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Aims: Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene-disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes., Methods and Results: Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3)., Conclusions: Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Pathogenic heterozygous NEXN variants are associated with progressive dilated cardiomyopathy (DCM) usually presenting around 50 years of age. We describe an asymptomatic boy who had transient DCM at 3 months of age, that resolved by 4 months. Presently, at 11 years of age, he has normal cardiac function with signs of mild DCM on cardiac MRI. Genetic diagnostics revealed a paternally derived, heterozygous 1949_1951del class 4 variant in NEXN. His father had mild DCM with mildly reduced systolic function. The second patient presented with fetal hydrops at 33 weeks gestation requiring emergency caesarian delivery. Postnatally she required ventilation and continuous inotropic support for left ventricle systolic dysfunction. She died after 2 weeks when therapy was withdrawn. Homozygous c.1174C > T,p.(R392*) class 4 variants in the NEXN gene were found via WES. Microscopic investigation showed endomyocardial fibroelastosis. Her parents, both heterozygous carriers, had normal cardiac function and the family history was normal. These patients show a new clinical spectrum of pediatric cardiac disease seen in heterozygous and homozygous NEXN variants, ranging from mild, transient DCM to a severe, fatal neonatal DCM. These patients support the inclusion of the NEXN gene in the investigation of pediatric patients with DCM, even in cases with transient DCM., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations., Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles)., Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; P =0.0078). Among SCN5A -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; P =0.0846). In SCN5A -negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; P =0.0146). Among E1784K- SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; P =0.0011)., Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility., Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score., Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance ( P <5×10 -8 ) near NOS1AP , KCNQ1 , and KLF12 , and 1 missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold ( P <10 -6 ). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r g =0.40; P =3.2×10 -3 ). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls ( P <10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive ( P <0.005)., Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

Background: Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required., Methods: Utilizing an evidence-based framework, 3 gene curation teams blinded to each other's work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams., Results: Of 17 genes reported as being causative for LQTS, 9 ( AKAP9, ANK2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1 ) were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes ( KCNQ1, KCNH2, SCN5A ) were curated as definitive genes for typical LQTS. Another 4 genes ( CALM1, CALM2, CALM3, TRDN ) were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene ( CACNA1C ) had moderate level evidence for causing LQTS., Conclusions: More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.

Objectives: This investigation was a retrospective study of catecholaminergic polymorphic ventricular tachycardia (CPVT) patients in Canada and the Netherlands to compare pregnancy, postpartum, and nonpregnant event rates., Background: CPVT is characterized by life-threatening arrhythmias during exertion or emotional stress. The arrhythmic risk in CPVT patients during pregnancy is unknown., Methods: Baseline demographics, genetics, treatment, and pregnancy complications were reviewed. Event rate calculations assumed a 40-week pregnancy and 24-week postpartum period., Results: Ninety-six CPVT patients had 228 pregnancies (median 2 pregnancies per patient; range: 1 to 10; total: 175.4 pregnant patient-years). The median age of CPVT diagnosis was 40.7 years (range: 12 to 84 years), with a median follow-up of 2.9 years (range: 0 to 20 years; total 448.1 patient-years). Most patients had pregnancies before CPVT diagnosis (82%). Pregnancy and postpartum cardiac events included syncope (5%) and an aborted cardiac arrest (1%), which occurred in patients who were not taking beta-blockers. Other complications included miscarriages (13%) and intrauterine growth restriction (1 case). There were 6 cardiac events (6%) during the nonpregnant period. The pregnancy and postpartum event rates were 1.71 and 2.85 events per 100 patient-years, respectively, and the combined event rate during the pregnancy and postpartum period was 2.14 events per 100 patient-years. These rates were not different from the nonpregnant event rate (1.46 events per 100 patient-years)., Conclusions: The combined pregnancy and postpartum arrhythmic risk in CPVT patients was not elevated compared with the nonpregnant period. Most patients had pregnancies before diagnosis, and all patients with events were not taking beta-blockers at the time of the event., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Accurate estimates of survival are indispensable for cardiologists, clinical geneticists, and genetic counselors dealing with families with an inherited cardiac disease. However, a bias towards a more severe disease with a worse outcome in the first publications may not accurately represent the actual survival forecast. We, therefore, evaluated the effect of ascertainment bias on survival in 3 different inherited cardiac diseases (idiopathic ventricular fibrillation, SCN5A overlap syndrome, and arrhythmogenic cardiomyopathy) caused by a founder mutation., Methods: We collected mortality data from mutation-positive subjects with either DPP6-associated idiopathic ventricular fibrillation, SCN5A overlap syndrome, and PLN-R14del-mediated arrhythmogenic cardiomyopathy >2 to 10 years of ongoing clinical/cascade genetic screening., Results: The median age of survival in DPP6 mutation-positive subjects increased from 44.6 years in the original cohort from 2008 (n=60; 95% CI, 36.8-52.4 years) to 68.2 years in the extended cohort from 2012 (n=235; 95% CI, 64.6-71.7 years; P<0.001). In the SCN5A overlap syndrome, survival increased from 56.1 years in 1999 (n=86; 95% CI, 48.0-64.2 years) to 69.7 years in 2009 (n=197; 95% CI, 61.3-78.2 years; P=0.049). In PLN-R14del positive patients, the median age of survival increased from 63.5 years in 2010 (n=89; 95% CI, 59.1-68.0 years) to 65.2 years in 2012 (n=370; 95% CI, 62.0-68.3 years; P=0.046)., Conclusions: The median age of survival in 3 different inherited cardiac diseases with an established pathogenic substrate significantly increased once genetic testing and cascade screening extended, after the first publication that elucidated the discovery of the disease-susceptibility gene/mutation. This underscores the direct and negative influence of ascertainment bias on survival forecasts and the importance of ongoing clinical/genetic follow-up to establish the most accurate disease prognosis for genetically mediated heart diseases.

Aims: Management of patients with inherited cardiac ion channelopathy is hindered by variability in disease severity and sudden cardiac death (SCD) risk. Here, we investigated the modulatory role of hypertrophy on arrhythmia and SCD risk in sodium channelopathy., Methods and Results: Follow-up data was collected from 164 individuals positive for the SCN5A-1795insD founder mutation and 247 mutation-negative relatives. A total of 38 (obligate) mutation-positive patients died suddenly or suffered life-threatening ventricular arrhythmia. Of these, 18 were aged >40 years, a high proportion of which had a clinical diagnosis of hypertension and/or cardiac hypertrophy. While pacemaker implantation was highly protective in preventing bradycardia-related SCD in young mutation-positive patients, seven of them aged >40 experienced life-threatening arrhythmic events despite pacemaker treatment. Of these, six had a diagnosis of hypertension/hypertrophy, pointing to a modulatory role of this co-morbidity. Induction of hypertrophy in adult mice carrying the homologous mutation (Scn5a1798insD/+) caused SCD and excessive conduction disturbances, confirming a modulatory effect of hypertrophy in the setting of the mutation. The deleterious effects of the interaction between hypertrophy and the mutation were prevented by genetically impairing the pro-hypertrophic response and by pharmacological inhibition of the enhanced late sodium current associated with the mutation., Conclusion: This study provides the first evidence for a modulatory effect of co-existing cardiac hypertrophy on arrhythmia risk and treatment efficacy in inherited sodium channelopathy. Our findings emphasize the need for continued assessment and rigorous treatment of this co-morbidity in SCN5A mutation-positive individuals.

Objectives: This study evaluated the yield of ajmaline testing and assessed the occurrence of confounding responses in a large cohort of families with unexplained cardiac arrest (UCA) or sudden unexplained death (SUD)., Background: Ajmaline testing to diagnose Brugada syndrome (BrS) is routinely used in the evaluation of SUD and UCA, but its yield, limitations, and appropriate dosing have not been studied in a large cohort., Methods: We assessed ajmaline test response and genetic testing results in 637 individuals from 482 families who underwent ajmaline testing for SUD or UCA., Results: Overall, 89 individuals (14%) from 88 families (18%) had a positive ajmaline test result. SCN5A mutations were identified in 9 of 86 ajmaline-positive cases (10%). SCN5A mutation carriers had positive test results at significantly lower ajmaline doses than noncarriers (0.75 [range: 0.64 to 0.98] mg/kg vs. 1.03 [range: 0.95 to 1.14] mg/kg, respectively; p < 0.01). In 7 of 88 families (8%), it was concluded that the positive ajmaline response was a confounder, either in the presence of an alternative genetic diagnosis accounting for UCA/SUD (5 cases) or noncosegregation of positive ajmaline response and arrhythmia (2 cases). The rate of confounding responses was significantly higher in positive ajmaline responses obtained at >1 mg/kg than in those obtained at ≤1 mg/kg (7 of 48 vs. 0 of 41 individuals; Fisher's exact test: p = 0.014)., Conclusions: In line with previous, smaller studies, a positive ajmaline response was observed in a large proportion of UCA/SUD families. Importantly, our data emphasize the potential for confounding possibly false-positive ajmaline responses in this population, particularly at high doses, which could possibly lead to a misdiagnosis. Clinicians should consider all alternative causes in UCA/SUD and avoid ajmaline doses >1 mg/kg., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Familial idiopathic ventricular fibrillation (IVF) is a severe disease entity and is notoriously difficult to manage because there are no clinical risk indicators for premature cardiac arrest. Previously, we identified a link between familial IVF and a risk haplotype on chromosome 7q36 (involving the arrhythmia gene DPP6)., Objective: The purpose of this study was to expand our knowledge of familial IVF and to discuss its (extended) clinical characteristics., Methods: We studied 601 family members and probands: 286 DPP6 risk-haplotype positive (haplotype-positive) and 315 DPP6 risk-haplotype negative (haplotype-negative) individuals. Clinical parameters, a combination of all-cause mortality and (aborted) cardiac arrest and differences between haplotype-positives and haplotype-negatives, were evaluated., Results: There were no differences in electrocardiographic indices between haplotype-positives and haplotype-negatives, or between haplotype-positives with or without events. Cardiac magnetic resonance documented slightly larger ventricular volumes in haplotype-positives compared to controls (P <.05), but these were not clinically useful. Mortality and/or cardiac arrest occurred in 85 haplotype-positives (30%) and 18 haplotype-negatives (6%). Twenty-four haplotype-positives (8% male) were resuscitated from ventricular fibrillation (VF). Documented VF was always elicited by monomorphic short-coupled extrasystoles from the right ventricular apex/lower free wall. Median survival in risk-haplotype haplotype-positives was 70 vs. 93 years for haplotype-negatives (P < .01), with a worse phenotype in males (median survival 63 vs. 83 years in females, P < .01). Implantable cardioverter-defibrillators were implanted in 99 patients (76 [77%] for primary prevention). Two arrhythmic events occurred in the primary prevention group during follow-up (5 ± 3 years)., Conclusion: Despite our extensive analysis, the complexity in identifying asymptomatic IVF family members at risk for future arrhythmias based on clinical parameters is once more demonstrated., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration., Methods and Results: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF <1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970)., Conclusion: Rare variants in the screened QRS-associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: The pathogenic phospholamban R14del mutation causes dilated and arrhythmogenic right ventricular cardiomyopathies and is associated with an increased risk of malignant ventricular arrhythmias and end-stage heart failure. We performed a multicentre study to evaluate mortality, cardiac disease outcome, and risk factors for malignant ventricular arrhythmias in a cohort of phospholamban R14del mutation carriers., Methods and Results: Using the family tree mortality ratio method in a cohort of 403 phospholamban R14del mutation carriers, we found a standardized mortality ratio of 1.7 (95% confidence interval, 1.4-2.0) with significant excess mortality starting from the age of 25 years. Cardiological data were available for 295 carriers. In a median follow-up period of 42 months, 55 (19%) individuals had a first episode of malignant ventricular arrhythmias and 33 (11%) had an end-stage heart failure event. The youngest age at which a malignant ventricular arrhythmia occurred was 20 years, whereas for an end-stage heart failure event this was 31 years. Independent risk factors for malignant ventricular arrhythmias were left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia with hazard ratios of 4.0 (95% confidence interval, 1.9-8.1) and 2.6 (95% confidence interval, 1.5-4.5), respectively., Conclusions: Phospholamban R14del mutation carriers are at high risk for malignant ventricular arrhythmias and end-stage heart failure, with left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia as independent risk factors. High mortality and a poor prognosis are present from late adolescence. Genetic and cardiac screening is, therefore, advised from adolescence onwards., (© 2014 American Heart Association, Inc.)

Background: Recently, we showed that the c.40&#95;42delAGA (p.Arg14del) mutation in the phospholamban (PLN) gene can be identified in 10-15 % of Dutch patients with dilated cardiomyopathy or arrhythmogenic cardiomyopathy. The arrhythmogenic burden of the p.Arg14del mutation was illustrated by the high rate of appropriate ICD discharges and a positive family history for sudden cardiac death., Methods: Our goal was to evaluate the geographical distribution and the origin of this specific mutation in the Netherlands and to get an estimation of the prevalence in a Dutch population cohort. Therefore, we investigated the postal codes of the places of residence of PLN p.Arg14del mutation carriers and places of birth of their ancestors. In addition, a large population-based cohort (PREVEND) was screened for the presence of this mutation., Results: By April 2012, we had identified 101 probands carrying the PLN p.Arg14del mutation. A total of 358 family members were also found to carry this mutation, resulting in a total of 459 mutation carriers. The majority of mutation carriers live in the northern part of the Netherlands and analysing their grandparents' places of birth indicated that the mutation likely originated in the eastern part of the province of Friesland. In the PREVEND cohort we identified six heterozygous PLN p.Arg14del mutation carriers out of 8,267 subjects (0.07 %)., Conclusion: The p.Arg14del mutation in the PLN gene is the most frequently identified mutation in Dutch cardiomyopathy patients. The mutation that arose 575-825 years ago is likely to have originated from the eastern part of the province of Friesland and is highly prevalent in the general population in the northern part of the Netherlands.

Aims: Mutations in the lamin A/C gene (LMNA) cause a variety of clinical phenotypes, including dilated cardiomyopathy. LMNA is one of the most prevalent mutated genes in dilated cardiomyopathy, and is associated with a high risk of arrhythmias, sudden cardiac death, and heart failure. There are few data on the impact of age and gender on cardiac disease penetrance and mortality., Methods and Results: In a multicentre cohort of 269 LMNA mutation carriers, we evaluated gender-specific penetrance of cardiac involvement and major cardiac events. All-cause mortality of mutation carriers [standardized mortality ratio (SMR)] was determined. Cardiac disease penetrance was age dependent and almost complete at the age of 70 years. The presence of an LVEF ≤45% was significantly higher in men (P < 0.001). However, there was no difference between genders in the prevalence of atrioventricular block, atrial tachyarrhythmias, and non-sustained ventricular tachycardia. Malignant ventricular arrhythmias (26% vs. 8%) and end-stage heart failure (28% vs. 14%) were more common in men than in women (P < 0.001 and P = 0.006, respectively). All-cause mortality of mutation carriers was significantly increased [SMR 4.0, 95% confidence interval (CI) 2.8-5.2] between the ages of 15 and 75 years. Mortality in men was higher than in women (hazard ratio 2.2, 95% CI 1.2-4.3)., Conclusions: This large cohort of LMNA mutation carriers demonstrates a high cardiac disease penetrance and a high mortality in mutation carriers. Male mutation carriers have a worse prognosis due to a higher prevalence of malignant ventricular arrhythmias and end-stage heart failure.

Background: For most arrhythmia syndromes, the risk of sudden cardiac death for asymptomatic mutation carriers is ill defined. Data on the natural history of these diseases, therefore, are essential. The family tree mortality ratio method offers the unique possibility to study the natural history at a time when the disease was not known and patients received no treatment., Methods and Results: In 6 inherited arrhythmia syndromes caused by specific mutations, we analyzed all-cause mortality with the family tree mortality ratio method (main outcome measure, standardized mortality ratio [SMR]). In long-QT syndrome (LQTS) type 1, severely increased mortality risk during all years of childhood was observed (1-19 years), in particular during the first 10 years of life (SMR, 2.9; 95% CI, 1.5-5.1). In LQTS type 2, we observed increasing SMRs starting from age 15 years, which just reached significance between age 30 and 39 (SMR, 4.0; 95% CI, 1.1-10.0). In LQTS type 3, the SMR was increased between age 15 and 19 years (SMR, 5.8; 95% CI, 1.2-16.9). In the SCN5A overlap syndrome, excess mortality was observed between age 10 and 59 years, with a peak between 20 and 39 years (SMR, 3.8; 95% CI, 2.5-5.7). In catecholaminergic polymorphic ventricular tachycardia, excess mortality was restricted to ages 20 to 39 years (SMR, 3.0; 95% CI, 1.3-6.0). In Brugada syndrome, excess mortality was observed between age 40 and 59 (SMR, 1.79; 95% CI, 1.2-2.4), particularly in men., Conclusions: We identified age ranges during which the mortality risk manifests in an unselected and untreated population, which can guide screening in these families.

In this part of a series on cardiogenetic founder mutations in the Netherlands, we review the Dutch founder mutations in hypertrophic cardiomyopathy (HCM) patients. HCM is a common autosomal dominant genetic disease affecting at least one in 500 persons in the general population. Worldwide, most mutations in HCM patients are identified in genes encoding sarcomeric proteins, mainly in the myosin-binding protein C gene (MYBPC3, OMIM #600958) and the beta myosin heavy chain gene (MYH7, OMIM #160760). In the Netherlands, the great majority of mutations occur in the MYBPC3, involving mainly three Dutch founder mutations in the MYBPC3 gene, the c.2373&#95;2374insG, the c.2864&#95;2865delCT and the c.2827C>T mutation. In this review, we describe the genetics of HCM, the genotype-phenotype relation of Dutch founder MYBPC3 gene mutations, the prevalence and the geographic distribution of the Dutch founder mutations, and the consequences for genetic counselling and testing. (Neth Heart J 2010;18:248-54.).

In this part of a series on founder mutations in the Netherlands, we review a Dutch family carrying the SCN5a 1795insD mutation. We describe the advances in our understanding of the premature sudden cardiac deaths that have accompanied this family in the past centuries. The mutation carriers show a unique overlap of long-QT syndrome (type 3), Brugada syndrome and progressive cardiac conduction defects attributed to a single mutation in the cardiac sodium channel gene SCN5a. It is at present one of the largest and best-described families worldwide and we have learned immensely from the mouse strains with the murine homologue of the SCN5a 1795insD mutation (SCN5a 1798insD). From the studies currently performed we are about to obtain new insights into the phenotypic variability in this monogenic arrhythmia syndrome, and this might also be relevant for other arrhythmia syndromes and the general population. (Neth Heart J 2009;17:422-8.).

Background: Among the most frequently encountered mutations in dilated cardiomyopathy (DCM) are those in the lamin A/C (LMNA) gene. Our goal was to analyze the LMNA gene in patients with DCM and/or conduction disease referred to the cardiogenetics outpatient clinic and to evaluate the prevalence of LMNA mutations and their clinical expression., Methods and Results: The LMNA gene was screened in 61 index patients. Eleven mutations (including 6 novel) were identified, mainly in the subgroup of familial DCM with cardiac conduction disease (3/10 index patients) and in patients with DCM and Emery-Dreifuss, Limb-Girdle, or unclassified forms of muscular dystrophy (7/8 index patients). In addition, a mutation was identified in 1 of 4 families with only cardiac conduction disease. We did not identify any large deletions or duplications. Genotype-phenotype relationships revealed a high rate of sudden death and cardiac transplants in carriers of the p.N195K mutation. Our study confirmed that the p.R225X mutation leads to cardiac conduction disease with late or no development of DCM, underscoring the importance of this mutation in putative familial "lone conduction disease." Nearly one third of LMNA mutation carriers had experienced a thromboembolic event., Conclusions: This study highlights the role of LMNA mutations in DCM and related disorders. A severe phenotype in p.N195K mutation carriers and preferential cardiac conduction disease in p.R225X carriers was encountered. Because of the clinical variability, including the development of associated symptoms in time, LMNA screening should be considered in patients with DCM or familial lone conduction disease.

Objective: To determine the pattern of referral of Dutch patients with a long-QT syndrome (LQTS) on the basis of the postal codes of the LQTS probands from whom blood samples were submitted for DNA diagnostics., Design: . Retrospective cohort study., Method: From the databases that are coupled to DNA diagnostics, all index patients were included for whom LQTS diagnostics had been requested during the period 1996-2005 at two clinical genetics centres (the University Medical Centre in Amsterdam and Maastricht University Hospital). The results were related to the postal code of the referred patient and corrected for the number of inhabitants of the region concerned., Results: A total of 421 potential LQTS probands were included. Corrected for the numbers of inhabitants in the various postal codes, the number of referrals varied from 3 per million to 110 per million inhabitants. In view of the most recent estimated prevalence of LQTS (1:2000), this means that only 15% ofthe carriers of the LQTS mutation have so far been detected., Conclusion: There were large regional differences in the Netherlands in the requests for DNA diagnostics in patients with clinical LQTS. The overwhelming majority of the LQTS patients in the Netherlands have not yet been referred or identified. Expanding the available courses for general practitioners and cardiologists that are given by the staff of the cardiogenetic centres would seem to be indicated.

The Crisponi syndrome is an infrequently described syndrome characterized by extensive muscular contractions in the face after even minimal stimuli, hypertonia, camptodactyly, and typical facial features (chubby cheeks, broad nose with anteverted nares, and long philtrum). Most patients have died in the first months of life due to hyperthermia. The syndrome has been described in Italians only; the inheritance pattern is most probably autosomal recessive. Here we describe a 4-year-old boy of Portuguese descent with this entity. Polysomnography during a paroxysmal muscle contraction showed severe obstructive breathing pattern. The overall breathing pattern outside the attacks showed a bizarre mix of disorders of control of breathing with central apneas, hypopnea, obstructive apneas, and long periods of expiratory apneas while the boy was awake. The hyperexcitability disappeared in the course of the first year of life. With time it became clear that he was developmentally delayed. A short review is provided, and the resemblance with the Stuve-Wiedemann syndrome is stressed., ((c) 2005 Wiley-Liss, Inc.)