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Background idiopathic dilated cardiomyopathy (DCM) is recognised to be a heritable disorder, yet clinical genetic testing does not produce a diagnosis in >50% of paediatric patients. identifying a genetic cause is crucial because this knowledge can affect management options, cardiac surveillance in relatives and reproductive decision-making. in this study, we sought to identify the underlying genetic defect in a patient born to consanguineous parents with rapidly progressive DCM that led to death in early infancy. Methods and results exome sequencing revealed a potentially pathogenic, homozygous missense variant, c.542g>t, p.(gly181Val), in SOD2. this gene encodes superoxide dismutase 2 (SOD2) or manganesesuperoxide dismutase, a mitochondrial matrix protein that scavenges oxygen radicals produced by oxidationreduction and electron transport reactions occurring in mitochondria via conversion of superoxide anion (O2-•) into H2O2. Measurement of hydroethidine oxidation showed a significant increase in O2-• levels in the patient's skin fibroblasts, as compared with controls, and this was paralleled by reduced catalytic activity of SOD2 in patient fibroblasts and muscle. lentiviral complementation experiments demonstrated that mitochondrial SOD2 activity could be completely restored on transduction with wild type SOD2. Conclusion Our results provide evidence that defective SOD2 may lead to toxic increases in the levels of damaging oxygen radicals in the neonatal heart, which can result in rapidly developing heart failure and death. We propose SOD2 as a novel nuclear-encoded mitochondrial protein involved in severe human neonatal cardiomyopathy, thus expanding the wide range of genetic factors involved in paediatric cardiomyopathies. [ABSTRACT FROM AUTHOR]

Abstract: Simultaneous analysis of multiple genes using next‐generation sequencing (NGS) technology has become widely available. Copy‐number variations (CNVs) in disease‐associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H‐TAD)‐associated genes. Eight hundred ten patients suspected of H‐TAD were analyzed by targeted NGS analysis of 21 H‐TAD associated genes. In addition, the eXome hidden Markov model (XHMM; an algorithm to identify CNVs in targeted NGS data) was used to detect CNVs in these genes. A pathogenic or likely pathogenic variant was found in 66 of 810 patients (8.1%). Of these 66 pathogenic or likely pathogenic variants, six (9.1%) were CNVs not detectable by routine NGS analysis. These CNVs were four intragenic (multi‐)exon deletions in MYLK, TGFB2, SMAD3, and PRKG1, respectively. In addition, a large duplication including NOTCH1 and a large deletion encompassing SCARF2 were detected. As confirmed by additional analyses, both CNVs indicated larger chromosomal abnormalities, which could explain the phenotype in both patients. Given the clinical relevance of the identification of a genetic cause, CNV analysis using a method such as XHMM should be incorporated into the clinical diagnostic care for H‐TAD patients. [ABSTRACT FROM AUTHOR]

Thoracic aortic aneurysm is a potentially life-threatening disease with a strong genetic contribution. Despite identification of multiple genes involved in aneurysm formation, little is known about the specific underlying mechanisms that drive the pathological changes in the aortic wall. The aim of our study was to unravel the molecular mechanisms underlying aneurysm formation in Marfan syndrome (MFS). We collected aortic wall samples from FBN1 variant-positive MFS patients (n = 6) and healthy donor hearts (n = 5). Messenger RNA (mRNA) expression levels were measured by RNA sequencing and compared between MFS patients and controls, and between haploinsufficient (HI) and dominant negative (DN) FBN1 variants. Immunohistochemical staining, proteomics and cellular respiration experiments were used to confirm our findings. FBN1 mRNA expression levels were highly variable in MFS patients and did not significantly differ from controls. Moreover, we did not identify a distinctive TGF-β gene expression signature in MFS patients. On the contrary, differential gene and protein expression analysis, as well as vascular smooth muscle cell respiration measurements, pointed toward inflammation and mitochondrial dysfunction. Our findings confirm that inflammatory and mitochondrial pathways play important roles in the pathophysiological processes underlying MFS-related aortic disease, providing new therapeutic options. [ABSTRACT FROM AUTHOR]

Pediatric cardiomyopathies are a clinically and genetically heterogeneous group of heart muscle disorders associated with high morbidity and mortality. Although knowledge of the genetic basis of pediatric cardiomyopathy has improved considerably, the underlying cause remains elusive in a substantial proportion of cases. In this study, we sought to identify the underlying genetic defect in a pair of siblings with rapidly progressive dilated cardiomyopathy leading to death in early infancy. Whole exome sequencing revealed compound heterozygous variants in both siblings in the highly conserved ASNA1 gene. ASNA1, also known as TRC40 or GET3, is an ATPase required for post-translational insertion of tail-anchored proteins into the endoplasmic reticulum. Histological and immunohistochemical analysis in myocardial tissue from both patients revealed disruption of intercalated discs and decreased ASNA1 expression. ASNA1 protein levels were also decreased in fibroblasts of one patient. In an in vitro tail-anchored protein insertion assay, recombinant mutant ASNA1 was more aggregation prone and less functional than the wild-type protein. Loss of asna1 in zebrafish resulted in reduced cardiac contractility, decreased circulation, and early lethality. Overexpression of human wild-type ASNA1 mRNA rescued this phenotype , whereas injection of either paternal or maternal mutant mRNA showed no improvement. In conclusion, we propose ASNA1 , encoding a cytosolic targeting factor for tail-anchored proteins, as a novel gene for pediatric cardiomyopathy with acute onset and rapid progression. We hypothesize that mislocalization of cardiac tail-anchored proteins (such as emerin and phospholamban) contributes to myocardial dysfunction. Our findings point toward a critical role of the tail-anchored membrane protein insertion pathway in vertebrate heart development and disease. [ABSTRACT FROM AUTHOR]

Introduction: Biallelic truncating variants in ALPK 3 have recently been described to cause pediatric cardiomyopathy (CMP). Functional studies have found disorganized intercalated discs and sarcomeres and calcium mishandling in both patients and mutant stem-cell-derived cardiomyocytes. Objectives: To delineate the clinical and genetic spectrum of ALPK3 -related disease and study genotype-phenotype correlations. Methods: We collected clinical and genetic data on ALPK3- related CMP patients, and performed ALPK3 staining in heart and skeletal muscle of 3 individuals carrying biallelic truncating variants. Results: We report biallelic ALPK3 mutations for a total of 18 patients: 9 previously reported cases and 9 novel patients from 6 families. Nine patients had biallelic truncating variants, 7 had a truncating and a missense variant, and 1 had a homozygous missense variant in ALPK3. Nine of 16 live-born patients showed (biventricular) DCM during neonatal life that transitioned to predominantly HCM with surveillance. Several patients showed extra-cardiac features, including short stature (8/13), contractures (6/15), severe scoliosis (5/12), cleft palate (CP) or velopharyngeal insufficiency (5/15), and dysmorphic (Noonan-like) facies (8/14). Biopsy of 4 patients showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis < 4 years of age, and myofibrillar disarray at adult age. ALPK3 staining confirmed its nuclear expression in heart and skeletal muscle, but no differences were observed between patients and controls. Mutations predominantly cluster in exon 6 and the alpha-kinase domain. No association between mutation type or location and disease severity was observed. Conclusion: Although it has been previously shown that HCM may progress to DCM, we describe a unique cardiac phenotype of DCM transitioning to predominantly HCM. We extend the ALPK3 phenotype to include CP and contractures, however no genotype-phenotype correlation could be established. Alpk3 -/- mice displayed a similar cardiac phenotype, but did not show fibrosis or extra-cardiac features. Expression of a truncated ALPK3 protein in humans may explain the differences in clinical manifestation between the patients and Alpk3-/- mice that do not produce ALPK3 protein. [ABSTRACT FROM AUTHOR]

Introduction: Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease. The impact of HCM on quality of life (QoL) and societal costs remains poorly understood. This prospective multi-centre burden of disease study estimated QoL and societal costs of genotyped HCM patients and genotype-positive phenotype-negative (G+/P-) subjects., Methods and Results: Participants were categorized into three groups based on genotype and phenotype: (i) G+/P- [left ventricular (LV) wall thickness <13 mm], (ii) non-obstructive HCM [nHCM, LV outflow tract (LVOT) gradient <30 mmHg], and (iii) obstructive HCM (oHCM, LVOT gradient ≥30 mmHg). We assessed QoL with EQ-5D-5L and Kansas City Cardiomyopathy Questionnaires (KCCQ). Societal costs were measured using medical consumption (Medical Consumption Questionnaire) and productivity cost (iMTA Productivity Cost Questionnaire) questionnaires. We performed subanalyses within three age groups: <40, 40-59, and ≥60 years. From three Dutch hospitals, 506 subjects were enrolled (84 G+/P-, 313 nHCM, 109 oHCM; median age 59 years, 39% female). HCM (both nHCM and oHCM) patients reported reduced QoL vs. G+/P- subjects (KCCQ: 88 vs. 98, EQ-5D-5L: 0.88 vs. 0.96; both P < 0.001). oHCM patients reported lower KCCQ scores than nHCM patients (83 vs. 89, P = 0.036). Societal costs were significantly higher in HCM patients (€19,035/year vs. €7385/year) compared with G+/P- controls, mainly explained by higher healthcare costs and productivity losses. Being symptomatic and of younger age (<60 years) particularly led to decreased QoL and increased costs., Conclusion: HCM is associated with decreased QoL and increased societal costs, especially in younger and symptomatic patients. oHCM patients were more frequently symptomatic than nHCM patients. This study highlights the substantial disease burden of HCM and can aid in assessing new therapy cost-effectiveness for HCM in the future., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: (i) Investigate the prevalence of hypertrophic cardiomyopathy (HCM) in individuals with pathogenic/likely pathogenic (P/LP) gene variants detected through family cascade testing in relatives, and (ii) evaluate phenotypic progression in genotype-positive phenotype-negative (G+/P-) individuals during follow-up., Results: From 2000 to 2023, 273 individuals underwent cardiologic evaluation following P/LP variant detection through family screening. Upon initial evaluation, HCM was diagnosed in 128 (47 %) individuals. Comparing with 145 G+/P- individuals, HCM patients were older (48 vs 38 years, p < 0.001) and more likely male (57 % vs 34 %, p < 0.001). During follow-up (median 11 years), 14 (11 %) of the HCM patients died (two from sudden cardiac death), four (3 %) underwent myectomy, 15 (12 %) developed atrial fibrillation and 17 (13 %) required implantable cardioverter-defibrillator implantation (15 primary prevention, 88 %). HCM-related adverse outcomes correlated with younger diagnosis age. During follow-up (median 8 years) of 118 (out of 145) G+/P- subjects with at least one year of follow-up, seven (6 %) individuals (71 % female, diagnosed age 39-77, after median follow-up 6 years) developed HCM (mean maximal wall thickness increasing from 10.2 mm to 13.3 mm). In this G+/P- cohort, significant echocardiographic changes from baseline to last visit were negligible. Over half (56 %) had <1 mm change of maximal wall thickness. No adverse cardiac outcomes occurred., Conclusion: The initial evaluation was high-yield, with HCM being diagnosed in 47 % of G+ individuals, more frequently in older males. Over a median 8-year follow-up, 6 % of G+/P- individuals developed mild HCM, with no adverse cardiac outcomes. These data support initial screening in all first degree relatives, but (very) low-frequency cardiologic evaluations for G+/P- individuals thereafter., Competing Interests: Declaration of competing interest AH received an institutional research grant and consultancy fees from GE Healthcare and speaker fees from GE Healthcare, Bayer, and Bristol Myers Squibb. He is also a member of the medical advisory board of Medis Medical Imaging Systems and was an MRI Core Lab supervisor of Cardialysis BV until 2022. PPZ is partially funded through a Dutch Heart Foundation Public Private Partnership Grant (CARMA, grant 01–003–2022-0358) and has received speaker fees from MedNet and consultancy fees from Bayer, Alnylam and Bristol Myers Squibb. JAEK received a research grant from Medtronic and from “Stichting Hartekind”. The institution of RAB has received research grants and/or fees from AstraZeneca, Abbott, Bristol Myers Squibb, Cardior Pharmaceuticals GmbH, Novo Nordisk, and Roche; RAB has had speaker engagements with and/or received fees from and/or served on an advisory board for Abbott, AstraZeneca, Bristol Myers Squibb, Cardior Pharmaceuticals GmbH, Novo Nordisk, and Roche; RAB received travel support from Abbott, Cardior Pharmaceuticals GmbH, and Novo Nordisk. MM received a research grant and speaker fees from Bristol Myers Squibb, consultancy fees from Cytokinetics, and speaker fees from Pfizer. The other authors declare that they have no competing conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Individuals harbouring SMAD3 pathogenic variants are at risk for aneurysms/dissections throughout the arterial tree. Based on prior reports of sex differences in thoracic aortic aneurysm/dissection, we investigated the sexual dimorphism for vascular events in SMAD3- variant-harbouring patients., Methods: We analysed two large pedigrees comprising 84 individuals segregating pathogenic missense variants affecting the same p.Arg287 residue in SMAD3 . We excluded individuals<40 years without vascular involvement, as they were too young to be classified. Individuals were subcategorised according to sex, the presence or absence and localisation (aneurysm/dissection with or without involvement of the aortic root/ascending aorta) of vascular lesions. We complemented our familial patient cohort with 178 SMAD3 patients reported in the literature between 2011 and 2023., Results: In our two pedigrees, 11/30 (37%) variant-harbouring females had no vascular involvement, whereas none of the variant-harboring males (n=23) had no vascular involvement (p=0.001). While the two groups did not differ by age, males were at higher risk of vascular complications (p=0.037), there was no age difference between sexes. Of the 19 females with vascular involvement, six (32%) had vascular involvment sparing the aortic root/ascending aorta, whereas of the 23 males with vascular invovlement, only one (4%) had vascular involvement sparing the aortic root/ascending aorta (p=0.034). In the literature, we identified 116 male and 62 female additional patients. In the combined cohort of 220 patients, we demonstrated an over-representation of males (p<0.001) and non-penetrance in females for vascular pathology involving the aortic root/ascending aorta (p=0.028)., Conclusions: Non-penetrance is more common in women, and normal echocardiography in at-risk females is not as reassuring for risk of vasculopathy in other locations. The higher non-penetrance in women creates an ascertainment bias and results in an over-representation of male patients in the literature., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Dilated cardiomyopathy (DCM) can be caused by truncating variants in the filamin C gene (FLNC). A new pathogenic FLNC variant, c.6864&#95;6867dup, p.(Val2290Argfs∗23), was recently identified in Dutch patients with DCM., Objectives: The report aimed to evaluate the phenotype of FLNC variant carriers and to determine whether this variant is a founder variant., Methods: Clinical and genetic data were retrospectively collected from variant carriers. Cardiovascular magnetic resonance studies were reassessed. Haplotypes were reconstructed to determine a founder effect. The geographical distribution and age of the variant were determined., Results: Thirty-three individuals (of whom 23 [70%] were female) from 9 families were identified. Sudden cardiac death was the first presentation in a carrier at the age of 28 years. The median age at diagnosis was 41 years (range 19-67 years). The phenotype was heterogeneous. DCM with left ventricular dilation and reduced ejection fraction (<45%) was present in 11 (33%) individuals, 3 (9%) of whom underwent heart transplantation. Cardiovascular magnetic resonance showed late gadolinium enhancement in 13 (65%) of the assessed individuals, primarily in a ringlike distribution. Nonsustained ventricular arrhythmias were detected in 6 (18%), and 5 (15%) individuals received an implantable cardioverter-defibrillator. A shared haplotype spanning 2.1 Mb was found in all haplotyped individuals. The variant originated between 275 and 650 years ago., Conclusion: The pathogenic FLNC variant c.6864&#95;6867dup, p.(Val2290Argfs∗23) is a founder variant originating from the south of the Netherlands. Carriers are susceptible to developing heart failure and ventricular arrhythmias. The cardiac phenotype is characterized by ringlike late gadolinium enhancement, even in individuals without significantly reduced left ventricular function., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: Heterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies., Methods: Index patients and relatives with a P/LP variant in ACTA2 were included. Data were collected through retrospective review of medical records using a standardized questionnaire., Results: A total of 49 individuals from 28 families participated in our study. In total, 20 different ACTA2 variants were detected. Aortic events occurred in 65% of the cases (78.6% index patients and 47.6% relatives). Male sex and hypertension emerged as significantly associated with aortic events. Of 20 individuals, 5 had an aortic diameter of <45 mm (1.77 inches) at the time of the type A dissection. Mean age at first aortic event was 49.0 ± 12.4 years. Severe surgical complications for type A and type B dissection occurred in 25% and 16.7% of the cases and in-hospital mortality rates were 9.5% and 0%, respectively., Conclusion: P/LP ACTA2 variants are associated with an increased risk for an aortic event and age-related penetrance, which emphasizes the importance of early recognition of the disease. Caregivers should be aware of the risk for aortic dissections, even in individuals with aortic diameters within the normal range., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study aimed to describe the current practice and results of genetic evaluation in Dutch children with dilated cardiomyopathy and to evaluate genotype-phenotype correlations that may guide prognosis., Methods: We performed a multicenter observational study in children diagnosed with dilated cardiomyopathy, from 2010 to 2017., Results: One hundred forty-four children were included. Initial diagnostic categories were idiopathic dilated cardiomyopathy in 67 children (47%), myocarditis in 23 (16%), neuromuscular in 7 (5%), familial in 18 (13%), inborn error of metabolism in 4 (3%), malformation syndrome in 2 (1%), and "other" in 23 (16%). Median follow-up time was 2.1 years [IQR 1.0-4.3]. Hundred-seven patients (74%) underwent genetic testing. We found a likely pathogenic or pathogenic variant in 38 children (36%), most often in MYH7 (n = 8). In 1 patient initially diagnosed with myocarditis, a pathogenic LMNA variant was found. During the study, 39 patients (27%) reached study endpoint (SE: all-cause death or heart transplantation). Patients with a likely pathogenic or pathogenic variant were more likely to reach SE compared with those without (hazard ratio 2.8; 95% CI 1.3-5.8, P = 0.007), while transplant-free survival was significantly lower ( P = 0.006). Clinical characteristics at diagnosis did not differ between the 2 groups., Conclusions: Genetic testing is a valuable tool for predicting prognosis in children with dilated cardiomyopathy, with carriers of a likely pathogenic or pathogenic variant having a worse prognosis overall. Genetic testing should be incorporated in clinical work-up of all children with dilated cardiomyopathy regardless of presumed disease pathogenesis.

Aims: Genetic testing in relatives of hypertrophic cardiomyopathy (HCM) patients leads to early identification of pathogenic DNA variant carriers (G+), before the onset of left ventricular hypertrophy. Routine phenotyping consists of electrocardiography (ECG) and transthoracic echocardiography (TTE). Cardiovascular magnetic resonance (CMR) has become valuable in the work-up of HCM. In this study, we investigated the value of CMR in phenotyping of G+ family members., Methods and Results: This study included 91 G+ subjects who underwent ECG, TTE and CMR, with a maximal wall thickness (MWT) <15 mm on TTE. The relative performance of TTE and CMR regarding wall thickness measurements and HCM diagnoses was assessed. HCM was defined as MWT of ≥13 mm. Logistic regression was performed to assess whether ECG and TTE parameters can predict CMR results. Most subjects (75%) had an MWT <13 mm on TTE, of which 23 (34%) were diagnosed with HCM based on CMR. MWT differences (range 1-10 mm) were often caused by an anterobasal hook-shaped thickening of the myocardium not visible on TTE. Two of 23 (9%) subjects with HCM on TTE were reclassified as no HCM on CMR. Normal ECG and TTE results almost excluded reclassifications by CMR. The prevalence of other HCM-related abnormalities on CMR was low., Conclusion: CMR reclassified 27% of subjects. Subjects with normal ECG/TTE results were reclassified in a low number of cases, justifying screening with ECG and TTE in G+ relatives. In subjects with abnormal ECGs and/or poor TTE image quality, CMR is indicated., Competing Interests: Conflicts of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background:  Turner syndrome (TS) is associated with aortic dilatation and dissection, but the underlying process is unclear. The aim of this study was to investigate the elastic properties and composition of the aortic wall in women with TS., Methods:  In this cross-sectional study, 52 women with TS aged 35 ± 13 years (50% monosomy, 12 with bicuspid aortic valve [BAV] and 4 with coarctation) were investigated using carotid-femoral pulse wave velocity (CF-PWV) by echocardiography and ascending aortic distensibility (AAD) and aortic arch pulse wave velocity (AA-PWV) by magnetic resonance imaging (MRI). As control group, 13 women with BAV without TS and 48 healthy patients were included., Results:  Women with TS showed a higher AA-PWV (β = 1.08, confidence interval [CI]: 0.54-1.62) after correcting for age and comorbidities compared with controls. We found no significant difference in AAD and CF-PWV. In women with TS, the presence of BAV, coarctation of the aorta, or monosomy (45, X) was not associated with aortic stiffness. In addition, aortic tissue samples were investigated with routine and immunohistochemical stains in five additional women with TS who were operated. The tissue showed more compact smooth muscle cell layers with abnormal deposition and structure of elastin and diminished or absent expression of contractile proteins desmin, actin, and caldesmon, as well as the progesterone receptor., Conclusion:  Both aortic arch stiffness measurements on MRI and histomorphological changes point toward an inherent abnormal thoracic aortic wall in women with TS., Competing Interests: The authors declare no conflict of interest related to this article., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Introduction: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined., Methods and Results: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10 -5 ; U.S. cohort, P = 2.2×10 -13 )., Conclusion: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: There is limited data on the experience with insertable cardiac monitors (ICMs) in patients with Brugada syndrome., Objective: To evaluate the outcome of ICM in symptomatic patients with Brugada syndrome who are at suspected low risk of sudden cardiac death (SCD)., Methods: We conducted a prospective single-center cohort study including all symptomatic patients with Brugada syndrome who received an ICM (Reveal LINQ) between July 2014 and October 2019. The main indication for monitoring was to exclude ventricular arrhythmias as the cause of symptoms and to establish a symptom-rhythm relationship., Results: A total of 20 patients (mean age, 39 ± 12 years; 55% male) received an ICM during the study period. Nine patients (45%) had a history of syncope (presumed nonarrhythmogenic), and 5 patients had a recent syncope (<6 months). During a median follow-up of 32 months (interquartile range, 11-36 months), 3 patients (15%) experienced an episode of nonsustained ventricular arrhythmia. No patient died suddenly or experienced a sustained ventricular arrhythmia, and no patient had a recurrence of syncope. Overall, 17 patients (85%) experienced symptoms during follow-up, of whom 10 patients had an ICM-detected arrhythmia. In 4 patients (20%), the ICM-detected arrhythmia was an actionable event. ICM-guided management included antiarrhythmic drug therapy for symptomatic ectopic beats (n = 3), pulmonary vein isolation, and oral anticoagulation for atrial fibrillation (n = 1), electrophysiological study for risk stratification (n = 1), and pacemaker implantation for atrioventricular block (n = 1)., Conclusions: An ICM can be used to exclude ventricular arrhythmias in symptomatic patients with Brugada syndrome at low risk of SCD. Furthermore, an ICM-detected arrhythmia changed clinical management in 20% of patients., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Background: Pediatric cardiomyopathies are a clinically and genetically heterogeneous group of heart muscle disorders associated with high morbidity and mortality. Although knowledge of the genetic basis of pediatric cardiomyopathy has improved considerably, the underlying cause remains elusive in a substantial proportion of cases., Methods: Exome sequencing was used to screen for the causative genetic defect in a pair of siblings with rapidly progressive dilated cardiomyopathy and death in early infancy. Protein expression was assessed in patient samples, followed by an in vitro tail-anchored protein insertion assay and functional analyses in zebrafish., Results: We identified compound heterozygous variants in the highly conserved ASNA1 gene (arsA arsenite transporter, ATP-binding, homolog), which encodes an ATPase required for post-translational membrane insertion of tail-anchored proteins. The c.913C>T variant on the paternal allele is predicted to result in a premature stop codon p.(Gln305*), and likely explains the decreased protein expression observed in myocardial tissue and skin fibroblasts. The c.488T>C variant on the maternal allele results in a valine to alanine substitution at residue 163 (p.Val163Ala). Functional studies showed that this variant leads to protein misfolding as well as less effective tail-anchored protein insertion. Loss of asna1 in zebrafish resulted in reduced cardiac contractility and early lethality. In contrast to wild-type mRNA, injection of either mutant mRNA failed to rescue this phenotype., Conclusions: Biallelic variants in ASNA1 cause severe pediatric cardiomyopathy and early death. Our findings point toward a critical role of the tail-anchored membrane protein insertion pathway in vertebrate cardiac function and disease.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain., Objective: The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients., Methods: We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders., Results: Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%-11%). Median age at diagnosis was 9.3 years (interquartile range 7.0-14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8-12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy., Conclusion: Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%-3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias., (Copyright © 2018. Published by Elsevier Inc.)