Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism

Abstract

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.

Figure 1

Truncating mutations on the paternal allele of MAGEL2. (a) GC content of MAGEL2 and flanking sequence on 15q11.2 (based on UCSC genome browser, hg19). (b) Truncating MAGEL2 mutations reported in this manuscript are indicated relative to their position in the coding sequence of this single-exon gene. For phasing of MAGEL2 mutations, genomic DNA was digested with the methylation-sensitive restriction endonuclease SmaI, which leaves only the methylated maternal MAGEL2 allele intact. Digestion is followed by long-range PCR. Red stars indicate SmaI digestion sites within the MAGEL2 sequence. Purple arrows indicate the position of oligonucleotide primers used for long-range PCR.