Twenty years ago, The New York Times published an article about three “apparently healthy” young people who died in seemingly mysterious ways, while sleeping, swimming and after playing soccer. In 2019, about 4,000 children and young adults died in the United States in similar, unusual ways. The apparent cause was long QT syndrome.
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. Much like the cases in the New York Times article, people with long QT syndrome can have arrythmias that are both unprovoked or a result of stress and exercise. But when the arrythmias do occur, they 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. The term “QT” refers to the segment of an electrocardiogram which measures the duration of time for the heart to relax after a heartbeat. In long QT syndrome, that duration of time is abnormally prolonged and creates a vulnerability to dangerous arrhythmias.
Ever since the syndrome was described in 1957, researchers have engaged in a genetic race to identify the genes associated with long QT syndrome, which currently includes 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, presenting in the newborn period with associated heart block, seizures or delays in development. The remaining ten genes did 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 for causing for this condition.