Autosomal recessive catecholamine- or exercise-induced polymorphic ventricular tachycardia - Clinical features and assignment of the disease gene to chromosome 1p13-21

Background-Catecholaminergic polymorphic ventricular tachycardia (PVT) is c haracterized by episodes of syncope, seizures, or sudden death in response to physiological or emotional stress. In 2 families with autosomal dominant inheritance, the disease gene was mapped to chromosome 1q42-43. The object ives of this study were to characterize the clinical features of the diseas e in a Bedouin tribe from Israel and to map the disease gene. Methods and Results - In this Bedouin tribe, 9 children (age, 7 +/-4 years) from 7 related families have died suddenly during the past decade, and 12 other children suffered from recurrent syncope and seizures starting at the age of 6 +/-3 years. Parents of affected individuals were asymptomatic and were all related (first-, second-, or third-degree cousins), Segregation a nalysis suggested autosomal recessive inheritance. All 12 symptomatic patie nts and 1 asymptomatic sibling (mean age, 13 +/-7 years) were found to have a relative resting bradycardia (64 +/- 13 bpm, versus 930 +/- 12 bpm in th e unaffected siblings), as well as PVT induced by treadmill or isoprotereno l infusion and appearing at a mean sinus rate of 110 +/-0 bpm. Patients res ponded favorably to treatment with P-blockers, A genome-wide search using p olymorphic DNA markers mapped the disease locus to a 16-megabase interval o n chromosome 1p13-21. A maximal lod score of 8.24 was obtained with D1S189 at theta =0.00, Sequencing of KCND3, a gene that encodes an I-tO potassium channel transporter, did not reveal any significant sequence alterations. Conclusions - This unique form of autosomal recessive PVT affects young chi ldren and may be lethal if left untreated. Linkage analysis maps this disor der to chromosome 1p13-21.