Case study: Identification of genomic modifiers of PTEN-related phenotypes

Key facts

Research category: Natural history/translational medicine

Lead researcher: Professor Charis Eng, MD PhD

Institution: Genomic Medicine Institute, Cleveland Clinic, USA

Project start: September 2020      Expected completion: December 2023

Project goals

To identify genomic modifiers predictive of clinical outcomes in PTEN mutation carriers, by performing whole genome sequencing (WGS) on a population of extensively phenotyped individuals with PHTS. Ultimately, it is hoped that this approach may provide a framework for stratifying PTEN-related disease risk at the individual level, as a basis for precision healthcare.


Studies have shown that individuals with the same PTEN mutation can display widely different clinical manifestations, even within a family. Thus, it remains impossible to predict at an individual level precisely which PTEN mutation carrier will develop which symptom(s). How mutations in one gene contribute to such disparate disorders, even in people with identical PTEN mutations, remains poorly understood. Earlier, PTEN Research-funded work conducted by Professor Eng and her team, have led them to hypothesise that PHTS aetiology is not driven by just the PTEN gene mutation, but may involve complex gene-gene interactions and that germline non-coding genomic modifiers in particular may modulate a major subset of clinical phenotypic manifestations in PHTS.

Study design

Whole genome sequencing will be performed on a well-characterised group of individuals with PHTS who have germline pathogenic, or likely pathogenic, mutations in PTEN, identified from the Cleveland Clinic prospective cohort for Cowden Syndrome and Bannayan-Riley-Ruvalcaba syndrome, and the Rare Disease Clinical Research Networks cohort. These data will then be interrogated in a variety of ways to identify if and what genetic variations in the genome of people with PHTS lead to disparate clinical outcomes.

Anticipated outcomes of this work

It is hoped that this research will lead to the identification of genetic markers that may be used to better inform the clinical outcome of individuals with PHTS, to optimise surveillance, and to develop medical management leading to precise risk stratification and biomarker-informed treatments and prevention. In addition, this rich and detailed dataset will be invaluable for future research to better understand PHTS and identify new and novel therapeutics.