Genes Previously Linked to Heart Condition Disputed

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New research examines why some children born with heart defects also have developmental disabilities. [Image courtesy of Mark L. Riccio

A new analysis of available data has convinced a panel genomic experts that nine genes previously believed to be associated with a rare, genetic heart condition—long QT syndrome—were an erroneously linked to the condition, as revealed in a new study funded by the National Human Genome Research Institute (NHGRI), a division of the National Institutes of Health (NIH).

Geneticists and heart specialists around the world had previously reported 17 genes to cause long QT syndrome. However, the Clinical Genome Resource’s (ClinGen) expert panel has critically reevaluated the scientific evidence for all 17 reported genes, and has concluded at least nine of the genes cannot be linked to the disease, and only three of the genes can be definitively associated with the most common form of the disease.

Long QT syndrome is caused by mutations in genes that regulate the heart’s electrical activity. These mutations can cause the heart to have sudden, irregular heart rhythms, or arrhythmias. People with long QT syndrome can have arrythmias that are both unprovoked or as a result of stress and exercise. These arrythmias can be fatal.

Many people with long QT syndrome may be unaware they have the condition, unless they get an unrelated electrocardiogram, know their family history, and have undergone genetic testing.

Ever since the syndrome was described in 1957, researchers have engaged in a genetic race to identify the genes associated with it, which currently includes the 17 genes. By using such a standardized, evidence-based framework, the international ClinGen panel experts on long QT syndrome were able to classify the 17 genes into specific groups.

Three genes, KCNQ1, KCNH2 and SCN5A, had sufficient evidence to be implicated as “definitive” genetic causes for typical long QT syndrome. Four other genes had strong or definitive evidence supporting their role in causing atypical forms of long QT syndrome, particularly if they presented in the newborn period with associated heart block, seizures or delays in development.

The remaining ten genes were deemed to not have sufficient evidence to support a causal role in the syndrome. In fact, nine of these 10 remaining genes were placed in the limited or disputed category. The study authors suggest that these genes not be routinely tested in clinical settings when evaluating patients and families with long QT syndrome, because they lack sufficient scientific evidence as a cause for the condition.

This removal of genes from the testing list impacts genetic testing providers, who use research papers to determine which genes to include in their testing panels for diagnostic reporting to physicians. Published papers reporting gene-disease associations vary widely in their study design and strength of evidence to support their conclusions. Until recently, standard guidelines that can differentiate between genes found with strong and valid scientific approaches versus those with insufficient evidence did not exist. Clearly, this is a problematic approach, and led to several studies drawing early conclusions.

ClinGen’s expert panels include researchers, clinicians, and genetic counselors who apply an evidence-based framework in evaluating the available data from research papers to place gene-disease relationships into “definitive,” “strong,” “moderate,” “limited,” “disputed,” or “refuted” categories.

“ClinGen is an impressive community effort. With over 1,000 researchers and clinicians from 30 countries volunteering their time and expertise, ClinGen is providing much needed clarity for the clinical genomics community regarding which gene-disease pairs have sufficient evidence to be used clinically,” said Erin Ramos, Ph.D., project scientist for ClinGen and program director in the Division of Genomic Medicine at NHGRI.

“Our study highlights the need to take a step back and to critically evaluate the level of evidence for all reported gene-disease associations, especially when applying genetic testing for diagnostic purposes in our patients. Testing genes with insufficient evidence to support disease causation only creates a risk of inappropriately interpreting the genetic information and leading to patient harm,” says Michael Gollob, M.D., senior author of the paper and researcher at the Toronto General Hospital Research Institute.

Moreover, testing for genes not definitively associated with long QT syndrome can result in inappropriate and costly medical interventions such as implanting of a cardioverter-defibrillator.

This is not the first time a team at ClinGen has clarified published research for clinicians. The same team of researchers published a similar study in 2018, covering another heart condition called Brugada syndrome. In 2019, the American Society of Human Genetics considered the paper as one of the top 10 advances in genomic medicine.

ClinGen is an NHGRI-funded resource created to define the clinical relevance and validity of genes associated with various genetic disorders.  It comprises more than 20 expert panels working on a variety of genetically influenced diseases, ensuring the reliability of gene-disease linkage. This work is also instrumental in determining which specific genes should be targeted for further study in precision medicine and research.

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