Lack of genotype-phenotype correlation in Brugada Syndrome and Sudden Arrhythmic Death Syndrome families with reported pathogenic SCN1B variants.

BACKGROUND: There is limited evidence that Brugada Syndrome (BrS) is due to SCN1B variants (BrS5). This gene may be inappropriately included in routine genetic testing panels for BrS or Sudden Arrhythmic Death Syndrome (SADS). OBJECTIVE: We sought to characterize the genotype-phenotype correlation in families who had BrS and SADS with reportedly pathogenic SCN1B variants and to review their pathogenicity. METHODS: Families with BrS and SADS were assessed from 6 inherited arrhythmia centers worldwide, and a comprehensive literature review was performed. Clinical characteristics including relevant history, electrocardiographic parameters and drug provocation testing results were studied. SCN1B genetic testing results were reclassified using American College of Medical Genetics criteria. RESULTS: A total of 23 SCN1B genotype-positive individuals were identified from 8 families. Four probands (17%) experienced ventricular fibrillation or sudden cardiac death at the time of presentation. All family members were free from syncope or ventricular arrhythmias. Only 2 of 23 genotype-positive individuals (9%) demonstrated a spontaneous BrS electrocardiographic pattern. Drug challenge testing for BrS in 87% (13 of 15) was negative. There was no difference in PR interval (161 ± 7 ms vs 165 ± 9 ms; P = .83), QRS duration (101 ± 6 ms vs 89 ± 5 ms; P = .35), or corrected QT interval (414 ± 35 ms vs 405 ± 8 ms; P = .7) between genotype-positive and genotype-negative family members. The overall frequency of previously implicated SCN1B variants in the Genome Aggregation Database browser is 0.004%, exceeding the estimated prevalence of BrS owing to SCN1B (0.0005%), including 15 of 23 individuals (65%) who had the p.Trp179X variant. CONCLUSION: The lack of genotype-phenotype concordance among families, combined with the high frequency of previously reported mutations in the Genome Aggregation Database browser, suggests that SCN1B is not a monogenic cause of BrS or SADS

Variant location is a novel risk factor for individuals with arrhythmogenic cardiomyopathy due to a desmoplakin (DSP) truncating variant.

BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management

Morbidity and development in childhood of infants born after temporising treatment of early onset pre-eclampsia.

Item does not contain fulltextOBJECTIVE: To assess morbidity and development in childhood of infants born after temporising management of severe early onset pre-eclampsia. DESIGN: Cohort study with matched controls. SETTING: University centre for high risk obstetrics. SAMPLES: Three groups of neonates matched for gender and year of birth: one born after temporising treatment of severe early onset (<32 weeks) pre-eclampsia with an average delay of delivery of two weeks (n= 193); one born at the duration of pregnancy [1 week] of the pre-eclamptic mother on admission (control group I, n = 192); and one born at the same gestational age [1 week] as the infant of the pre-eclamptic mother (control group II, n= 189). METHOD: Follow up at four years of age or more using medical records and questionnaires. MAIN OUTCOME MEASURES: The presence of various morbidities including mental retardation, cerebral palsy, motor skill problems, visual handicap, hearing loss, speech and language problems, education level and acute or chronic respiratory problems. RESULTS: Median follow up of seven years (range 4-12) was achieved in 159 infants in the study group (83%), 122 in control group I (64%) and 110 in control group II (58%). Missing data analysis showed no differences in neonatal characteristics and morbidity between infants with and without follow up in the study group. All major and minor handicaps were less frequent in the study group than in control group I but statistical significance was reached only for acute and chronic respiratory disorders in the study group (13.8%) compared with control group I (27%). CONCLUSION: Average delay of delivery of two weeks with temporising management in severe early onset pre-eclampsia is associated with a reduced risk of respiratory disorders in childhood

Genotype-Phenotype Correlation of SCN5A Genotype in Patients With Brugada Syndrome and Arrhythmic Events: Insights From the SABRUS in 392 Probands.

BACKGROUND: Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, SCN5A. However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to SCN5A genotype in a large cohort of BrS probands with first arrhythmic event. METHODS: Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, and SCN5A genotype adjudicated. Patients without appropriate genetic data were excluded. Associations of genotype with clinical features were analyzed. RESULTS: The study group comprised 392 probands: 92 (23.5%) SCN5A+(44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) SCN5A-. SCN5A missense variants and the patients hosting them were similar regardless of adjudication. A higher proportion of patients with P/LP were pediatric (<16 years) compared with SCN5A- (11.4% versus 3%, P=0.023). The proportion of females was higher among patients with P/LP compared with SCN5A- (18.2% versus 6.3%, P=0.013). P/LP probands were more likely to have a family history of sudden cardiac death compared with SCN5A- (41.9% versus 16.8%, P<0.001). A higher proportion of patients with P/LP were White compared with SCN5A- (87.5% versus 47%, P<0.001). Ethnicity (odds ratio, 5.41 [2.8-11.19], P<0.001) and family history of sudden cardiac death (odds ratio, 2.73 [1.28-5.82], P=0.009) were independent variables associated with P/LP genotype following logistic regression. CONCLUSIONS: The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with SCN5A-. In addition, they were more likely to be White and to have family history of sudden cardiac death. Among females, a P/LP variant suggests an increased risk of being symptomatic. This association should be further studied on an ethnically specific basis in large prospectively collected international cohorts