Partial Duplication and Poly(A) Insertion in KCNQ1 Not Detected by Next-Generation Sequencing in Jervell and Lange–Nielsen Syndrome
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Jervell and Lange–Nielsen syndrome is caused by absence of the voltage-gated potassium current IKs through either homozygous recessive or compound heterozygous mutations in KCNQ1 or KCNE1. We report here a case of Jervell and Lange–Nielsen syndrome with typical clinical features in which clinical genetic testing using next-generation sequencing (NGS) revealed only a known single heterozygous KCNQ1 mutation (R518X), but failed to recognize an unusual and complex 52-bp duplication-insertion. This type of variant has not been previously reported in Long QT syndrome (LQTS) and may therefore account for a portion of genetic variant negative cases.
A 47-year-old woman with congenital deafness, severe QT prolongation (≥800 ms on Holter monitoring; Figure 1A and 1B), and striking exercise-induced QT lability and torsades de pointes was seen in referral. She had her first episode of syncope at 6 years of age, was reported to have marked QT prolongation, started β-blocker therapy, and was then lost to follow-up. At age 40, she had an episode of syncope while working outdoors in the heat, and β-blocker (propranolol at that time) was continued although she admitted to incomplete compliance because of fatigue. At age 46, she had another syncopal episode and was switched to metoprolol 100 mg daily. An implantable cardioverter-defibrillator was recommended but she declined. During an exercise test to assess the adequacy of β-blockade, she developed marked T wave lability followed by a 40-second, self-terminating episode of torsades de pointes, during which she lost consciousness (Figure 1C). Notably, this T wave instability occurred in an unusual (nonalternans) pattern,1 compatible with temporal variability in repolarization with …