Editors' ChoiceCardiovascular Disease

Understanding the Genetic Risk of Sudden Cardiac Death

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Science Translational Medicine  13 Aug 2014:
Vol. 6, Issue 249, pp. 249ec140
DOI: 10.1126/scitranslmed.3010121

Diagnosing genetic diseases can be deceptively difficult. Although long QT syndrome (LQTS) is the best-understood genetic cause of sudden cardiac death, ~75% of patients with the phenotype have unidentifiable mutations. This hinders definitive diagnosis when LQTS is suspected as the cause of sudden cardiac death. These limitations create even greater clinical challenges when trying to diagnose relatives of patients with unexplained sudden cardiac death, many of whom are either concerned about their own risk after losing a close relative or are worried about their children after having lost a spouse. Now, Gong et al. have identified a new genetic mutation for LQTS type 2 that could improve diagnostic testing for the disorder, as well as identify new areas to study for potential genetic therapy to prevent sudden cardiac death.

Approximately 1 in 7000 Americans have LQTS, which is an important risk factor for sudden cardiac death. Affected patients require preventive treatment and careful avoidance of QT-prolonging medications. Genetic testing is important for making the correct diagnosis because the LQTS phenotype is not definitive: There is a “gray area” of QT prolongation on the electrocardiogram; the QT interval for any individual can vary from day to day; and warning symptoms such as passing-out spells can also occur for unrelated reasons. Thus, the uncertainty created by the limited accuracy of current genetic testing in the setting of moderate to high clinical risk of LQTS poses substantial challenges for physicians and patients.

Gong et al. studied three generations of a family with LQTS type 2 and sudden cardiac death. They identified a new splice site mutation in intron 9 of the KCNH2 gene that was associated with a significantly prolonged QT interval and T wave morphology typical of LQTS. The mutant gene was cloned and transfected into cultured HL-1 mouse cardiac myocytes. The investigators studied mRNA production, cellular trafficking, and membrane voltage characteristics of cells transfected with the wild-type versus mutated gene. They found that the mutation abolished the K+ ion current in the KCNH2 channel protein, likely through expression of a nonfunctional isoform of the protein due to proximal polyadenylation of its mRNA. This discovery of a new mechanism of pathogenesis in LQTS could lead to more accurate genetic testing for sudden cardiac arrest through the identification of more disease-causing mutations, as well as expand the range of potential options for future genetic therapy for LQTS.

Q. Gong et al., Identification of Kv11.1 isoform switch as a novel pathogenic mechanism of long QT syndrome. Circ. Cardiovasc. Genet. 10.1161/​CIRCGENETICS.114.000586 (2014). [Abstract]

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