Prevalence and aetiology of PWS low level mosaicism in UPD undetected by standard testing

Prader-Willi syndrome (PWS) is a severe neurodevelopmental disorder found in ~1 in 15,000 to 20,000 births. PWS phenotype caused by the loss of function of several genes located on chromosome 15. These genes are usually ‘switched on’ on the chromosome 15 that is inherited from the father and ‘switched off’ on the chromosome 15 inherited from the mother. The mechanism of this ‘switch’ is a chemical change called ‘methylation’. Most commonly PWS is caused by either a deletion on the paternal chromosome 15, or to both chromosome 15s coming from the mother (maternal uniparental disomy 15). In this study we will use several new state of the art techniques which we have developed that can measure methylation, number of copies and gene expression on chromosome 15 with very great precision. This type of analysis has never been done in PWS. In our preliminary studies we have identified a subset of individuals with PWS in whom there are small numbers of cells in which some of the PWS genes on chromosome 15 remain active ‘switched on’ / unmethylated. We will undertake further studies in 140 PWS patients to determine how common this phenomenon is in two patient cohorts (one from Australia and another from USA), and whether it correlates with gene expression the type of PWS and the severity of symptoms.

Importance of research, next steps, and downstream projects:
This proposal will lead to the development of new tests that can accurately quantify subtle differences in methylation in PWS individuals. The results of these studies will:
a) open new avenues to explain the cause of PWS and the variability in symptoms between different PWS individuals
b) identify new sensitive biomarkers that will be able to be used in clinical trials to help analyse and predict response to various treatments
c) allow the development of tests that will help predict future health problems in young children with PWS
d) identify more sensitive ways to screen drug libraries for compounds that may re-activate genes that are switched off in PWS.

Research Outcomes:

Exploring autism symptoms in an Australian cohort of patients with Prader-Willi and Angelman syndromes. Baker EK, Godler D, Bui M, Hickerton C, Rogers C, Field M, Amor D, and Bretheton B. Journal of Neurodevelopmental Disorders. 2018,10:24

Funded Year:


Awarded to:

David Godler, PhD




Murdoch Childrens Research Institute, Australia


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