Expert genomics panel disputes certain genes linked to a dangerous heart condition

By Sally Robertson, B.Sc.Jan 27 2020

A panel of genomics experts has said that nine genes previously reported to be linked to a dangerous heart disorder called long QT syndrome, are not associated with the condition.

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After re-evaluating the evidence for 17 genes that specialists worldwide thought were linked to the syndrome, the Clinical Genome Resource's (ClinGen) panel disputed the involvement of nine genes and confirmed that only three have a “definitive” gene-disease association with the most common form of the syndrome.

Funded by the National Human Genome Research Institute (NHGRI), ClinGen is a resource that evaluates the scientific evidence supporting the inclusion of certain genes in the assessment of various genetic disorders for precision medicine and research.

Their recent findings of the genes thought to be involved in long QT syndrome have now been published in Circulation - a journal of The American Heart Association.

About long QT syndrome

Long QT syndrome (LQTS) is an uncommon inherited disorder of the heart’s electr​ical activity. Mutations in the genes that regulate this activity cause a sudden, irregular heart rate or rhythm (arrhythmia) that seems to be unprovoked or simply a response to stress or exercise, for example.   

Not everybody with LQTS experiences symptoms, but those who do, usually experience dangerous blackouts, seizures or heart palpitations. Since the condition can be asymptomatic, some people only become aware of it once they have an electrocardiogram (ECG) for another reason or because they get checked due to a family history of the condition.

“Long QT” refers to an abnormal pattern of electrical activity between two of five waves (P, Q, R, S, and T) seen on an ECG during the cycle of a heartbeat. In healthy individuals, this interval occurs for about one-third of a cycle, but for people with LQTS, the interval is longer as the heart takes more time to recharge after a heartbeat. This increases the risk of dangerous arrhythmia.

Since the condition was discovered in the late 1950s, scientists have been trying to identify any associated genes, with the number currently standing at 17. However, the genes that providers include in their diagnostic testing panels are based on research papers looking at gene-disease associations, which can vary significantly in study design and the strength of their supporting evidence.

Where does ClinGen come in?

ClinGen was established by the NHGRI as a resource to address this very problem in precision medicine. The panel is made up of genetics experts who use an evidence-based framework to assess research papers and categorize the association between disease and certain genes as one of "definitive," "strong," "moderate," "limited," "disputed" or "refuted.”

"ClinGen is an impressive community effort,” says Erin Ramos, project scientist for ClinGen and program director in the Division of Genomic Medicine at NHGRI. “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."

After applying this framework to evidence available for LQTS, the panel categorized 17 genes previously associated with the condition into three that had “definitive” causes; four that had “strong” or “definitive” evidence to support a role in atypical forms of the condition and ten that had no sufficient evidence to support cause. The researchers placed the ten genes with no sufficient evidence in the “limited” or “disputed” category and suggested not including them as part of routine clinical testing for LQTS.

"Our study highlights the need to take a step back”

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,”

Michael Gollob, Toronto General Hospital Research Institute.

Testing genes that are not definitively linked to the LQTS, for example, can lead to expensive interventions such as implanting a cardioverter-defibrillator to correct dangerous heart rhythms when it is not needed.

“Testing genes with insufficient evidence to support disease causation only creates a risk of inappropriately interpreting the genetic information and leading to patient harm," concludes Gollob.