Homozygosity for a HERG potassium channel mutation causes a severe form oflong-QT syndrome: Identification of an apparent founder mutation in the Finns

OBJECTIVES We studied the clinical characteristics and molecular background underlying a severe phenotype of long QT syndrome (LQTS). BACKGROUND Mutations of cardiac ion channel genes cause LQTS, manifesting a s increased risk of ventricular tachycardia and sudden death. METHODS We studied two siblings showing prolonged QT intervals corrected fo r heart rate (QTc), their asymptomatic parents with only marginally prolong ed QTc intervals and their family members. The potassium channel gene HERG was screened for mutations by deoxyribonucleic acid sequencing, and the ele ctrophysiologic consequences of the mutation were studied in vitro using th e whole-cell patch-clamp technique. RESULTS A novel missense mutation (L552S) in the HERG channel, present in t he homozygous state in the affected siblings and in the heterozygous state in their parents, as well as in 38 additional subjects from six LQTS famili es, was identified. One of the homozygous siblings had 2:1 atrioventricular block immediately after birth, and died at the age of four years after exp eriencing unexplained hypoglycemia. The other sibling had an episode of tor sade de pointes at the age of two years. The mean QTc interval differed sig nificantly (p < 0.001) between heterozygous symptomatic mutation carriers ( 500 +/- 59 ms), asymptomatic mutation carriers (452 +/- 34 ms) and noncarri ers (412 +/- 23 ms). When expressed in vitro, the HERG-L552S formed functio nal channels with increased activation and deactivation rates. CONCLUSIONS Our data demonstrate that homozygosity for a HERG mutation can cause a severe cardiac repolarization disorder without other phenotypic abn ormalities. Absence of functional HERG channels appears to be one cause for intrauterine and neonatal bradycardia and 2:1 atrioventricular block. (J A m Coll Cardiol 2000;35:1919-25) (C) 2000 by the American College of Cardiol ogy.