Molecular genetics in 1991 arrhythmia probands and 2782 relatives in Norway: Results from 17 years of genetic testing in a national laboratory.

The aim of this study was to explore the prevalence of likely pathogenic or pathogenic variants and assess the diagnostic yield from genetic testing for cardiac arrhythmias in Norway since 2003. Data from 1991 probands and 2782 relatives were retrospectively collected from the laboratory information management system at Unit for Cardiac and Cardiovascular Genetics, Oslo University hospital. Of 1991 probands, 57.4% were females, age at genetic testing was 33.1 (±22.7) years, and 32.5% were under the age of 18. A likely pathogenic or pathogenic variant (including 14 novel) was detected in 15.4% in total. Of the 2782 relatives, 53.7% were females, age at genetic testing was 35.6 (±22.5) years, 27.3% were under the age of 18, and 45.3% carried the family variant. Probands and relatives combined, 1/3356 persons in the Norwegian population were heterozygous for an arrhythmia-causing variant. The founder variant p.Q530X (NM_000218.2: c.1588C>T) in KCNQ1 accounted for 34% of all variants in Norway. In conclusion, genetic testing provided a genetic basis of the arrhythmia in 15.4% of the probands. Familial cascade screening identified four times as many variant-positive relatives, allowing early detection and prompt stratification of arrhythmic risk of those variant carriers.

A novel KCNQ1 nonsense variant in the isoform-specific first exon causes both jervell and Lange-Nielsen syndrome 1 and long QT syndrome 1: a case report.

BACKGROUND: According to previous KCNQ1 (potassium channel, voltage gated, KQT-like subfamily, member 1) gene screening studies, missense variants, but not nonsense or frame-shift variants, cause the majority of long QT syndrome (LQTS; Romano-Ward syndrome [RWS]) 1 cases. Several missense variants are reported to cause RWS by a dominant-negative mechanism, and some KCNQ1 variants can cause both Jervell and Lange-Nielsen Syndrome (JLNS; in an autosomal recessive manner) and LQTS1 (in an autosomal dominant manner), while other KCNQ1 variants cause only JLNS. The human KCNQ1 gene is known to have two transcript isoforms (kidney isoform and pancreas isoform), and both isoforms can form a functional cardiac potassium channel. CASE PRESENTATION: Here, we report a novel nonsense KCNQ1 variant causing not only JLNS, but also significant QTc prolongation identical to RWS in an autosomal dominant manner. Our case study supports that haploinsufficiency in the KCNQ1 gene is causative of significant QTc prolongation identical to RWS. Interestingly, the nonsense variant (NM_000218.2:c.115G > T [p.Glu39X]) locates in exon 1a of KCNQ1, which is a kidney-isoform specific exon. The variant is located closer to the N-terminus than previously identified nonsense or frame-shift variants. CONCLUSION: To the best of our knowledge, this is the first report showing that a nonsense variant in exon 1a of KCNQ1, which is the kidney-isoform specific exon, causes JLNS. Our findings may be informative to the genetic pathogenesis of RWS and JLNS caused by KCNQ1 variants.

Genotype-phenotype analysis of Jervell and Lange-Nielsen syndrome in six families from Saudi Arabia.

We sought to explore the genotype-phenotype of Jervell and Lange-Nielsen syndrome (JLNS) patients in Saudi Arabia. We have also assessed the plausible effect of consanguinity into the pathology of JLNS. Six families with at least one JLNS-affected member attended our clinic between 2011 and 2013. Retrospective and prospective clinical data were collected and genetic investigation was performed. Pathogenic mutations in the KCNQ1 gene were detected in all JLNS patients. The homozygous mutations detected were Leu273Phe, Asp202Asn, Ile567Thr, and c.1486_1487delCT and compound heterozygous mutations were c.820_ 830del and c.1251+1G>T. All living JLNS patients except one had a QTc of >500 ms and a history of recurrent syncope. ß-Blockers abolished the cardiac-related events in all patients except two siblings with homozygous Ile567Thr mutation. Four of the six mutations were originally reported in autosomal dominant long QT syndrome (LQTS) patients. Eighty percent of the heterozygote mutation carriers showed prolongation of QTc, but majority of these reported no symptoms attributable to arrhythmias. Mutations detected in this study will be advantageous in tribe and region-specific cascade screening of LQTS in Saudi Arabia.

LQTS in Northern BC: homozygosity for KCNQ1 V205M presents with a more severe cardiac phenotype but with minimal impact on auditory function.

Long QT syndrome (LQTS), a rare congenital cardiac condition associated with life-threatening ventricular arrhythmias is characterized by a prolonged QT interval on electrocardiograph corrected for heart rate [corrected QT (QTc)]. LQTS has been historically categorized into the autosomal dominant Romano-Ward syndrome (RWS) and the autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS). JLNS is associated with prelingual sensorineural deafness. Both types of LQTS can be caused by mutations in channel genes (e.g. KCNQ1) responsible for potassium homeostasis in cardiac myocytes and cochlea. Autosomal dominant mutations often cause the RWS phenotype and homozygous or compound heterozygous mutations contribute to JLNS. Two First Nations communities in northern British Columbia are affected disproportionately with LQTS largely due to the V205M mutation in KCNQ1, however, the pathology and phenotypic expression for those V205M homozygous has been unknown. Here, we show that four V205M homozygous individuals have a significantly higher 'peak' QTc, and a more severe cardiac phenotype compared with 41 V205M heterozygous carriers and 57 first to third degree relatives without mutations. Given the lack of prelingual deafness the homozygous V205M LQTS patients present with a phenotype more typical of RWS than JLNS.

Treatment on arrhythmia electric storm in a Jervell and Lange-Nielsen syndrome patient by ablation of the triggering premature ventricular contraction: a case report.

Jervell and Lange-Nielsen syndrome (JLNS) is a subtype of congenital long QT syndrome (LQTS), which is a potentially life-threatening ion channelopathy characterized by delayed myocardial repolarization that leads to QT prolongation. Since JLNS is a rare disease, there have been few in-depth studies on this disease since yet. Previous studies have found that the pathogenesis of JLNS is related to KCNQ1 or KCNE1 gene mutation. There are a relatively small number of studies reporting the successful ablation treatment on JLNS patient due to the extremely low incidence rate. We report a 51-year-old female patient diagnosed with JLNS through gene detection. The patient has A to G missense mutation in KCNE1 gene, and a subunit with abnormal structure, which is the basis for congenital deafness. The main clinical manifestation of this patient is frequent fatal ventricular arrhythmia triggered by premature ventricular contraction (PVC). Ablation was successfully performed to eliminate the triggering PVC. The patient was not able to have implantable cardioverter defibrillator (ICD) implantation due to economic reasons. During the 12-month follow-up, no syncope or fatal arrhythmia was found in this patient. Our case showed that radiofrequency catheter ablation (RFCA) was an effective way to treat fatal arrhythmia in JLNS patient.

Identification of KCNQ1 compound heterozygous mutations in three Chinese families with Jervell and Lange-Nielsen Syndrome.

CONCLUSION: Besides expanding the spectrum of KCNQ1 mutations causing Jervell and Lange-Nielsen Syndrome (JLNS), the results showed diversity of its phenotypes, and emphasized the importance of molecular genetic analysis in confirming clinical diagnosis and making diagnosis possible before the emergency symptoms for deaf individuals. OBJECTIVES: This study aimed to investigate four patients from three Chinese families with congenital hearing loss clinically and genetically. METHOD: Genetic analysis of previously reported deafness genes based on massively parallel sequencing was conducted in more than five thousand Chinese hearing loss patients. Detailed clinical features of the patients with compound heterozygous or homozygous mutations of KCNQ1 gene were collected and analyzed. RESULTS: Compound mutations of KCNQ1 were found to be the genetic etiology of four patients from three families. Among the six KCNQ1 mutations, c.546C > A was identified as a novel mutation, c.965C > T had been reported in JLNS, while c.683 + 5G > A, c.1484_1485delCT, c.905C > T and c.1831G > A were previously reported in LQT1. In addition to congenital profound hearing loss in all subjects, two sibling subjects showed typical JLNS cardiac phenotype of prolonged QTc and recurrent syncopal episodes. One subject presented not only JLNS, but also iron-deficiency anemia and epilepsy. The other subject did not present any cardiac phenotype.

Left thoracoscopic sympathectomy for cardiac denervation in patients with life-threatening ventricular arrhythmias.

BACKGROUND: We reported the outcomes of a single-institution experience using video-assisted thoracoscopic left cardiac sympathetic denervation as an adjunctive therapeutic technique in pediatric and young adult patients with life-threatening ventricular arrhythmias. METHODS: We conducted a retrospective clinical review of all patients who underwent left cardiac sympathetic denervation by means of video-assisted thoracoscopic surgery at our institution. From August 2000 to December 2011, 24 patients (13 with long QT syndrome, 9 with catecholaminergic polymorphic ventricular tachycardia, and 2 with idiopathic ventricular tachycardia) were identified from the cardiology database and surgical records. RESULTS: There were no intraoperative complications. The median postoperative length of stay was 2 days (range, 1-32 days). There were no major perioperative complications. Longer-term follow-up was available in 22 of 24 patients at a median follow-up of 28 months (range, 4-131 months). Sixteen (73%) of the 22 patients experienced a marked reduction in their arrhythmia burden, with 12 (55%) becoming completely arrhythmia free after sympathectomy. Six (27%) of the patients were nonresponsive to treatment; each had persistent symptoms at follow-up. CONCLUSIONS: Video-assisted thoracoscopic left cardiac sympathetic denervation can be safely and effectively performed in most patients with life-threatening ventricular arrhythmias. This minimally invasive procedure is a promising adjunctive therapeutic option that achieves a beneficial response in most symptomatic patients. These results support the inclusion of thoracoscopic cardiac sympathetic denervation among the treatment armamentarium in all patients with ventricular arrhythmias refractive to conventional medical therapy.