Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40–50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype–phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype–phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families.

Phenotypic Expression, Natural History and Risk Stratification of Cardiomyopathy Caused by Filamin C Truncating Variants

Background: Filamin C truncating variants ( FLNCtv ) cause a form of arrhythmogenic cardiomyopathy (ACM): the mode of presentation, natural history and risk stratification of FLNCtv remain incompletely explored. We sought to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of FLNCtv carriers. Methods: FLNCtv carriers were identified from ten tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), non-arrhythmic death/HT/LVAD and SCD/major ventricular arrhythmias (SCD/MVA). Previously established cohorts of 46 patients with LMNA and 60 with DSP -related ACM were used for prognostic comparison. Results: Eighty-five patients carrying FLNCtv were included (42±15 years, 53% males, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction (LVEF) was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area - right ventricular end-systolic area)/ right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) non-arrhythmic death/HT/LVAD and 23 (27%) SCD/MVA. The SCD/MVA incidence of FLNCtv carriers did not significantly differ from LMNA carriers and DSP carriers. In FLNCtv carriers, LVEF was associated with the risk of D/HT/LVAD and non-arrhythmic death/HT/LVAD. C Conclusions: Among patients referred to tertiary referral centers, FLNCtv ACM is phenotypically heterogeneous and characterized by high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of LV dysfunction.

Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death

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.

Unique clinical features and long term follow up of survivors of sudden cardiac death in an Asian multicenter study

There has been no long-term clinical follow-up data of survivors or victims of sudden cardiac death (SCD). The Taiwan multi-center sudden arrhythmia death syndrome follow-up and clinical study (TFS-SADS) is a collaborative multi-center study with median follow-up time 43 months. In this cohort, the clinical characteristics of these SADS patients were compared with those with ischemic heart disease (IHD). In this SCD cohort, around half (42%) were patients with IHD, which was different from Caucasian SCD cohorts. Among those with normal heart, most had Brugada syndrome (BrS). Compared to those with SADS, patients with IHD were older, more males and more comorbidities, more arrhythmic death, and lower left ventricular ejection fraction. In the long-term follow-up, patients with SADS had a better survival than those with IHD (p < 0.001). In the Cox regression analysis to identify the independent predictors of mortality, older age, lower LVEF, prior myocardial infarction and history of out-of-hospital cardiac arrest were associated with higher mortality and beta blocker use and idiopathic ventricular fibrillation or tachycardia (IVF/IVT) with a better survival during follow-up. History of prior MI was associated with more arrhythmic death. Several distinct features of SCD were found in the Asia–Pacific region, such as higher proportion of SADS, poorer prognosis of LQTS and better prognosis of IVF/IVT. Patients with SADS had a better survival than those with IHD. For those with SADS, patients with channelopathy had a better survival than those with cardiomyopathy.

H1153Y-KCNH2 Mutation Identified in a Sudden Arrhythmic Death Syndrome Case Alters Channel Gating

Long QT syndrome is one of the most common hereditary channelopathies inducing fatal arrhythmias and sudden cardiac death. We identified in a sudden arrhythmic death syndrome case a C-term KCNH2 mutation (c.3457C > T; p.His1153Tyr) classified as variant of unknown significance and functional impact. Heterologous expression in HEK293 cells combined with western-blot, flow-cytometry, immunocytochemical and microscope analyses shows no modification of channel trafficking to the cell membrane. Electrophysiological studies reveal that the mutation causes a loss of HERG channel function through an alteration of channel biophysical properties that reduces the current density leading to LQT2. These results provide the first functional evidence for H1153Y-KCNH2 mutation-induced abnormal channel properties. They concur with previous biophysical and clinical presentations of a survived patient with another variant that is G1036D. Therefore, the present report importantly highlights the potential severity of variants that may have useful implications for treatment, surveillance, and follow-up of LQT2 patients.

Rare health conditions 49: sudden arrhythmic death syndrome (SADS), sudden infant death syndrome (SIDS), and Hansen's disease

The purpose of this series is to highlight a range of rare health conditions. Rare health conditions are those that affect no more and usually fewer than 1 person in every 2000. Many healthcare assistants and nurses will encounter some of these conditions, given the high number of them. This 49th article will explore three of these conditions: sudden arrhythmic death syndrome (SADS); sudden infant death syndrome (SIDS); and Hansen's disease.

Inhalation of helium in plastic bag suffocation with suicidal purpose: Observation and differences of two cases

The use of helium in plastic bag suffocation is a suicide method recently found in forensic cases. Although it is not common practice, there has been a strong increase in its use during the past 20 years, thanks to the accessibility of information on the web and materials needed to implement it. From a pathophysiological point of view, there are various theories on how helium can change the timing and, also, the cause of death when the head is inside a plastic bag. We report two cases where we believe that the action of helium, whose unequivocal use is demonstrated by the circumstantial data, has unfolded in a different way. In the first case, the discovery of an intense cyanosis of the face, blood leakage from the respiratory orifices and the destruction of numerous alveolar septa with histologically demonstrated blood extravasation, was left for a longer agonic period and a no negligible rate of pulmonary barotrauma in determination of death. In the second case, the total absence of external pathological phenomena, internal and histological, allows us to hypothesise an onset of death that is faster and catalysed by helium and explained by the known sympathetic hyperactivation and consequent cardiac arrhythmic death described in similar plastic bag suffocation cases.

Development and Validation of a Risk Prediction Model for Ventricular Arrhythmia in Elderly Patients with Coronary Heart Disease

Background. Sudden cardiac death is a leading cause of death from coronary heart disease (CHD). The risk of sudden cardiac death (SCD) increases with age, and sudden arrhythmic death remains a major cause of mortality in elderly individuals, especially ventricular arrhythmias (VA). We developed a risk prediction model by combining ECG and other clinical noninvasive indexes including biomarkers and echocardiology for VA in elderly patients with CHD. Method. In the retrospective study, a total of 2231 consecutive elderly patients (≥60 years old) with CHD hospitalized were investigated, and finally 1983 patients were enrolled as the model group. The occurrence of VA within 12 months was mainly collected. Study parameters included clinical characteristics (age, gender, height, weight, BMI, and past medical history), ECG indexes (QTcd, Tp-e/QT, and HRV indexes), biomarker indexes (NT-proBNP, Myo, cTnT, CK-MB, CRP, K+, and Ca2+), and echocardiology indexes. In the respective study, 406 elderly patients (≥60 years old) with CHD were included as the verification group to verify the model in terms of differentiation and calibration. Results. In the multiparameter model, seven independent predictors were selected: LVEF, LAV, HLP, QTcd, sex, Tp-e/QT, and age. Increased HLP, Tp-e/QT, QTcd, age, and LAV were risk factors (RR > 1), while female and increased LVEF were protective factors (RR < 1). This model can well predict the occurrence of VA in elderly patients with CHD (for model group, AUC: 0.721, 95% CI: 0.669∼0.772; for verification group, AUC: 0.73, 95% CI: 0.648∼0.818; Hosmer–Lemeshow χ 2 = 13.541, P = 0.095 ). After adjusting the predictors, it was found that the combination of clinical indexes and ECG indexes could predict VA more efficiently than using clinical indexes alone. Conclusions. LVEF, LAV, QTcd, Tp-e/QT, gender, age, and HLP were independent predictors of VA risk in elderly patients with CHD. Among these factors, the echocardiology indexes LVEF and LAV had the greatest influence on the predictive efficiency of the model, followed by ECG indexes, QTcd and Tp-e/QT. After verification, the model had a good degree of differentiation and calibration, which can provide a certain reference for clinical prediction of the VA occurrence in elderly patients with CHD.

Usefulness of the MADIT-ICD Benefit Score in a S-ICD Patient Cohort

Background: The subcutaneous ICD (S-ICD) is used in an increasing number of patients for primary and secondary prevention of sudden cardiac death. Decision-making in primary prevention is not always trivial and many clinical scenarios are not reflected in current ICD guidelines. To help evaluating the patient’s individual risk, a new score trying to predict the benefit of an ICD implantation for primary prevention, the MADIT-ICD benefit score, which tries to predict occurrence of ventricular arrhythmias and non-arrhythmic death, has been proposed. We therefore aimed at examining its usefulness in a large single centre register of S-ICD patients Methods and results: All S-ICD patients with a primary preventive indication for ICD implantation from our large single centre database were included in the analysis (n=173). During a follow-up of 1227±978 days 27 patients developed sustained ventricular arrhythmias, while 6 patients died for non-arrhythmic reasons. Occurrence of ventricular arrhythmias could not sufficiently be predicted by the MADIT-ICD VT/VF score (p=0.3) in patients with (n=142, p=0.19) as well as patients without structural heart disease (n=31, p=0.88). However, there was a significant correlation for patients with ischemic cardiomyopathy (ICM) (n=29, p=0.04). Only one parameter (non-sustained ventricular tachycardia) was significantly associated with sustained ventricular arrhythmias (p=0.02). Of note, non-arrhythmic death could effectively be predicted by the proposed non-arrhythmic mortality score as part of the benefit score (p=0.001, r=0.3) also mainly driven by ICM patients. Age, diabetes mellitus, and a BMI <23 kg/m2 were key predictors of non-arrhythmic death implemented in the score.Conclusion: The MADIT-ICD benefit score adds a new option to evaluate expected benefit of ICD implantation for primary prevention. However, in our S-ICD cohort, the only group in which the score worked properly for prediction of sudden and non-sudden death were ICM patients, so that a larger validation in more heterogeneous cohorts in mandatory to claim general validity for this score in risk stratification for primary preventive ICD implantation.