Long QT syndrome (LQTS) is the most common inherited cardiac arrhythmia (affecting 1 in 2,000 individuals) and has been associated with mutations in 17 different genes. However, according to a new assessment, the evidence that many of these genes are actually causative for LQTS is limited or disputed. This finding has important implications for genetic testing, diagnosis and treatment.
The International, Multicentered LQTS ClinGen Working Group identified 17 genes reported to cause LQTS. In the context of a contemporary understanding of natural variation in the human genome, the group found that only three genes (KCNQ1, KCNH2 and SCN5A) had definitive evidence for causing typical LQTS. These genes are traditionally classified as causing LQTS types 1–3, respectively. A further four genes (CALM1, CALM2, CALM3 and TRDN) were found to have strong or definitive evidence for causing atypical LQTS, including neonatal atrioventricular block. One gene (CACNA1C) had moderate evidence for causing LQTS.
By contrast, three genes (CAV3, KCNE1 and KCNJ2) had limited evidence and six genes (AKAP9, ANK2, KCNE2, KCNJ5, SCN4B and SNTA1) had disputed evidence for causing LQTS. Two of these genes (KCNE1 and KCNE2) had a strong level of evidence for causing acquired LQTS.
“Genes with disputed or limited evidence for causation of LQTS should not be routinely tested for diagnostic purposes”
“Genes with disputed or limited evidence for causation of LQTS should not be routinely tested for diagnostic purposes in patients with suspected LQTS,” says Michael Gollob, who designed and led the study. “Testing genes that lack scientific evidence for disease causation creates a risk of misinterpretation of the genetic information, and potentially an incorrect diagnosis in a patient and their family members. Many of us have seen numerous cases of wrongly diagnosed patients based on misinterpreted genetics, many of whom have suffered undue mental health and physical consequences because of these errors.”
Adler, A. et al. An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome. Circulation https://doi.org/10.1161/CIRCULATIONAHA.119.043132 (2020)
Offerhaus, J. A. et al. Epidemiology of inherited arrhythmias. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-019-0266-2 (2019)
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Lim, G.B. Reappraisal of LQTS-causing genes. Nat Rev Cardiol 17, 200–201 (2020). https://doi.org/10.1038/s41569-020-0349-0