MAGEL2 gene mutation

A 2/12 year old female patient of mine with global developmental delay, dysmorphic features and poor feeding was recently found by whole exome sequencing to have a pathogenic MAGEL2 gene mutation.  MAGEL2 is a gene within the Prader-Willi syndrome domain at 15q11.2. Of interest, all mutations thus far have been found to be in the paternal allele.  Neither parent of this patient has the mutation.  Whether in this patient it is the paternal allele that mutated is under investigation.

Schaaf CP, Gonzalez-Garay ML, Xia F, Potocki L, Gripp KW, Zhang B, Peters BA,
McElwain MA, Drmanac R, Beaudet AL, Caskey CT, Yang Y. Truncating mutations of
MAGEL2 cause Prader-Willi phenotypes and autism. Nat Genet. 2013 Nov;45(11):1405-8.

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.

Buiting K, Di Donato N, Beygo J, Bens S, von der Hagen M, Hackmann K,
Horsthemke B. Clinical phenotypes of MAGEL2 mutations and deletions. Orphanet J
Rare Dis. 2014 Mar 25;9:40. (letter to the editor)

Although it has long been known that Prader-Willi syndrome (PWS) is caused by the loss of function of imprinted, paternally expressed genes in 15q11q13, the contribution of the different genes within this region has not yet been completely resolved. Based on the identification of rare deletions affecting only the snoRNA gene cluster SNORD116 it has been suggested that this is the major locus. Recently, Schaaf et al. have described truncating mutations of MAGEL2 in four patients with a broad range of clinical phenotypes. The authors conclude that "MAGEL2 loss of function can contribute to several aspects of the PWS phenotype". While this may be true, we think that the available data are not sufficient to justify this conclusion...

We conclude that it is important to distinguish between point mutations and whole gene deletions and that the effect of the genes in the PWS chromosomal region may be epistatic rather than additive. Therefore, the role of MAGEL2 in PWS remains unclear.