Clinical interpretation of KCNH2 variants using a robust PS3/BS3 functional patch-clamp assay.

Long QT syndrome (LQTS), caused by the dysfunction of cardiac ion channels, increases the risk of sudden death in otherwise healthy young people. For many variants in LQTS genes, there is insufficient evidence to make a definitive genetic diagnosis. We have established a robust functional patch-clamp assay to facilitate classification of missense variants in KCNH2, one of the key LQTS genes. A curated set of 30 benign and 30 pathogenic missense variants were used to establish the range of normal and abnormal function. The extent to which variants reduced protein function was quantified using Z scores, the number of standard deviations from the mean of the normalized current density of the set of benign variant controls. A Z score of -2 defined the threshold for abnormal loss of function, which corresponds to 55% wild-type function. More extreme Z scores were observed for variants with a greater loss-of-function effect. We propose that the Z score for each variant can be used to inform the application and weighting of abnormal and normal functional evidence criteria (PS3 and BS3) within the American College of Medical Genetics and Genomics variant classification framework. The validity of this approach was demonstrated using a series of 18 KCNH2 missense variants detected in a childhood onset LQTS cohort, where the level of function assessed using our assay correlated to the Schwartz score (a scoring system used to quantify the probability of a clinical diagnosis of LQTS) and the length of the corrected QT (QTc) interval.

Bioactive adrenomedullin (bio-ADM) is associated with endothelial dysfunction in infants and children with complex congenital heart disease undergoing open-heart surgery on cardiopulmonary bypass.

OBJECTIVES: Children with congenital heart disease (CHD) undergoing cardiac surgery on cardiopulmonary bypass (CPB) are at risk for systemic inflammation leading to endothelial dysfunction associated with increased morbidity. Bioactive adrenomedullin (bio-ADM) is a peptide regulating vascular tone and endothelial permeability. The aim of this study was to evaluate the dynamics of plasma bio-ADM in this patient cohort and its role in capillary leak. METHODS: Plasma samples from 73 pediatric CHD patients were collected for bio-ADM measurement at five different timepoints (TP) in the pre-, intra-, and post-operative period. The primary endpoint was a net increase in bio-ADM levels after surgery on CPB. Secondary endpoints included association of bio-ADM levels with clinical signs for endothelial dysfunction. RESULTS: Bio-ADM levels increased after surgery on CPB from pre-operative median of 12 pg/mL (IQR [interquartile range] 12.0-14.8 pg/mL) to a maximum post-operative median of 48.8 pg/mL (IQR 34.5-69.6 pg/mL, p<0.001). Bio-ADM concentrations correlated positively with post-operative volume balance, (r=0.341; p=0.005), increased demand for vasoactive medication (duration: r=0.415; p<0.001; quantity: TP3: r=0.415, p<0.001; TP4: r=0.414, p<0.001), and hydrocortisone treatment for vasoplegia (bio-ADM median [IQR]:129.1 [55.4-139.2] pg/mL vs. 37.9 [25.2-64.6] pg/mL; p=0.034). Patients who required pleural effusion drainage revealed higher bio-ADM levels compared to those who did not (median [IQR]: 66.4 [55.4-90.9] pg/mL vs. 40.2 [28.2-57.0] pg/mL; p<0.001). CONCLUSIONS: Bio-ADM is elevated in children after cardiac surgery and higher levels correlate with clinical signs of capillary leakage. The peptide should be considered as biomarker for endothelial dysfunction and as potential therapeutic target in this indication.

Differentiating primary sarcomeric hypertrophic cardiomyopathy from Noonan syndrome: can the electrocardiogram be of use?

Noonan syndrome is a multi-system genetic disorder and patients may suffer from hypertrophic cardiomyopathy. Previous studies have identified electrocardiographic features that may support a diagnosis of Noonan syndrome. In this two-centre retrospective study, we analysed typical Noonan syndrome-related electrocardiographic features in 30 patients with Noonan syndrome with hypertrophic cardiomyopathy and compared these with the electrocardiographic features in 15 children with sarcomeric hypertrophic cardiomyopathy. Typical Noonan syndrome-related electrocardiographic features are a negative aVF, small left precordial R-waves, large right precordial S-waves, and abnormal Q-wave. We also analysed electrocardiographic features of hypertrophic cardiomyopathy: ST-segment abnormalities and T-wave abnormalities. A negative aVF was seen in 83% of patients with Noonan syndrome-related hypertrophic cardiomyopathy in contrast to 27% of patients with primary sarcomeric hypertrophic cardiomyopathy (p < 0.001). An extreme QRS axis in the north-west was seen only in patients with Noonan syndrome-related hypertrophic cardiomyopathy. This QRS axis deviation is likely to be determined by the Noonan syndrome-related hypertrophic cardiomyopathy and not by the type of hypertrophic cardiomyopathy. There were no differences between the two groups in the frequency of large right precordial S-waves and small R-waves in the left precordial leads V5 and V6. However, an abnormal R/S ratio was more often seen in patients with Noonan syndrome-related hypertrophic cardiomyopathy (p < 0.001). Pathologic Q-waves were seen statistically more frequently in patients with sarcomeric hypertrophic cardiomyopathy (p = 0.009). The occurrence of ST-segment and T-wave pathology did not statistically differ between the two groups. Electrography can be of use in differentiating sarcomeric hypertrophic cardiomyopathy from Noonan syndrome-related hypertrophic cardiomyopathy.

Epicardioid single-cell genomics uncovers principles of human epicardium biology in heart development and disease.

The epicardium, the mesothelial envelope of the vertebrate heart, is the source of multiple cardiac cell lineages during embryonic development and provides signals that are essential to myocardial growth and repair. Here we generate self-organizing human pluripotent stem cell-derived epicardioids that display retinoic acid-dependent morphological, molecular and functional patterning of the epicardium and myocardium typical of the left ventricular wall. By combining lineage tracing, single-cell transcriptomics and chromatin accessibility profiling, we describe the specification and differentiation process of different cell lineages in epicardioids and draw comparisons to human fetal development at the transcriptional and morphological levels. We then use epicardioids to investigate the functional cross-talk between cardiac cell types, gaining new insights into the role of IGF2/IGF1R and NRP2 signaling in human cardiogenesis. Finally, we show that epicardioids mimic the multicellular pathogenesis of congenital or stress-induced hypertrophy and fibrotic remodeling. As such, epicardioids offer a unique testing ground of epicardial activity in heart development, disease and regeneration.

EGFR and MMP-9 are associated with neointimal hyperplasia in systemic-to-pulmonary shunts in children with complex cyanotic heart disease.

Systemic-to-pulmonary shunt malfunction contributes to morbidity in children with complex congenital heart disease after palliative procedure. Neointimal hyperplasia might play a role in the pathogenesis increasing risk for shunt obstruction. The aim was to evaluate the role of epidermal growth factor receptor (EGFR) and matrix-metalloproteinase 9 (MMP-9) in the formation of neointimal within shunts. Immunohistochemistry was performed with anti-EGFR and anti-MMP-9 on shunts removed at follow-up palliative or corrective procedure. Whole-genome single-nucleotide polymorphisms genotyping was performed on DNA extracted from patients´ blood samples and allele frequencies were compared between the group of patients with shunts displaying severe stenosis (≥ 40% of lumen) and the remaining group. Immunohistochemistry detected EGFR and MMP-9 in 24 of 31 shunts, located mainly in the luminal area. Cross-sectional area of EGFR and MMP-9 measured in median 0.19 mm2 (IQR 0.1-0.3 mm2) and 0.04 mm2 (IQR 0.03-0.09 mm2), respectively, and correlated positively with the area of neointimal measured on histology (r = 0.729, p < 0.001 and r = 0.0479, p = 0.018, respectively). There was a trend of inverse correlation between the dose of acetylsalicylic acid and the degree of EGFR, but not MMP-9, expression within neointima. Certain alleles in epidermal growth factor (EGF) and tissue inhibitor of metalloproteinases 1 (TIMP-1) were associated with increased stenosis and neointimal hyperplasia within shunts. EGFR and MMP-9 contribute to neointimal proliferation in SP shunts of children with complex cyanotic heart disease. SP shunts from patients carrying certain risk alleles in the genes encoding for EGF and TIMP-1 displayed increased neointima.

Genetic and phenotypic spectrum in the NONO-associated syndromic disorder.

The non-POU domain-containing octamer-binding (NONO) protein is involved in multiple steps of gene regulation such as RNA metabolism and DNA repair. Hemizygous pathogenic variants in the NONO gene were confirmed to cause a rare X-linked syndromic disorder. Through our in-house diagnostics and subsequent matchmaking, we identified six unrelated male individuals with pathogenic or likely pathogenic NONO variants. For a detailed comparison, we reviewed all published characterizations of the NONO-associated disorder. The combined cohort consists of 16 live-born males showing developmental delay, corpus callosum anomalies, non-compaction cardiomyopathy and relative macrocephaly as leading symptoms. Seven prenatal literature cases were characterized by cardiac malformations. In this study, we extend the phenotypic spectrum through two more cases with epilepsy as well as two more cases with hematologic anomalies. By RNA expression analysis and structural modeling of a new in-frame splice deletion, we reinforce loss-of-function as the pathomechanism for the NONO-associated syndromic disorder.

Fetal Bradycardia Caused by Monogenic Disorders-A Review of the Literature.

Introduction: The standard obstetric definition of fetal bradycardia is a sustained fetal heart rate < 110 bpm over at least 10 min. Fetal bradycardia can be the first and only prenatal presentation of a heart disease. We present an overview on different genetic disorders that should be taken into consideration in case of diagnosed fetal bradycardia. Methods: A literature review was conducted using a PubMed- and OMIM-based search for monogenetic disorders causing fetal bradycardia in September 2022. Results: The review on the literature identified nine monogenic diseases that could lead to fetal bradycardia. Four of these disorders can be associated with extracardiac findings. Discussion: Genetic testing should be considered in cases with fetal bradycardia, especially in cases of additional extracardiac findings. Broad sequencing techniques and improved prenatal phenotyping could help to establish a diagnosis in an increasing number of cases.

Neointimal hyperplasia in systemic-to-pulmonary shunts of children with complex cyanotic congenital heart disease.

OBJECTIVES: Neointimal hyperplasia might affect systemic-to-pulmonary shunt failure in infants with complex cyanotic congenital heart disease. The aim of this study was to elucidate histopathologic changes in polytetrafluoroethylene shunts and to determine whether increased neointimal formation is associated with early interventions comprising balloon dilatation, stent implantation and shunt revision. Furthermore, we intended to identify clinical factors associated with increased neointimal proliferation. METHODS: Removed shunts were processed for histopathological analysis. Slides were stained with hematoxylin/eosin and Richardson. Immunohistochemistry was performed with anti-alpha-smooth muscle actin and anti-CD68. Non-parametric analysis and univariable regressions were performed to identify clinical factors associated with neointimal hyperplasia and shunt stenosis. RESULTS: Fifty-seven shunts (39 modified Blalock-Taussig anastomosis, 8 right ventricle-to-pulmonary artery anastomosis, 10 central shunts) were analysed. Area of neointimal proliferation within the shunt was in median 0.75 mm2 (interquartile range, 0.3-1.57 mm2) and relative shunt stenosis in median 16.7% (interquartile range, 6.7-30.8%). Neointimal hyperplasia and shunt stenosis correlated with each other and were significantly greater in the group that required early interventions and shunt revision. Univariable linear regression identified smaller shunt size and lower acetylsalicylic acid dosage as factors to be associated with greater neointimal proliferation and shunt stenosis. CONCLUSIONS: In infants with complex cyanotic congenital heart disease, neointimal hyperplasia in systemic-to-pulmonary shunts is associated with early interventions comprising balloon dilatation, stent implantation and shunt revision. Smaller shunt size and lower aspirin dosage are associated with increased neointimal proliferation.

Peak Oxygen Uptake on Cardiopulmonary Exercise Test Is a Predictor for Severe Arrhythmic Events during Three-Year Follow-Up in Patients with Complex Congenital Heart Disease.

Patients with congenital heart disease (CHD) are at increased risk for severe arrhythmia and sudden cardiac death (SCD). Although implantable cardioverter defibrillators (ICD) effectively prevent SCD, risk stratification for primary prophylaxis in patients with CHD remains challenging. Patients with complex CHD undergoing CPET were included in this single-center study. Univariable and backwards stepwise multivariable logistic regression models were used to identify variables associated with the endpoint of severe arrhythmic event during three years of follow-up. Cut-off values were established with receiver operating characteristic (ROC) curve analysis. Survival analysis was conducted via Kaplan-Meier plots. Severe Arrhythmia was documented in 97 of 1194 patients (8.1%/3 years). Independent risk factors for severe arrhythmia during follow-up were old age and a low peak oxygen uptake (V.O2peak) on multivariable analysis. Patients with more advanced age and with V.O2peak values of less than 24.9 mL/min/kg were at significantly increased risk for the occurrence of severe arrhythmias during follow-up. The combined analysis of both risk factors yielded an additional benefit for risk assessment. Age at CPET and V.O2peak predict the risk for severe arrhythmic events and should be considered for risk stratification of SCD in patients with complex CHD.

Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome.

Childhood-onset myocardial hypertrophy and cardiomyopathic changes are associated with significant morbidity and mortality in early life, particularly in patients with Noonan syndrome, a multisystemic genetic disorder caused by autosomal dominant mutations in genes of the Ras-MAPK pathway. Although the cardiomyopathy associated with Noonan syndrome (NS-CM) shares certain cardiac features with the hypertrophic cardiomyopathy caused by mutations in sarcomeric proteins (HCM), such as pathological myocardial remodeling, ventricular dysfunction, and increased risk for malignant arrhythmias, the clinical course of NS-CM significantly differs from HCM. This suggests a distinct pathophysiology that remains to be elucidated. Here, through analysis of sarcomeric myosin conformational states, histopathology, and gene expression in left ventricular myocardial tissue from NS-CM, HCM, and normal hearts complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11 N308S/+ induced pluripotent stem cells, we demonstrate distinct disease phenotypes between NS-CM and HCM and uncover cell cycle defects as a potential driver of NS-CM.

Management of cardiac aspects in children with Noonan syndrome - results from a European clinical practice survey among paediatric cardiologists.

BACKGROUND: The majority of children with Noonan syndrome (NS) or other diseases from the RASopathy spectrum suffer from congenital heart disease. This study aims to survey cardiac care of this patient cohort within Europe. METHODS: A cross-sectional exploratory survey assessing the treatment and management of patients with NS by paediatric endocrinologists, cardiologists and clinical geneticists was developed. This report details responses of 110 participating paediatric cardiologists from multiple countries. RESULTS: Most paediatric cardiologists responding to the questionnaire were associated with university hospitals, and most treated <10 patients/year with congenital heart disease associated with the NS spectrum. Molecular genetic testing for diagnosis confirmation was initiated by 81%. Half of the respondents reported that patients with NS and congenital heart disease typically present <1y of age, and that a large percentage of affected patients require interventions and pharmacotherapy early in life. A higher proportion of infant presentation and need for pharmacotherapy was reported by respondents from Germany and Sweden than from France and Spain (p = 0.031; p = 0.014; Fisher's exact test). Older age at first presentation was reported more from general hospitals and independent practices than from university hospitals (p = 0.031). The majority of NS patients were followed at specialist centres, but only 37% reported that their institution offered dedicated transition clinic to adult services. Very few NS patients with hypertrophic cardiomyopathy (HCM) were reported to carry implantable cardioverter defibrillators for sudden cardiac death prevention. Uncertainty was evident in regard to growth hormone treatment in patients with NS and co-existing HCM, where 13% considered it not a contra-indication, 24% stated they did not know, but 63% considered HCM either a possible (20%) or definite (15%) contraindication, or a cause for frequent monitoring (28%). Regarding adverse reactions for patients with NS on growth hormone therapy, 5/19 paediatric cardiology respondents reported a total of 12 adverse cardiac events. CONCLUSIONS: Congenital heart disease in patients with NS or other RASopathies is associated with significant morbidity during early life, and specialty centre care is appropriate. More research is needed regarding the use of growth hormone in patients with NS with congenital heart disease, and unmet medical needs have been identified.

European Medical Education Initiative on Noonan syndrome: A clinical practice survey assessing the diagnosis and clinical management of individuals with Noonan syndrome across Europe.

INTRODUCTION: Noonan syndrome (NS) is a rare genetic disorder caused by mutations in genes encoding components of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. Patients with NS exhibit certain characteristic features, including cardiac defects, short stature, distinctive facial appearance, skeletal abnormalities, cognitive deficits, and predisposition to certain cancers. Here, a clinical practice survey was developed to learn more about differences in the diagnosis and management of this disease across Europe. The aim was to identify gaps in the knowledge and management of this rare disorder. MATERIALS AND METHODS: The European Medical Education Initiative on NS, which comprised a group of 10 experts, developed a 60-question clinical practice survey to gather information from European physicians on the diagnosis and clinical management of patients with diseases in the NS phenotypic spectrum. Physicians from three specialities (clinical genetics, paediatric endocrinology, paediatric cardiology) were invited to complete the survey by several national and European societies. Differences in answers provided by respondents between specialities and countries were analysed using contingency tables and the Chi-Squared test for independence. The Friedman's test was used for related samples. RESULTS: Data were analysed from 364 respondents from 20 European countries. Most respondents came from France (21%), Spain (18%), Germany (16%), Italy (15%), United Kingdom (8%) and the Czech Republic (6%). Respondents were distributed evenly across three specialities: clinical genetics (30%), paediatric endocrinology (40%) and paediatric cardiology (30%). Care practices were generally aligned across the countries participating in the survey. Delayed diagnosis did not emerge as a critical issue, but certain unmet needs were identified, including transition of young patients to adult medical services and awareness of family support groups. CONCLUSION: Data collected from this survey provide a comprehensive summary of the diagnosis and clinical management practices for patients with NS across different European countries.

Management of growth failure and other endocrine aspects in patients with Noonan syndrome across Europe: A sub-analysis of a European clinical practice survey.

AIM: To date, there is a lack of international guidelines regarding the management of the endocrine features of individuals with Noonan syndrome (NS). The aim was to develop a clinical practice survey to gather information on current treatment and management of these patients across Europe. MATERIALS AND METHODS: A group of 10 experts from three clinical specialities involved in the management of NS patients (clinical geneticists, paediatric endocrinologists, and paediatric cardiologists) developed a 60-question clinical practice survey. The questionnaire was implemented in Survey Monkey and sent to physicians from these three specialities via European/national societies. Contingency tables and the Chi-Squared test for independence were used to examine differences between specialities and countries. RESULTS: In total, responses of 364 specialists (paediatric endocrinologists, 40%; geneticists, 30%; paediatric cardiologists, 30%) from 20 European countries were analysed. While endocrinologists mostly referred to national growth charts for the general population, geneticists mostly referred to NS-specific growth charts. Approximately half of the endocrinologists perform growth hormone (GH) stimulation tests in short patients with low IGF1 levels. Two thirds of endocrinologists begin GH treatment for short patients in early childhood (4-6.9 years), and over half of them selected a threshold of -2 standard deviation score (SDS) according to national growth charts. The main concerns about GH treatment appear to be presence of hypertrophic cardiomyopathy (HCM) (59%), increased risk of malignancy (46%), and limited efficacy (31%). When asked if they consider HCM as a contraindication for GH treatment, one third of respondents skipped this question, and among those who replied, two thirds selected 'cannot answer', suggesting a high level of uncertainty. A total of 21 adverse cardiac responses to GH treatment were reported. Although most respondents had not encountered any malignancy during GH treatment, six malignancies were reported. Finally, about half of the endocrinologists expected a typical final height gain of 1-1.5 SDS with GH treatment. CONCLUSION: This survey describes for the first time the current clinical practice of endocrine aspects of NS across Europe and helps us to identify gaps in the management but also in the knowledge of this genetic disorder.

Compound Mutation in Cardiac Sarcomere Proteins Is Associated with Increased Risk for Major Arrhythmic Events in Pediatric Onset Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is associated with adverse left ventricular (LV) remodeling causing dysfunction and malignant arrhythmias. Severely affected patients present with disease onset during childhood and sudden cardiac death risk (SCD) stratification is of the highest importance in this cohort. This study aimed to investigate genotype-phenotype association regarding clinical outcome and disease progression in pediatric onset HCM. Medical charts from forty-nine patients with pediatric HCM who had undergone genetic testing were reviewed for retrospective analysis. Demographic, clinical, transthoracic echocardiographic, electrocardiographic, long-term electrocardiogram, cardiopulmonary exercise test, cardiac magnetic resonance, and medication data were recorded. Childhood onset HCM was diagnosed in 29 males and 20 females. Median age at last follow-up was 18.7 years (range 2.6-51.7 years) with a median follow-up time since diagnosis of 8.5 years (range 0.2-38.0 years). Comparison of patients carrying mutations in distinct genes and comparison of genotype-negative with genotype-positive individuals, revealed no differences in functional classification, LV morphology, hypertrophy, systolic and diastolic function, fibrosis and cardiac medication. Patients with compound mutations had a significantly higher risk for major arrhythmic events than a single-mutation carrier. No association between affected genes and disease severity or progression was identified in this cohort.

Low-molecular-weight heparin administered by subcutaneous catheter is a safe and effective anti-coagulation regimen in selected inpatient infants and children with complex congenital heart disease.

BACKGROUND/HYPOTHESIS: Disadvantages of intravenous therapeutic unfractionated heparin, the first-line anti-coagulant agent in children with complex congenital heart disease, include unpredictable pharmacokinetics requiring frequent phlebotomies and the need for continuous intravenous access. OBJECTIVE: To compare efficacy and safety of low-molecular-weight heparin administered by a subcutaneous indwelling catheter with intravenous unfractionated heparin. MATERIALS AND METHODS: Clinical data from 31 inpatients prospectively enrolled to receive subcutaneous low-molecular-weight heparin were compared with those from a historical group of 44 inpatients receiving intravenous unfractionated heparin. Investigation of parents' satisfaction by telephone survey. RESULTS: The percentage of anti-factor Xa levels outside therapeutic range was lower in the subcutaneous low-molecular-weight heparin group compared with the percentage of activated partial thromboplastin times outside therapeutic range in the intravenous unfractionated heparin group (40% versus 90%, p < 0.001). Neither group had a major complication. Transient local reactions occurred in 19% of patients of the subcutaneous low-molecular-weight heparin group. The number of needle punctures and that of placement of indwelling catheters were significantly lower in the subcutaneous low-molecular-weight heparin compared with the intravenous unfractionated heparin group (p < 0.001). In total, 84.2% of parents in the subcutaneous low-molecular-weight heparin group reported a positive experience when asked about comparison with prior intravenous unfractionated heparin treatment. CONCLUSION: Subcutaneous low-molecular-weight heparin offers a safe anti-coagulation regimen for children with complex congenital heart disease providing more efficient therapeutic anti-coagulation and a reduction in needle punctures, thus causing less pain and anxiety in this children.

NADPH oxidases and HIF1 promote cardiac dysfunction and pulmonary hypertension in response to glucocorticoid excess.

Cardiovascular side effects are frequent problems accompanying systemic glucocorticoid therapy, although the underlying mechanisms are not fully resolved. Reactive oxygen species (ROS) have been shown to promote various cardiovascular diseases although the link between glucocorticoid and ROS signaling has been controversial. As the family of NADPH oxidases has been identified as important source of ROS in the cardiovascular system we investigated the role of NADPH oxidases in response to the synthetic glucocorticoid dexamethasone in the cardiovascular system in vitro and in vivo in mice lacking functional NADPH oxidases due to a mutation in the gene coding for the essential NADPH oxidase subunit p22phox. We show that dexamethasone induced NADPH oxidase-dependent ROS generation, leading to vascular proliferation and angiogenesis due to activation of the transcription factor hypoxia-inducible factor-1 (HIF1). Chronic treatment of mice with low doses of dexamethasone resulted in the development of systemic hypertension, cardiac hypertrophy and left ventricular dysfunction, as well as in pulmonary hypertension and pulmonary vascular remodeling. In contrast, mice deficient in p22phox-dependent NADPH oxidases were protected against these cardiovascular side effects. Mechanistically, dexamethasone failed to upregulate HIF1α levels in these mice, while vascular HIF1α deficiency prevented pulmonary vascular remodeling. Thus, p22phox-dependent NADPH oxidases and activation of the HIF pathway are critical elements in dexamethasone-induced cardiovascular pathologies and might provide interesting targets to limit cardiovascular side effects in patients on chronic glucocorticoid therapy.

Reclassification of genetic variants in children with long QT syndrome.

BACKGROUND: Genes encoding cardiac ion channels or regulating proteins have been associated with the inherited form of long QT syndrome (LQTS). Complex pathophysiology and missing functional studies, however, often bedevil variant interpretation and classification. We aimed to evaluate the rate of change in variant classification based on current interpretation standards and dependent on clinical findings. METHODS: Medical charts of children with a molecular genetic diagnosis of LQTS presenting at our centers were retrospectively reviewed. Reinterpretation of originally reported variants in genes associated with LQTS was performed based on current knowledge (March 2019) and according to the "Standards and Guidelines for the Interpretation of Sequence Variants" by the ACMG 2015. RESULTS: About 84 distinct (likely) pathogenic variants identified in 127 patients were reinterpreted. In 12 variants (12/84, 14.3%), classification changed from (likely) pathogenic to variant of unknown significance (VUS). One of these variants was a hypomorphic allele escaping the standard variant classification. Individuals with variants that downgraded to VUS after reevaluation showed significantly lower Schwartz scores and QTc intervals compared to individuals with unchanged variant characterization. CONCLUSION: This finding confirms genetic variant interpretation as a dynamic process and underlines the importance of ongoing genetic counseling, especially in LQTS patients with minor clinical criteria.

No increased extracellular volume fraction or conduction time after childhood septal myectomy.

OBJECTIVES: The aim of this study was to assess the effect of surgical septal myectomy performed during early childhood for severe, drug-refractory hypertrophic cardiomyopathy with left ventricular outflow tract obstruction on the extent of septal myocardial extracellular volume fraction and the potential risk of developing atrioventricular cardiac conduction system disease. METHODS: In this retrospective study, data from 30 patients with a confirmed diagnosis of childhood-onset hypertrophic cardiomyopathy were reviewed including cardiovascular magnetic resonance (CMR) with myocardial T1 mapping and late gadolinium enhancement, histopathology of myocardial specimens, transthoracic echocardiography, electrocardiography, 24-h Holter and cardiopulmonary exercise testing. Eighteen patients without were compared to 12 patients with prior septal myectomy performed during childhood (non-operated versus myectomy patients). RESULTS: Late gadolinium enhancement on CMR as a correlate for focal myocardial fibrosis was found in 53% of patients, predominantly located in the septal region, with no difference between groups. As compared to non-operated patients, those after myectomy showed a similar amount of total and septal extracellular volume fraction, as calculated from pre- and post-contrast CMR T1 mapping, which is a correlate for diffuse interstitial myocardial fibrosis. PQ-intervals or the occurrence of higher degree conduction system disease were equal between the 2 groups. CONCLUSIONS: Data from CMR and electrocardiography suggest that surgical septal myectomy performed during early childhood for severe obstructive hypertrophic cardiomyopathy does not cause an increased septal extracellular volume fraction or delayed atrioventricular conduction time on long-term follow-up.

Long-term outcomes of childhood onset Noonan compared to sarcomere hypertrophic cardiomyopathy.

BACKGROUND: To compare outcome and cardiac pathology between patients with Noonan syndrome (N-HCM) and sarcomere protein-associated (S-HCM) childhood onset hypertrophic cardiomyopathy (HCM). METHODS: Clinical data were recorded from medical charts. Primary endpoint was survival. Secondary endpoints were survival without hospitalization, without intervention or without arrhythmic events. Functional clinical status and results from genetic testing, imaging, electrocardiographic (ECG) studies, cardiopulmonary exercise testing (CPET) and histopathology were compared between groups. RESULTS: Childhood HCM was diagnosed in 29 N-HCM and 34 S-HCM patients. Follow-up time was greater than 10 years in more than half of all patients. Mortality was below 7% and not different between groups. Children with N-HCM presented at a younger age and there was less time of survival without hospitalization for heart failure or intervention in N-HCM compared to S-HCM patients. Clinical functional status improved over time in N-HCM patients. On long-term follow-up, left ventricular posterior wall thickness indexed to body surface area decreased in N-HCM and increased in S-HCM patients. There was a trend to lower risk for severe arrhythmic events in N-HCM patients and only S-HCM individuals received an implantable cardioverter-defibrillator. There were no differences between groups in ventricular function, ECG and CPET parameters. Myocardial fibrosis as assessed by histopathology of myocardial specimens and cardiovascular magnetic resonance with late gadolinium enhancement or T1 mapping was present in both groups. CONCLUSIONS: When compared to S-HCM patients, children with N-HCM have increased morbidity during early disease course, but favorable long-term outcome with low mortality, stagnation of myocardial hypertrophy, and low risk for malignant arrhythmias.