KCNH2 Duplication Variant (c.2164_2181dup) Associated With Sudden Cardiac Death in a Family With Congenital Long QT...

Congenital long QT syndrome (LQTS) is an inherited arrhythmogenic disorder characterised by prolonged QTc intervals and T-wave abnormalities on electrocardiography (ECG). Prolonged QT intervals can lead to syncope, seizures, torsades de pointes, and sudden cardiac death. There are several genes, including KCNH2, known to be associated with congenital LQTS, and genetic variations in KCNH2 are known to cause a reduction in the delayed rectifier potassium current (I_Kr).

Clinical genetic testing and variant reclassification were performed by Blueprint Genetics. The functional effect of the KCNH2 variant was quantified with the use of a calibrated automated patch clamp electrophysiology assay.

We discuss a case in which postmortem genetic testing of a 34-year-old woman revealed a variant of uncertain significance (VUS) (c.2164_2181dup) in KCNH2. Subsequent cascade genetic testing in her father and brother identified the same VUS, and both showed evidence of clinical LQTS. Patch clamp analysis shows that c.2164_2181dup causes a severe loss-of-function phenotype and can be assigned with a strong level of functional evidence (PS3) for VUS reclassification.

With previous reports of LQTS associated with c.2164_2181dup, the phenotypes observed in this family, and the strong level of functional evidence obtained from patch clamp analysis, c.2164_2181dup has been clinically reclassified as likely pathogenic.