Case study: Genomic modifiers of PHTS

Introduction

Studies have shown that individuals with the same PTEN variant can display widely different clinical manifestations, even within a family. Currently, it is not possible to predict the phenotypic presentation of an individual with PHTS based on knowledge of their specific PTEN variant.

How variants in one gene contribute to such disparate disorders, even in people with identical PTEN variants, 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 variant alone, but may involve complex gene-gene interactions and that constitutive non-coding genomic modifiers in particular may modulate a major subset of clinical phenotypic manifestations in PHTS.

Project goals

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

Project overview

Whole genome sequencing was performed on a well-characterised group of approximately 600 individuals with PHTS from the Cleveland Clinic cohort. These data were then interrogated in a variety of ways to identify if and what genetic variations in the genome of people with PHTS led to disparate clinical outcomes.