Background— The prevalence of genetic arrhythmogenic diseases is unknown. For the long-QT syndrome (LQTS), figures ranging from 1:20 000 to 1:5000 were published, but none was based on actual data. Our objective was to define the prevalence of LQTS. Methods and Results— In 18 maternity hospitals, an ECG was performed in 44 596 infants 15 to 25 days old (43 080 whites). In infants with a corrected QT interval (QTc) >450 ms, the ECG was repeated within 1 to 2 weeks. Genetic analysis, by screening 7 LQTS genes, was performed in 28 of 31 (90%) and in 14 of 28 infants (50%) with, respectively, a QTc >470 ms or between 461 and 470 ms. A QTc of 451 to 460, 461 to 470, and >470 ms was observed in 177 (0.41%), 28 (0.06%), and 31 infants (0.07%). Among genotyped infants, disease-causing mutations were found in 12 of 28 (43%) with a QTc >470 ms and in 4 of 14 (29%) with a QTc of 461 to 470 ms. One genotype-negative infant (QTc 482 ms) was diagnosed as affected by LQTS on clinical grounds. Among family members of genotype-positive infants, 51% were found to carry disease-causing mutations. In total, 17 of 43 080 white infants were affected by LQTS, demonstrating a prevalence of at least 1:2534 apparently healthy live births (95% confidence interval, 1:1583 to 1:4350). Conclusions— This study provides the first data-based estimate of the prevalence of LQTS among whites. On the basis of the nongenotyped infants with QTc between 451 and 470 ms, we advance the hypothesis that this prevalence might be close to 1:2000. ECG-guided molecular screening can identify most infants affected by LQTS and unmask affected relatives, thus allowing effective preventive measures.

Background— The hypothesis that some cases of sudden infant death syndrome (SIDS) could be caused by long-QT syndrome (LQTS) has been supported by molecular studies. However, there are inadequate data regarding the true prevalence of mutations in arrhythmia-susceptibility genes among SIDS cases. Given the importance and potential implications of these observations, we performed a study to more accurately quantify the contribution to SIDS of LQTS gene mutations and rare variants. Methods and Results— Molecular screening of 7 genes ( KCNQ1 , KCNH2 , SCN5A , KCNE1 , KCNE2 , KCNJ2 , CAV3 ) associated with LQTS was performed with denaturing high-performance liquid chromatography and nucleotide sequencing of genomic DNA from 201 cases diagnosed as SIDS according to the Nordic Criteria, and from 182 infant and adult controls. All SIDS and control cases originated from the same regions in Norway. Genetic analysis was blinded to diagnosis. Mutations and rare variants were found in 26 of 201 cases (12.9%). On the basis of their functional effect, however, we considered 8 mutations and 7 rare variants found in 19 of 201 cases as likely contributors to sudden death (9.5%; 95% CI, 5.8 to 14.4%). Conclusions— We demonstrated that 9.5% of cases diagnosed as SIDS carry functionally significant genetic variants in LQTS genes. The present study demonstrates that sudden arrhythmic death is an important contributor to SIDS. As these variants likely modify ventricular repolarization and QT interval duration, our results support the debated concept that an ECG would probably identify most infants at risk for sudden death due to LQTS either in infancy or later on in life.

Background—: Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause. Methods and Results—: We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with the use of exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in 2 genes encoding calmodulin. We discovered 3 heterozygous de novo mutations in either CALM1 or CALM2 , 2 of the 3 human genes encoding calmodulin, in the 2 probands and in 2 additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several-fold reductions in calcium binding affinity. Conclusions—: Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart, affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy.

Catecholaminergic polymorphic ventricular tachycardia is a potentially lethal disease characterized by adrenergically mediated ventricular arrhythmias manifested especially in children and teenagers. Beta-blockers are the cornerstone of therapy, but some patients do not have a complete response to this therapy and receive an implantable cardioverter–defibrillator (ICD). Given the nature of catecholaminergic polymorphic ventricular tachycardia, ICD shocks may trigger new arrhythmias, leading to the administration of multiple shocks. We describe the long-term efficacy of surgical left cardiac sympathetic denervation in three young adults with catecholaminergic polymorphic ventricular tachycardia, all of whom had symptoms before the procedure and were symptom-free afterward.