The scientist Sarah Mortonattending physician at the Boston Children’s Division of Neonatal Medicine, has devoted his career to identifying the genetic causes of congenital heart diseasethe leading cause of death in children, after infections.
Congenital heart disease: the importance of finding out which genes are involved
It is well known in the scientific community that congenital heart disease has a strong genetic component. Despite this valuable information, fewer than half of patients receive a genetic diagnosis. Working in the Boston Infants’ Neonatal Genomics Program and in collaboration with Amy Roberts, director of the Cardiovascular Genetics Research Program, Morton has been dedicated to solving more cases, enabling more personalized approaches to improve neonatal health.
“Knowing about genetic diagnosis will allow us to improve care by anticipating patients’ special needs and providing targeted care to improve outcomes after heart surgery“, Declared the scholar:”More than 400 genes are estimated to contribute to coronary heart disease, but we have only found 200 ″.
Variants of these genes are very rare and require complex genetic technologies to be detected. The Pediatric Cardiac Genomics Consortium (PCGC), where Morton collaborates, she has a database of over 16,000 children. About a fifth of them are al Boston Children’s. More than 5,000 consortium participants had their exome sequenced and more than 3,000 sequenced their complete genome. Thanks to this work it was possible to discover several new genes.
Research has led to a frequent genetic connection between CHD and neurodevelopmental disorders. In the past, these disorders were often attributed to complications from heart surgery or to simply having a weak heart. But these factors only explain about 30 percent of the risk: “Many genes in cardiac development and neurodevelopment are shared”explained the scientist
The history of the TAF1 gene illustrates this point. Several years ago, Morton carefully studied the records of a patient born with a ventricular septal defect, hydrocephalus, and global developmental delay. Through genomic sequencing, Morton and her colleagues found a variant in TAF1. This gene has never been linked to congenital cardiomyopathy, but has been linked to syndromic intellectual disability, intrauterine growth restriction, hypotonia and dystonia / parkinsonism.
Morton began taking stock when he met a second patient at Boston Children’s with a TAF1 variant, Fallot’s tetralogy, and motor and verbal delays. Looking through the reports in the medical literature, she noted that many patients with TAF1 variants and intellectual or developmental delay (ID / DD) also had cardiac diagnoses, although they were not highlighted.
In all, she identified 26 patients with TAF1 mutations in the literature and found that about half of the patients observed had coronary artery disease. The scientist reported these results, corroborated by PCGC data, in a 2020 publication .
In related investigations, Morton partnered with Ellen Grant, Jane Newburgerand other colleagues to conduct brain MRI studies in patients with tetralogy of Fallot and single ventricle CHD. the team of experts tracked changes in brain folding that could predict which children with congenital heart disease are most at risk for cognitive impairment. These children could benefit from early diagnosis and consequently from targeted and timely therapeutic interventions.
Another branch of Morton’s research is considering the genetic relationship between congenital heart disease and the risk of a cancer diagnosis: “We know that CHD patients get cancer earlier and at a higher rate “, the expert specified: “It is difficult to know if genetic variants are responsible, because cancer is so rare in children. I am interested in enrolling patients and learning more “.
She noted that many genes that play key roles in early development can also act as cancer genes if their function is lost later. In 2021, it has published a study in JAMA Cardiology which involved 4,443 CHD patients from the PCGC database with 9,808 controls.
Patients with CHD had a 30% increased rate of damaging variants in cancer-associated genes. These variants were found more often in patients who also had non-cardiac conditions, including ID / DD: “If there is a link between CHD and cancer, it would be a huge indication to change cancer screening approaches for CHD patients” Morton specified.
In search of further genetic causes of CHD, the scientist is particularly interested in studying variants in DNA segments that do not code for proteins but instead regulate the expression of other genes, turning them on or off.
As detailed in a full article in Nature Reviews Cardiology variants in these non-coding regions could account for approximately 55% of genetically unexplained CHD cases. Many of these variants arise after conception rather than being inherited and often affect genes that are expressed in the first heart cells to emerge.
And that’s another approach Morton is taking: looking for genes involved in heart development in general, aided by machine learning, and looking for variants in these regions in CHD patients. She could later model their effects in human heart cells created through stem cell technology, in collaboration with William Pu’s lab, she thinks this could fill another 5 percent of cases.
As NICU intensifies its genomic testing program, Morton can share genetic information with families of children born with CHD, provided that any identified variants have been adequately screened as a likely contributor: “As soon as we can move a gene over the threshold, we can incorporate it into genetic testing and move medicine forward“, Concluded the expert.
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