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Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multi-center collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (JLNS2, N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc > 460ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 JLNS2 patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9 + 38.6ms) compared to genotype positive family members (441.8 + 30.9ms, p<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR]: 11.6, 95% confidence interval [CI]: 2.6-52.2; p=0.001). Event incidence did not differ significantly for JLNS2 patients relative to the overall heterozygous cohort (10.5% [2/19]; HR: 1.7, 95% CI: 0.3-10.8, p=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database (gnomAD), which is a human database of exome and genome sequencing data from now over 140,000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs. 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT-prolongation, however the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for JLNS2 patients.

A nine-year-old girl presented to the emergency department in the fall of 2009 with a one-week history of cough, neck swelling, sore throat and mild diarrhea, but no fever or vomiting. She had a history of asthma, which was treated with montelukast. Her physical examination showed subcutaneous emphysema above the clavicles. A chest radiograph showed pneumomediastinum (Figure 1). She was discharged home but returned several hours later with worsening symptoms. A neck radiograph showed massive subcutaneous emphysema in the prevertebral space (Figure 2). An echocardiogram showed a very small localized pneumopericardium over the left ventricle. Polymerase chain reaction testing of nasal secretions was positive for pandemic (H1N1) 2009 virus. She was admitted to the pediatric intensive care unit and given 100% oxygen therapy, inhaled salbutamol and oral oseltamivir. She was also given antibiotics empirically, because of the potential loss of sterility of the prevertebral space. Apart from lingering fever, she recovered uneventfully and was discharged after five days.A 14-year-old boy presented to the emergency department in the fall of 2009 with a fiveday history of fever, cough, sore throat, abdominal pain and fatigue. There was no history of vomiting. He had a history of very mild asthma, having last used inhaled salbutamol over a year earlier. He had mild tachypnea. There was limitation in lateral neck movement, but no subcutaneous emphysema on palpation. Neck and chest radiographs showed subcutaneous air at the sternoclavicular notch and anterior to the cervical vertebra, but no pneumomediastinum or pneumopericardium. Testing of nasal secretions by polymerase chain reaction was positive for pandemic (H1N1) 2009 virus. He was given oral oseltamivir; he rapidly improved and was discharged within three days.A three-year-old boy presented to the emergency department in the fall of 2009 with a fourday history of fever, cough, runny nose and sudden-onset neck swelling. He had vomited once. He had been diagnosed with asthma six months earlier, but had been using inhaled corticosteroids and bronchodilators inconsistently for the past five months. He was tachycardic, with a maximum heart rate of 160 beats/min, and tachypneic, with a maximum respiratory rate of 62 breaths/min. He required supplemental oxygen to maintain oxygen saturation above 92%. There was palpable subcutaneous emphysema at the face, neck, chest and upper abdomen. He had increased respiratory effort and a prolonged expiratory phase. His chest radiograph showed subcutaneous emphysema and pneumomediastinum. Testing of his nasal secretions by polymerase chain reaction was positive for pandemic (H1N1) 2009 virus. He was given oral oseltamivir, 100% oxygen therapy, antibiotics, inhaled salbutamol and oral corticosteroids. He had an uncomplicated course and was discharged after four days. DiscussionInfection with pandemic (H1N1) 2009 virus has been associated with severe respiratory complications in children, including secondary bacterial pneumonia and respira...