Background-Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death. Methods and Results-Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b (Ca v␤2b ), CACNA2D1 (Ca v␣2␦1 ), and CACNA1C tagged with enhanced yellow fluorescent protein (Ca v 1.2). Whole-cell patch-clamp studies were performed after 48 to 72 hours. Three probands displaying ST-segment elevation and corrected QT intervals Յ360 ms had mutations in genes encoding the cardiac L-type calcium channel. Corrected QT ranged from 330 to 370 ms among probands and clinically affected family members. Rate adaptation of QT interval was reduced. Quinidine normalized the QT interval and prevented stimulation-induced ventricular tachycardia. Genetic and heterologous expression studies revealed loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the ␣ 1 -and ␤ 2b -subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Ca v 1.2 channels but normal trafficking of channels containing G490R Ca v 1.2 or S481L Ca v␤2b -subunits. Conclusions-This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals. Key Words: arrhythmia Ⅲ genetics Ⅲ electrophysiology Ⅲ tachycardia Ⅲ fibrillation C ardiac arrhythmias are responsible for an estimated 1 million cases of syncope and sudden cardiac death (SCD) among Europeans and Americans each year. 1 Cardiac arrhythmias can be acquired as a consequence of coronary heart disease or may be secondary to familial or inherited syndromes. The past decade has witnessed an explosion of information linking cardiac ion channel mutations with a wide variety of inherited arrhythmia syndromes. 2 The long-QT syndrome has been associated with 10 different Clinical Perspective p 449genes, in large part owing to the pioneering studies of Keating and coworkers. The LQT8 form of long-QT syndrome, also known as Timothy syndrome, is associated with gain-offunction mutations in cardiac calcium channel activity. 3,4 The cardiac L-type calcium channel is a protein complex formed by at least 3 subunits, ␣ 1 , ␤, and ␣ 2␦ . The pore-forming Ca v 1. subunit, encoded by CACNB2b, modulates calcium channel activity in the human heart and enables trafficking by suppressing an endoplasmic reticulum retention signal in the I-II loop of the ␣ 1 -subunit. 5 The short-QT syndrome (SQTS), a clinical entity first described in 2000,6 has been associated ...

Background-Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG. Methods and Results-Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac I Kr channel HERG (KCNH2). The mutations dramatically increase I Kr , leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to I Kr blockers. Conclusions-We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.