Tetralogy of Fallot (TOF) is a birth defect affecting normal blood flow through a baby’s heart. Transposition of the great arteries (TGA) is another where the aorta and pulmonary artery develop in the wrong position, in the wrong ventricle. Both are serious, both require surgical procedures, and both have unknown causes.
The Ted Rogers Centre’s Cardiac Precision Medicine Program is at the heart of a three-year-old international study where researchers are hunting for genetic clues to how such congenital heart disease develops.
The study is called PROCEED, and is led by our scientific lead Dr. Seema Mital, and includes collaborators first in Germany and the Netherlands, now expanded to Australia. Having multiple sites around the world allows for diversity and the ability to analyze TOF and TGA from multiple angles at the same time.
“The main goal is to be able to give families their genetic diagnoses and an understanding of risk and outcomes,” says Robert Lesurf, SickKids senior bioinformatician and data scientist on the project. “This empowers them to make family planning decisions, to proactively screen for babies and other family members, and to be able to track disease throughout their lives.”
The hunt for disease-causing variants
So far, PROCEED collaborators have performed whole genome sequencing on over 1,400 affected families. The mission is to find pathogenic genetic variants – what is causing TOF and TGA. Only through analyzing a whole genome can these answers be uncovered.
“This study allows us to take new approaches and look at new types of variants, which are very difficult to capture using standard genetic tests,” Robert says. “It’s cutting-edge, as we are also leveraging new bioinformatics tools and data workflows to take this effort in new directions.”
Such innovations are bringing newfound precision and efficiency to genomic research, which at its core is akin to hunting for needles in haystacks.
PROCEED collaborators are also collecting RNA sequencing and proteomics data on actual heart tissues to test any suspicious variants they detect through whole genome sequencing – and possibly prove that it is causing disease.
To date, four studies have been published through this partnership. One reports on a genomic region that contains a gene of interest for TGA. One links rare functional variants to the development of TOF. Another details how to incorporate genomic research findings into a patient’s care. And the fourth assessed the economic costs of performing such analyses, which helps pave the way for whole genome sequencing to be embedded in models of care.
It’s expected that through PROCEED we will build a pipeline to translate findings across broader geographic regions, harmonize how we analyze the genome, and truly expedite discoveries that so many families need.