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Pathogenicity of all missense variants in KCNH2

Victor Chang Cardiac Research Institute

  • Cardiovascular Senior Scientist Grant
Organ System:
  • Cardiovascular
Date Funded:
  • 31 May, 2019
Chief Investigator/s:
  • Professor Jamie Ian Vandenberg

Project summary

Determining the probability of pathogenicity of all missense variants in KCNH2, the genetic basis of congenital long QT syndrome type 2.

What is the issue for NSW?

The spectacular developments in sequencing the human genome have led many to speculate that we will soon enter an era of personalised genome guided precision medicine. However, the speed with which we can now “read” the human genome far exceeds our capacity to interpret how gene mutations affect protein function and clinical outcomes. We urgently need to dramatically improve our skills at characterising how mutations affect gene outputs, i.e. functional genomics.

Mutations in the KCNH2 gene are a well-established cause of sudden cardiac death, caused by disturbed electrical signalling, in otherwise healthy young people. Yet, we now appreciate that the majority of variants identified in the KCNH2 gene do not change its function. The planned global efforts to sequence millions of genomes in the next few years will result in thousands of variants being identified in the KCNH2 gene; some of these will identify patients at increased risk of sudden death but most of these variants will be benign.

What does the research aim to do and how?

To cope with this deluge of variants of unknown significance we will develop a high throughput functional assay to assess how every possible mutation in KCNH2 affects the electrical function of heart cells.

To achieve this, we will utilise state-of-the art robotic platforms to first help generate thousands of mutations in KCNH2 and then to assess the electrical consequences of these mutated genes. This data will be made available to geneticists, treating physicians and their patients through publicly accessible databases, such as ClinVar, so that all patients (both in NSW and throughout the world) who have their genome sequenced can access this data.

Successful completion of this project would pave the way for using a similar approach to tackle other genes associated with sudden cardiac death and ultimately any cardiac disorder where it is possible to develop a high throughput assay to quantify altered function. It will also help to establish the Victor Chang Cardiac Research Institute and NSW as a world centre for functional genomics for inherited heart diseases.