The Jervell and Lange-Nielsen syndrome (JLNS) comprises profound congenital sensorineural deafness associated with syncopal episodes. These are caused by ventricular arrhythmias secondary to abnormal repolarisation, manifested by a prolonged QT interval on the electrocardiogram. Recently, in families with JLNS, Neyroud et al. reported homozygosity for a single mutation in KVLQT1 , a gene which has previously been shown to be mutated in families with dominantly inherited isolated long QT syndrome [Neyroud et al . (1997) Nature Genet ., 15, 186-189]. We have analysed a group of families with JLNS and shown that the majority are consistent with mutation at this locus: five families of differing ethnic backgrounds were homozygous by descent for markers close to the KVLQT1 gene and a further three families from the same geographical region were shown to be homozygous for a common haplotype and to have the same homozygous mutation of the KVLQT1 gene. However, analysis of a single small consanguineous family excluded linkage to the KVLQT1 gene, establishing genetic heterogeneity in JLNS. The affected children in this family were homozygous by descent for markers on chromosome 21, in a region containing the gene IsK . This codes for a transmembrane protein known to associate with KVLQT1 to form the slow component of the delayed rectifier potassium channel. Sequencing of the affected boys showed a homozygous mutation, demonstrating that mutation in the IsK gene may be a rare cause of JLNS and that an indistinguishable phenotype can arise from mutations in either of the two interacting molecules.

Background-Data on the Jervell and Lange-Nielsen syndrome (J-LN), the long-QT syndrome (LQTS) variant associated with deafness and caused by homozygous or compound heterozygous mutations on the KCNQ1 or on the KCNE1 genes encoding the I Ks current, are still based largely on case reports. Methods and Results-We analyzed data from 186 J-LN patients obtained from the literature (31%) and from individual physicians (69%). Most patients (86%) had cardiac events, and 50% were already symptomatic by age 3. Their QTc was markedly prolonged (557Ϯ65 ms

Jervell and Lange-Nielsen syndrome (MIM 220400; JLNS), is a rare form of profound congenital deafness combined with syncopal attacks and sudden death due to prolonged QTc; it is an autosomal recessive trait. After its first description in Norway in 1957, later reports from many other countries have confirmed its occurrence. Nowhere is the prevalence so high as in Norway, where we estimate a prevalence of at least 1:200,000. The KCNQ1 and KCNE1 proteins coassemble in a potassium channel, and mutations in either the KCNQ1 gene or the KCNE1 gene disrupt endolymph production in the stria vascularis in the cochlea, causing deafness. KCNQ1 seems to be the major gene in JLNS. Long QT syndrome (LQTS) is a separate disorder of either autosomal dominant or recessive inheritance caused by mutations in four different ion channel genes; KCNQ1 is the one most frequently involved. Some heterozygous carriers of JLNS mutations in either gene may suffer from prolonged QTc and be symptomatic LQTS patients with a need for appropriate medical treatment to prevent life-threatening cardiac arrhythmia. In general, frameshift/stop mutations cause JLNS, and missense/splice site mutations cause LQTS, but a precise genotype-phenotype correlation in LQTS and JLNS is not established, which complicates both genetic counseling and clinical risk evaluation in carriers. We review JLNS from a Norwegian perspective because of the unusually high prevalence, the genetic homogeneity associated with considerable mutational heterogeneity, and some evidence for recurrent mutational events as well as one founder mutation. We outline the clinical implications for investigation of deaf children and cases of sudden infant death syndrome as well as careful electrocardiographic monitoring of identified mutation carriers to prevent sudden death. Am. J. Med. Genet. (Semin. Med. Genet.) 89:137-146, 1999.

AimCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac disease predisposing to lifethreatening arrhythmias. We aimed to determine the prevalence of arrhythmias and efficacy of b-blocker treatment in mutation-positive family members diagnosed by cascade genetic screening. Methods and resultsRelatives of six unrelated CPVT patients were tested for the relevant mutation in the ryanodine receptor-2 gene. Mutation carriers underwent an exercise test at inclusion time and 3 months after the initiation of b-blocker therapy in the highest tolerable dose. The occurrence of ventricular premature beats, couplets, and non-sustained ventricular arrhythmias (nsVT) were recorded in addition to the heart rate at which they occurred. Thirty family members were mutation carriers and were followed for 22 (13 -288) months. Previous undiagnosed CPVTrelated symptoms were reported by eight subjects. Exercise test induced ventricular arrhythmias in 23 of the 30 mutation carriers. On b-blocker treatment, exercise-induced arrhythmias occurred at a lower heart rate (117 + 17 vs. 135 + 34 beats/min, P ¼ 0.02) but at similar workload (P ¼ 0.78). b-Blocker treatment suppressed the occurrence of exercise-induced nsVT in three of the four patients, while less severe arrhythmias were unchanged. One patient died during follow-up. ConclusionExercise test revealed a high prevalence of arrhythmias in CPVT mutation carriers diagnosed by cascade genetic screening. b-Blocker therapy appeared to suppress the most severe exercise-induced arrhythmias, while less severe arrhythmias occurred at a lower heart rate.--

Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive syndrome characterised by profound congenital sensorineural deafness and prolongation of the QT interval on the electrocardiogram, representing abnormal ventricular repolarisation. In a study of ten British and Norwegian families with JLNS, we have identified all of the mutations in the KCNQ1 gene, including two that are novel. Of the nine mutations identified in this group of 10 families, five are nonsense or frameshift mutations. Truncation of the protein proximal to the recently identified C-terminal assembly domain is expected to preclude assembly of KCNQ1 monomers into tetramers and explains the recessive inheritance of JLNS. However, study of a frameshift mutation, with a dominant effect phenotypically, suggests the presence of another assembly domain nearer to the N-terminus.