Researchers uncover genetic basis of heart defects and facial differences in syndrome

A new discovery from a team of researchers at The Hospital for Sick Children (SickKids) and University of Toronto (U of T) may enable doctors to provide more personalized care to children and families affected by congenital heart disease.

"We’ve identified a cause of congenital heart disease that wasn’t previously known," says Rebekah Jobling, a medical geneticist at SickKids and an assistant professor of paediatrics at U of T's Temerty Faculty of Medicine.

"Knowing this allows us to give a more accurate explanation to families of why the disease occurred, if it’s likely to happen again in a family and for affected individuals, how likely they are to pass it on."

The findings, which were published recently in the American Journal of Human Genetics, describe a set of genetic variations in two genes called EIF3A and EIF3B. In addition to congenital heart disease, these variations also led to other traits including facial differences and mild developmental delays.

The researchers first identified these variations in two people who were part of a study at the Cardiac Genome Clinic, a program at the Ted Rogers Centre for Heart Research that investigates the genetic causes of heart failure. Jobling says two factors alerted her that these genetic variations could be significant.

"The first was that the mutation was new in the affected individual, which is an immediate flag for us. We could also see from our population databases that it’s very uncommon for people to have one copy of these genes that doesn’t work," she notes.

Both EIF3A and EIF3B are involved in the critical process of initiating protein synthesis. The variations discovered by the researchers either inactivated these genes or severely reduced their function.

The researchers next turned to GeneMatcher, a matchmaking website that connects clinicians and researchers from around the world who have a shared interest in the same gene. Through GeneMatcher, the SickKids team learned of 16 other individuals in England who also carried similar variations in either EIF3A or EIF3B.

By studying these 18 people — 14 with variations in EIF3B and four with variations in EIF3A — the researchers uncovered a more complete picture of the impact of these genetic changes.

In addition to congenital heart disease, which affected nearly all 18 individuals, the other most commonly observed traits were neurodevelopmental differences like speech and language delays and learning disabilities, and facial differences like drooping eyelid and cleft lip and palate. A number of people also had hearing loss and behavioural conditions like attention-deficit hyperactivity disorder (ADHD).

To confirm the role of these variations in causing congenital heart disease and the other characteristics, Jobling teamed up with Ian Scott, a Senior Scientist in Developmental, Stem Cell & Cancer Biology at SickKids and a professor of molecular genetics at U of T’s Temerty Faculty of Medicine.

Scott’s lab uses zebrafish as a model to study heart development and disease. Zebrafish embryos are transparent, making it easy for researchers to observe the heart as it develops in real time.

Led by PhD student Esra Erkut in the Scott Lab, the researchers used CRISPR-Cas9 gene editing technology to inactivate both copies of the zebrafish version of the EIF3B gene. They found that these zebrafish had underdeveloped hearts and reduced cardiac function as well as smaller eye and head size.

"The characteristics we saw in the model organism was quite supportive of what we saw clinically, which is strong evidence that this mutation is causative of the disease," says Scott. "Establishing this model is really useful for downstream studies of how these mutations lead to disease and to explore potential therapeutic approaches to correct these defects."

Jobling says that because of their study, genetic testing labs around the world can now include variations in EIF3A and EIF3B as reportable genetic changes, which will inform the counselling that families receive.

"Now we can give families with this diagnosis a more accurate set of other things to look out for in their child, such as learning issues at school and ADHD," she says. "It allows not just better counselling around congenital heart disease, but better, more holistic care of that patient going forward."

This study was supported by the Canadian Institutes of Health Research and the Ted Rogers Centre for Heart Research. This story was originally posted by the University of Toronto Temerty Faculty of Medicine.