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Aims: We identified the first Belgian SCN5A founder mutation, c.4813 + 3_4813 + 6dupGGGT. To describe the clinical spectrum and disease severity associated with this mutation, clinical data of 101 SCN5A founder mutation carriers and 46 non-mutation carrying family members from 25 Belgian families were collected.Methods and Results: The SCN5A founder mutation was confirmed by haplotype analysis. The clinical history and electrocardiographic parameters of the mutation carriers and their family members were gathered and compared. A cardiac electrical abnormality was observed in the majority (82%) of the mutation carriers. Cardiac conduction defects, defined as PR or QRS prolongation on electrocardiogram (ECG), were most frequent, occurring in 65% of the mutation carriers. Brugada syndrome (BrS) was the second most prevalent phenotype identified in 52%, followed by atrial dysrythmia in 11%. Overall, 33% of tested mutation carriers had a normal sodium channel blocker test. Negative tests were more common in family members distantly related to the proband. Overall, 23% of the mutation carriers were symptomatic, with 8% displaying major adverse events. As many as 13% of the patients tested with a sodium blocker developed ventricular arrhythmia. One family member who did not carry the founder mutation was diagnosed with BrS.Conclusion: The high prevalence of symptoms and sensitivity to sodium channel blockers in our founder population highlights the adverse effect of the founder mutation on cardiac conduction. The large phenotypical heterogeneity, variable penetrance, and even non-segregation suggest that other genetic (and environmental) factors modify the disease expression, severity, and outcome in these families. [ABSTRACT FROM AUTHOR]

Background: The international study ThromboGenomics has evaluated the diagnostic rate using a targeted multigene panel test for the screening of inherited bleeding, thrombotic and platelet disorders., Objectives: We retrospectively analyzed the results of the implementation of genetic testing for inherited bleeding, thrombotic and platelet disorders in Belgian clinical practice and evaluated possible reclassification of reported variants., Patients/methods: We implemented a Thrombosis-Hemostasis multigene panel test using whole exome sequencing to diagnose 487 patients recruited by 27 different Belgian hospitals with the implementation of stringent laboratory accreditation standards and by studying up to 100 diagnostic-grade genes., Results: This Thrombosis-Hemostasis multigene panel test was able to detect at least one genetic variant in 58% of the 487 patients of which 50% were (likely) pathogenic variants and the others were variants of unknown significance. Polygenic variants were detected in 65 patients (13%). A multi-step workflow for results discussion by multidisciplinary team meetings and patients' recalls for segregation studies and additional laboratory testing was set up. Variants were also submitted to the GoldVariants database from the International Society on Thrombosis and Haemostasis (ISTH). The aim of these approaches is to optimize variant interpretation and to (re)classify variants of unknown significance as (likely) pathogenic or (likely) benign., Conclusions: The growing implementation of multigene panel tests in clinical diagnostics comes with difficulties in interpreting genetic results. Additional efforts are needed to continuously optimize the diagnostic outcome., Competing Interests: Declaration of competing interest All authors declare they have no conflict of interest to disclose., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Aims: We identified the first Belgian SCN5A founder mutation, c.4813 + 3_4813 + 6dupGGGT. To describe the clinical spectrum and disease severity associated with this mutation, clinical data of 101 SCN5A founder mutation carriers and 46 non-mutation carrying family members from 25 Belgian families were collected., Methods and Results: The SCN5A founder mutation was confirmed by haplotype analysis. The clinical history and electrocardiographic parameters of the mutation carriers and their family members were gathered and compared. A cardiac electrical abnormality was observed in the majority (82%) of the mutation carriers. Cardiac conduction defects, defined as PR or QRS prolongation on electrocardiogram (ECG), were most frequent, occurring in 65% of the mutation carriers. Brugada syndrome (BrS) was the second most prevalent phenotype identified in 52%, followed by atrial dysrythmia in 11%. Overall, 33% of tested mutation carriers had a normal sodium channel blocker test. Negative tests were more common in family members distantly related to the proband. Overall, 23% of the mutation carriers were symptomatic, with 8% displaying major adverse events. As many as 13% of the patients tested with a sodium blocker developed ventricular arrhythmia. One family member who did not carry the founder mutation was diagnosed with BrS., Conclusion: The high prevalence of symptoms and sensitivity to sodium channel blockers in our founder population highlights the adverse effect of the founder mutation on cardiac conduction. The large phenotypical heterogeneity, variable penetrance, and even non-segregation suggest that other genetic (and environmental) factors modify the disease expression, severity, and outcome in these families., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Introduction: Loss-of-function (LoF) mutations in the SCN5A gene cause multiple phenotypes including Brugada Syndrome (BrS) and a diffuse cardiac conduction defect. Markers of increased risk for sudden cardiac death (SCD) in LoF SCN5A mutation carriers are ill defined. We hypothesized that late potentials and fragmented QRS would be more prevalent in SCN5A mutation carriers compared to SCN5A-negative BrS patients and evaluated risk markers for SCD in SCN5A mutation carriers., Methods: We included all SCN5A loss-of-function mutation carriers and SCN5A-negative BrS patients from our center. A combined arrhythmic endpoint was defined as appropriate ICD shock or SCD., Results: Late potentials were more prevalent in 79 SCN5A mutation carriers compared to 39 SCN5A-negative BrS patients (66% versus 44%, p = .021), while there was no difference in the prevalence of fragmented QRS. PR interval prolongation was the only parameter that predicted the presence of a SCN5A mutation in BrS (OR 1.08; p < .001). Four SCN5A mutation carriers, of whom three did not have a diagnostic type 1 ECG either spontaneously or after provocation with a sodium channel blocker, reached the combined arrhythmic endpoint during a follow-up of 44 ± 52 months resulting in an annual incidence rate of 1.37%., Conclusion: LP were more frequently observed in SCN5A mutation carriers, while fQRS was not. In SCN5A mutation carriers, the annual incidence rate of SCD was non-negligible, even in the absence of a spontaneous or induced type 1 ECG. Therefore, proper follow-up of SCN5A mutation carriers without Brugada syndrome phenotype is warranted., (© 2018 Wiley Periodicals, Inc.)

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterised by skeletal dysplasia, exocrine pancreatic insufficiency and bone marrow failure. Various other conditions, such as hepatopathy and failure to thrive have been associated with SDS. A retrospective study was conducted to describe mutations, clinical features, and the immunological profile of 11 Belgian patients with genetically confirmed diagnosis of SDS. This study confirms the existing understanding of the classical features of SDS although the typical triad was present in only six out of nine fully studied patients. The following important observations are made in this cohort. Four out of eleven patients were misdiagnosed as having Asphyxiating Thoracic Dystrophy (Jeune syndrome) because of severe thoracic dystrophy. Another two patients presented with unexplained episodes of symptomatic hypoglycaemia. The immunological phenotype was heterogeneous although laboratory abnormalities were noticed in eight out of ten patients assessed. Three patients experienced a life threatening viral infection (respiratory syncytial virus, cytomegalovirus (CMV) and rotavirus). In one patient, CMV infection caused an episode of haemophagocytic lymphohistiocytosis. One patient has bronchiectasis at the age of 3 years due to recurrent respiratory tract infections. These findings strengthen the suspicion of an abnormal immune system in SDS. Liver anomalies, usually described as benign and transitory in SDS patients, were severe in two patients of the cohort. One patient developed hepatopulmonary syndrome. The findings in this national cohort of SDS patients could contribute to the prevention of misdiagnosis in the future and enable more rapid recognition of certain severe complications.