Somatic mosaicism, the occurrence and propagation of genetic variation in cell lineages after fertilization, is increasingly recognized to play a causal role in a variety of human diseases. We investigated the case of life-threatening arrhythmia in a 10-day-old infant with long QT syndrome (LQTS). Rapid genome sequencing suggested a variant in the sodium channel Na V 1.5 encoded by SCN5A, NM_000335:c.5284G > T predicting p.(V1762L), but read depth was insufficient to be diagnostic. Exome sequencing of the trio confirmed read ratios inconsistent with Mendelian inheritance only in the proband. Genotyping of single circulating leukocytes demonstrated the mutation in the genomes of 8% of patient cells, and RNA sequencing of cardiac tissue from the infant confirmed the expression of the mutant allele at mosaic ratios. Heterologous expression of the mutant channel revealed significantly delayed sodium current with a dominant negative effect. To investigate the mechanism by which mosaicism might cause arrhythmia, we built a finite element simulation model incorporating Purkinje fiber activation. This model confirmed the pathogenic consequences of cardiac cellular mosaicism and, under the presenting conditions of this case, recapitulated 2:1 AV block and arrhythmia. To investigate the extent to which mosaicism might explain undiagnosed arrhythmia, we studied 7,500 affected probands undergoing commercial gene-panel testing. Four individuals with pathogenic variants arising from early somatic mutation events were found. Here we establish cardiac mosaicism as a causal mechanism for LQTS and present methods by which the general phenomenon, likely to be relevant for all genetic diseases, can be detected through singlecell analysis and next-generation sequencing.here is growing recognition that somatic mosaicism, i.e., genetic variation within an individual that arises from errors in DNA replication during early development, may play a role in a variety of human diseases other than cancer (1). However, the extent to which cellular heterogeneity contributes to disease is minimally understood. One report suggests that 6.5% of de novo mutations presumed to be germline in origin may instead have arisen from postzygotic mosaic mutation events (2), and recent genetic investigations directly interrogating diseased tissues in brain malformations, breast cancer, and atrial fibrillation have revealed postzygotic causal mutations absent from germline DNA (3-6). Pathogenic mosaic structural variation is also detectable in children with neurodevelopmental disorders (7). However, a consequential category of genetic variation has not been surveyed systematically in clinical or research studies of other human diseases.The pathophysiological basis of long-QT syndrome (LQTS) is prolongation of cardiac ventricular repolarization by acquired factors such as drug exposure or genetic variation in the proteins controlling transmembrane ion-concentration gradients (8, 9); parental gonadal mosaicism is an infrequently described phenomenon in LQTS (10...
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Background The advent of clinical next generation sequencing is rapidly changing the landscape of rare disease medicine. Molecular diagnosis of long QT syndrome (LQTS) can impact clinical management, including risk stratification and selection of pharmacotherapy based on the type of ion channel affected, but results from current gene panel testing requires 4 to 16 weeks before return to clinicians. Objective A term female infant presented with 2:1 atrioventricular block and ventricular arrhythmias consistent with perinatal LQTS, requiring aggressive treatment including epicardial pacemaker, and cardioverter-defibrillator implantation and sympathectomy on day of life two. We sought to provide a rapid molecular diagnosis for optimization of treatment strategies. Methods We performed CLIA-certified rapid whole genome sequencing (WGS) with a speed-optimized bioinformatics platform to achieve molecular diagnosis at 10 days of life. Results We detected a known pathogenic variant in KCNH2 that was demonstrated to be paternally inherited by followup genotyping. The unbiased assessment of the entire catalog of human genes provided by whole genome sequencing revealed a maternally inherited variant of unknown significance in a novel gene. Conclusions Rapid clinical WGS provides faster and more comprehensive diagnostic information by 10 days of life than standard gene-panel testing. In selected clinical scenarios such as perinatal LQTS, rapid WGS may be able to provide more timely and clinically actionable information than a standard commercial test.
In view of the increasing complexity of both cardiovascular implantable electronic devices (CIEDs) and patients in the current era, practice guidelines, by necessity, have become increasingly specific. This document is an expert consensus statement that has been developed to update and further delineate indications and management of CIEDs in pediatric patients, defined as ≤21 years of age, and is intended to focus primarily on the indications for CIEDs in the setting of specific disease categories. The document also highlights variations between previously published adult and pediatric CIED recommendations and provides rationale for underlying important differences. The document addresses some of the deterrents to CIED access in low- and middle-income countries and strategies to circumvent them. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by class of recommendation and level of evidence. Several questions addressed in this document either do not lend themselves to clinical trials or are rare disease entities, and in these instances recommendations are based on consenus expert opinion. Furthermore, specific recommendations, even when supported by substantial data, do not replace the need for clinical judgment and patient-specific decision-making. The recommendations were opened for public comment to Pediatric and Congenital Electrophysiology Society (PACES) members and underwent external review by the scientific and clinical document committee of the Heart Rhythm Society (HRS), the science advisory and coordinating committee of the American Heart Association (AHA), the American College of Cardiology, (ACC) and the Association for European Paediatric and Congenital Cardiology (AEPC). The document received endorsement by all the collaborators and the Asia Pacific Heart Rhythm Society (APHRS), the Indian Heart Rhythm Society (IHRS), and the Latin American Heart Rhythm Society (LAHRS). This document is expected to provide support for clinicians and patients to allow for appropriate CIED use, appropriate CIED management, and appropriate follow-up in pediatric patients.
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Children and adolescents with cardiac disease (CCD) have significant morbidity and lower quality of life. However, there are no broadly applicable tools similar to the frailty score as described in the elderly, to define functional phenotype in terms of physical capability and psychosocial wellbeing in CCD. The purpose of this study is to investigate the domains of the frailty in CCD. We prospectively recruited CCD (8-17.5 years old, 70% single ventricle, 27% heart failure, 12% pulmonary hypertension; NYHA classes I, II and III) and age and gender matched healthy controls (total n = 56; CCD n = 34, controls n = 22; age 12.6 ± 2.6 years; 39.3% female). We measured the five domains of frailty: slowness, weakness, exhaustion, body composition and physical activity using developmentally appropriate methods. Age and gender-based population norms were used to obtain Z scores and percentiles for each measurement. Two-tailed t-tests were used to compare the two groups. The CCD group performed significantly worse in all five domains of frailty compared to healthy controls. Slowness: 6-min walk test with Z score −3.
Objectives: Many children diagnosed with COVID-19 infections did not require hospitalisation. Our objective was to analyse electrocardiographic changes in children with asymptomatic, mild or moderate COVID-19 who did not require hospitalisation Methods: All children are seen in a paediatric cardiology clinic who had asymptomatic, mild or moderate COVID-19 that did not require hospitalisation and had at least one electrocardiogram after their diagnosis were included in this retrospective analysis. Records were reviewed to determine COVID-19 disease severity and presence of Long COVID. Rhythm assessment, atrial enlargement, ventricular hypertrophy, PR/QRS/QT interval duration and ST-T wave abnormalities were analysed by a paediatric electrophysiologist. Clinically ordered echocardiograms were reviewed for signs of myopericarditis (left ventricular ejection fraction and pericardial effusion) on any subject with an electrocardiographic abnormality. Results: Of the 82 children meeting inclusion criteria (14.4 years, range 1–18 years, 57% male), 17 patients (21%) demonstrated electrocardiographic changes. Ten patients (12%) had electrocardiogram of borderline significance, which included isolated mild PR prolongation or mild repolarisation abnormalities. The other seven patients (9%) had concerning electrocardiographic findings consisting of more significant repolarisation abnormalities. None of the patients with an abnormal electrocardiogram revealed any echocardiographic abnormality. All abnormal electrocardiograms normalised over time except in two cases. Across the entire cohort, greater COVID-19 disease severity and long COVID were not associated with electrocardiographic abnormalities. Conclusions: Electrocardiographic abnormalities are present in a minority of children with an asymptomatic, mild or moderate COVID-19 infection. Many of these changes resolved over time and no evidence of myopericarditis was present on echocardiography.
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