Genome Sequencing Enables Discovery of Mutation Leading to Prader-Willi Syndrome, with Link to Autism

Highly accurate whole genome sequencing technology has played a pivotal role in identifying a mutation involved in causing Prader-Willi Syndrome, helping to resolve a diagnostic conundrum.

Prader-Willi Syndrome (PWS) is a rare (around 1:15,000) genetic disorder that leads to poor muscle tone, low levels of sex hormones, and a constant feeling of hunger often leading to obesity. It occurs in males and females equally, and affects all races. The whole genome sequencing technology of Complete Genomics, Inc. (Mountain View, CA, USA), subsidiary of BGI-Shenzhen, was used in the identification of a point mutation causing PWS, a discovery that helped resolve a diagnostic conundrum for four young male patients who tested PWS-negative as infants.


The study, published September 29, 2013, in the journal Nature Genetics, is a collaborative effort of researchers at Baylor College of Medicine (BCM; Houston, TX, USA), the Jan and Dan Duncan Neurological Research Institute (Duncan NRI; Houston, TX, USA), and the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (Houston, TX, USA).

The first patient tested PWS negative by age one year, but over the next 12 years began to manifest some of the typical PWS symptoms. Complete Genomics’ sequencing service was used in an analysis determining the genetic basis of his symptoms: a single mutation, a base deletion, was identified in the protein-coding MAGEL2 gene, in a section of chromosome 15 previously linked to PWS, and in a difficult to sequence GC rich region. It proved to be a frame-shift deletion, truncating mutation, which disrupts the MAGEL2 protein product. As MAGEL2 is only known to be expressed from the paternal gene allele (the maternal allele being silenced), it was also important to determine whether the mutation was on the maternal or paternal version of chromosome 15. In this case, the MAGEL2 mutation was confirmed to be on the paternal allele using a modified version of Complete Genomics’ Long Fragment Read technology.

To further investigate MAGEL2’s role in PLW, the researchers reviewed over 1,200 exome sequencing reports, searching for other patients with loss-of-function mutations in that gene. Three additional patients were identified – one with classic PWS, the other two with PWS-like symptoms. However, all had negative PWS tests as infants. All four patients were also diagnosed with autism spectrum disorder (ASD) and intellectual disability. 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.

“This is the first study to show that point mutations can cause Prader-Willi Syndrome,” said Dr. Schaaf, assistant professor of molecular and human genetics at BCM and faculty member at the Duncan NRI; “This is an important development that increases our understanding of this complex disorder, and also gives four boys a diagnosis, which they and their parents have sought for many years.” “It also underscores the importance of being able to distinguish between maternal and paternal variants because only patients who had point mutations on the paternal copy of the MAGEL2 gene would experience the disorder,” added Dr. Brock Peters, director of research at Complete Genomics.

Related Links:
Complete Genomics
Baylor College of Medicine
The Jan and Dan Duncan Neurological Research Institute (of Texas Children's Hospital)