular and Human Genetics at the Baylor College of Medicine, which derives revenue from whole-exome sequencing analysis offered in the Medical Genetics Laboratory. B.A.P., M.A.M. and R.D. are employees of Complete Genomics, a company that derives revenue from whole-genome sequencing analysis. Complete Genomics has filed several patents on sequencing technology. The remaining authors declare no conflict of interest.

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Schaaf, C., Gonzalez-Garay, M., Xia, F. et al. Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism. Nat Genet 45, 1405–1408 (2013).

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