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© 2016 The AuthorsGermline mutations in BRAF cause cardio-facio-cutaneous syndrome (CFCS), whereby 40% of patients develop hypertrophic cardiomyopathy (HCM). As the role of the RAS/MAPK pathway in HCM pathogenesis is unclear, we generated a human induced p

Efforts to implement and evaluate genome sequencing (GS) as a screening tool for newborns and infants are expanding worldwide. The first iteration of the BabySeq Project (2015-2019), a randomized controlled trial of newborn sequencing, produced novel evidence on medical, behavioral, and economic outcomes. The second iteration of BabySeq, which began participant recruitment in January 2023, examines GS outcomes in a larger, more diverse cohort of more than 500 infants up to one year of age recruited from pediatric clinics at several sites across the United States. The trial aims for families who self-identify as Black/African American or Hispanic/Latino to make up more than 50% of final enrollment, and key aspects of the trial design were co-developed with a community advisory board. All enrolled families receive genetic counseling and a family history report. Half of enrolled infants are randomized to receive GS with comprehensive interpretation of pathogenic and likely pathogenic variants in more than 4,300 genes associated with childhood-onset and actionable adult-onset conditions, as well as larger-scale chromosomal copy number variants classified as pathogenic or likely pathogenic. GS result reports include variants associated with disease (Mendelian disease risks) and carrier status of autosomal-recessive and X-linked disorders. Investigators evaluate the utility and impacts of implementing a GS screening program in a diverse cohort of infants using medical record review and longitudinal parent surveys. In this perspective, we describe the rationale for the second iteration of the BabySeq Project, the outcomes being assessed, and the key decisions collaboratively made by the study team and community advisory board., Competing Interests: Declaration of interests H.S.S. has received consulting income from Illumina unrelated to this work. N.D.S. is a member of the Scientific Advisory Board for Neuberg Center for Genomic Medicine. A.L.M. is a paid advisor for Nurture Genomics. B.R.K. is a member of medical advisory boards for Alexion, SpringWorks, Healx, Infixion, and Recursion and has stock options in GenomeMedical. R.C.G. has received compensation for advising Allelica, Atria, Fabric, Genome Web, and Genomic Life and is a cofounder of Genome Medical and Nurture Genomics., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Due to improvements in recognition and management of their multisystem disease, the long-term survival of infants, children, and adolescents with trisomy 21 and congenital heart disease now matches children with congenital heart disease and no genetic condition in many scenarios. Although this improved survival is a triumph, individuals with trisomy 21 and congenital heart disease have unique and complex care needs in the domains of physical, developmental, and psychosocial health, which affect functional status and quality of life. Pulmonary hypertension and single ventricle heart disease are 2 known cardiovascular conditions that reduce life expectancy in individuals with trisomy 21. Multisystem involvement with respiratory, endocrine, gastrointestinal, hematological, neurological, and sensory systems can interact with cardiovascular health concerns to amplify adverse effects. Neurodevelopmental, psychological, and functional challenges can also affect quality of life. A highly coordinated interdisciplinary care team model, or medical home, can help address these complex and interactive conditions from infancy through the transition to adult care settings. The purpose of this Scientific Statement is to identify ongoing cardiovascular and multisystem, developmental, and psychosocial health concerns for children with trisomy 21 and congenital heart disease from birth through adolescence and to provide a framework for monitoring and management to optimize quality of life and functional status.

Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder that results from the loss of one functional copy of the SHANK3 gene. While many clinical features of PMS are well-understood, there is currently limited literature on cardiovascular abnormalities in PMS. This report aims to evaluate the prevalence of aortic root dilation (ARD) among individuals with PMS and to understand if underlying genetic variation relates to risk for ARD. We present findings from 59 participants collected from a multisite observational study evaluating the phenotype and natural history of PMS. Individual echocardiographic and genetic reports were analyzed for aortic root measurements and genetic variant data, respectively. Our a priori hypothesis was that participants with chromosome 22 deletions with hg19 start coordinates on or before 49,900,000 (larger deletions) would have more instances of ARD than participants with deletion start coordinates after 49,900,000 (smaller deletions). Eight participants (14%) had ARD, and its presence was statistically significantly associated with large deletions (p = 0.047). Relatedly, participants with ARD had significantly more genes deleted on chromosome 22 than participants without ARD (p = 0.013). These results could aid in the identification of individuals with PMS who are at higher risk for ARD., (© 2024 Wiley Periodicals LLC.)

Congenital heart defects (CHDs) are the most common structural birth defect and are present in 40-50% of children born with Down syndrome (DS). To characterize the genetic architecture of DS-associated CHD, we sequenced genomes of a multiethnic group of children with DS and a CHD (n=886: atrioventricular septal defects (AVSD), n=438; atrial septal defects (ASD), n=122; ventricular septal defects (VSD), n=170; other types of CHD, n=156) and DS with a structurally normal heart (DS+NH, n=572). We performed four GWAS for common variants (MAF>0.05) comparing DS with CHD, stratified by CHD-subtype, to DS+NH controls. Although no SNP achieved genome-wide significance, multiple loci in each analysis achieved suggestive significance (p<2×10 -6 ). Of these, the 1p35.1 locus (near RBBP4 ) was specifically associated with ASD risk and the 5q35.2 locus (near MSX2 ) was associated with any type of CHD. Each of the suggestive loci contained one or more plausible candidate genes expressed in the developing heart. While no SNP replicated (p<2×10 -6 ) in an independent cohort of DS+CHD (DS+CHD: n=229; DS+NH: n=197), most SNPs that were suggestive in our GWASs remained suggestive when meta-analyzed with the GWASs from the replication cohort. These results build on previous work to identify genetic modifiers of DS-associated CHD.

Background: Few reports describe the yield of postmortem genetic testing from medical examiners' offices or correlate genetic test results with autopsy-confirmed phenotypes from a large cohort., Objectives: To report results from cardiomyopathy- and cardiac arrhythmia-associated genetic testing in conjunction with autopsy findings of cases investigated at the United States' largest medical examiner office., Methods: Postmortem cases tested from 2015 to 2022 with a cardiomyopathy- and cardiac arrhythmia-associated gene panel were reviewed. American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines were used to classify variant pathogenicity. Correlations of pathogenic/likely pathogenic variants (P/LPVs) with cardiac pathology were evaluated., Results: The cohort included 1107 decedents of diverse ages and ethnicities. P/LPVs were detected in 87 (7.9%) cases, with 73 and 14 variants in cardiomyopathy and cardiac arrhythmia genes, respectively. Variants of uncertain significance were detected in 437 (39.5%) cases. The diagnostic yield (percentage of P/LPV) in decedents with cardiomyopathy (26.1%) was significantly higher than those without (P<.0001). The diagnostic yield was significantly lower in infants (0.7%) than older age groups (ranging from 1 to 74 years old, 5.7%-25.9%), which had no statistical difference between their yields. The diagnostic yields by cardiac autopsy findings were 54.0% for hypertrophic cardiomyopathy, 47.1% for arrhythmogenic cardiomyopathy, 20.0% for myocardial fibrosis, 19.0% for dilated cardiomyopathy, and 11.3% for myocarditis. Most P/LPVs were in MYBPC3, TTN, PKP2, SCN5A, MYH7, and FLNC. Ten P/LPVs were novel., Conclusions: Our results support the importance of performing postmortem genetic testing on decedents of all ages with cardiomyopathy, cardiac lesions insufficient to diagnosis a specific cardiomyopathy (e.g., myocardial fibrosis), and myocarditis. Combined postmortem cardiac examination and genetic analysis are advantageous in accurately determining the underlying cause of death and informing effective clinical care of family members., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes., Competing Interests: Declaration of competing interest A. Kushki received grants from the National Science and Engineering Research Council during the conduct of the study and holds a patent for Anxiety Meter with royalties paid from Awake Labs. E. King reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Goldmuntz reported receiving grants from the NIH during the conduct of the study. T. A. Miller reported receiving grants from the NIH during the conduct of the study. N. H. Thomas reported receiving grants from the NIH, including the Clinical and Translational Science Awards Program, during the conduct of the study. J. F. Cnota reported receiving grants from the NIH during the conduct of the study and from Additional Ventures outside the submitted work. C. S. Goldberg reported receiving grants from the NIH related to work for the Pediatric Heart Network during the conduct of the study. P. McQuillen reported receiving grants from the NIH during the conduct of the study. G. A. Porter reported receiving grants from the University of Rochester Medical Center. A. E. Roberts reported receiving grants from the NIH during the conduct of the study. C. E. Seidman serves as a consultant for Maze Therapeutics and on the board of directors for Merck and the Burroughs Wellcome Fund; these companies had no role in the design, execution, or analyses of this study. J. W. Newburger has served as a consultant to and received grant funds from Pfizer: received honoraria from Daiichi-Sankyo for membership on a trial Steering Committee; and chaired Independent Clinical Events Committees for Bristol Myer Squibb, Pfizer, and Novartis. E. Anagnostou has received grants from Roche and Anavex, served as a consultant to Roche, Quadrant Therapeutics, Ono, and Impel Pharmaceuticals, has received in-kind support from AMO Pharma and CRA-Simons Foundation, holds a patent for the device, “Anxiety Meter”, has received royalties from APPI and Springer, and has received an editorial honorarium from Wiley. The remaining authors have reported no potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The NKX2-5 gene encodes a transcription factor that plays a role in atrioventricular nodal and myocardial development. Pathogenic variants of NKX2-5 are associated with congenital heart disease and sudden cardiac death. The missense variant in this case is one of the more common ones in Northern Europe and has high penetrance in familial cases. To our knowledge, this is the youngest person who died due to this variant. Case summary: This was a healthy, asymptomatic 14-year-old male with well-managed mild congenital dilated cardiomyopathy who died unexpectedly in his home. Postmortem examination revealed the NKX2-5 pathogenic missense variant, p.Phe145Leu, as the only explicable cause of death. Discussion: We propose that immediate family members of those who die suddenly due to NKX2-5 disease undergo genetic counseling and longitudinal screening to include this gene, as pathogenic variants in the NKX2-5 gene may manifest in a time-dependent manner., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (©2024 The Author(s).)

Genetic testing with exome sequencing and genome sequencing is increasingly offered to infants and children with cardiovascular diseases. However, the rates of positive diagnoses after genetic testing within the different categories of cardiac disease and phenotypic subtypes of congenital heart disease (CHD) have been little studied. We report the diagnostic yield after next-generation sequencing in 500 patients with CHD from diverse population subgroups that were enrolled at three different sites in the Clinical Sequencing Evidence-Generating Research consortium. Patients were ascertained due to a primary cardiovascular issue comprising arrhythmia, cardiomyopathy, and/or CHD, and corresponding human phenotype ontology terms were selected to describe the cardiac and extracardiac findings. We examined the diagnostic yield for patients with arrhythmia, cardiomyopathy, and/or CHD and phenotypic subtypes of CHD comprising conotruncal defects, heterotaxy, left ventricular outflow tract obstruction, septal defects, and "other" heart defects. We found a significant increase in the frequency of positive findings for patients who underwent genome sequencing compared to exome sequencing and for syndromic cardiac defects compared to isolated cardiac defects. We also found significantly higher diagnostic rates for patients who presented with isolated cardiomyopathy compared to isolated CHD. For patients with syndromic presentations who underwent genome sequencing, there were significant differences in the numbers of positive diagnoses for phenotypic subcategories of CHD, ranging from 31.7% for septal defects to 60% for "other". Despite variation in the diagnostic yield at each site, our results support genetic testing in pediatric patients with syndromic and isolated cardiovascular issues and in all subtypes of CHD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

There is increasing evidence of the clinical utility of genetic and genomic testing (GT); however, factors influencing personal utility of GT, especially in diverse, multilingual populations, remain unclear. We explored these factors in a diverse cohort of parents/guardians (participants) whose children received clinical GT through the NYCKidSeq program. A total of 847 participants completed surveys at baseline, post-results disclosure, and 6 months (6m) post-results. The largest population groups were Hispanic/Latino(a) (48%), White/European American (24%), and Black/African American (16%). Personal utility was assessed using the Personal Utility (PrU) scale, adapted for pediatric populations and included on the surveys. Three PrU subscales were identified using factor analysis: practical, educational, and parental psychological utility. Overall personal utility summary score and the three subscales significantly decreased after receiving results and over time. Hispanic/Latino(a) participants identified greater overall personal utility than European American and African American participants at all time points (p < 0.001) as did participants whose children received positive/likely positive results compared with those with negative and uncertain results (post-results: p < 0.001 and p < 0.001; 6m post-results: p = 0.002 and p < 0.001, respectively). Post-results, higher subscale scores were associated with lower education levels (practical, parental psychological: p ≤ 0.02) and higher levels of trust in the healthcare system (practical, parental psychological: p ≤ 0.04). These findings help to understand the perspectives of diverse parents/guardians, which is critical to tailoring pre- and post-test counseling across a variety of populations and clinical settings., Competing Interests: Declaration of interests N.S.A.-H. is currently employed by 23andMe, was previously employed by Regeneron Pharmaceuticals, received personal fees from Genentech, Allelica, and 23andMe, received research funding from Akcea, and serves as a scientific advisory board member for Allelica. E.E.K. received personal fees from Illumina, 23andMe, Allelica, and Regeneron Pharmaceuticals, received research funding from Allelica, and serves as a scientific advisory board member for Encompass, Bio, Overtone, and Galateo Bio., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To examine associations between Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales and PedsQL Infant Scales with formal health care resource utilization (HCRU) and informal caregiver burden., Methods: We studied a pediatric cohort of 837 patients (median age: 8.4 years) with suspected genetic disorders enrolled January 2019 through July 2021 in the NYCKidSeq program for diagnostic sequencing. Using linked ~ nine-month longitudinal survey and physician claims data collected through May 2022, we modeled the association between baseline PedsQL scores and post-baseline HCRU (median follow-up: 21.1 months) and informal care. We also assessed the longitudinal change in PedsQL scores with physician services using linear mixed-effects models., Results: Lower PedsQL total and physical health scores were independently associated with increases in 18-month physician services, encounters, and weekly informal care. Comparing low vs. median total scores, increases were 10.6 services (95% CI: 1.0-24.6), 3.3 encounters (95% CI: 0.5-6.8), and $668 (95% CI: $350-965), respectively. For the psychosocial domain, higher scores were associated with decreased informal care. Based on adjusted linear mixed-effects modeling, every additional ten physician services was associated with diminished improvement in longitudinal PedsQL total score trajectories by 1.1 point (95% confidence interval: 0.6-1.6) on average. Similar trends were observed in the physical and psychosocial domains., Conclusion: PedsQL scores were independently associated with higher utilization of physician services and informal care. Moreover, longitudinal trajectories of PedsQL scores became less favorable with increased physician services. Adding PedsQL survey instruments to conventional measures for improved risk stratification should be evaluated in further research., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation., (© 2024. The Author(s).)

Background: Germline HRAS gain-of-function pathogenic variants cause Costello syndrome (CS). During early childhood, 50% of patients develop multifocal atrial tachycardia, a treatment-resistant tachyarrhythmia of unknown pathogenesis. This study investigated how overactive HRAS activity triggers arrhythmogenesis in atrial-like cardiomyocytes (ACMs) derived from human-induced pluripotent stem cells bearing CS-associated HRAS variants., Methods: HRAS Gly12 mutations were introduced into a human-induced pluripotent stem cells-ACM reporter line. Human-induced pluripotent stem cells were generated from patients with CS exhibiting tachyarrhythmia. Calcium transients and action potentials were assessed in induced pluripotent stem cell-derived ACMs. Automated patch clamping assessed funny currents. HCN inhibitors targeted pacemaker-like activity in mutant ACMs. Transcriptomic data were analyzed via differential gene expression and gene ontology. Immunoblotting evaluated protein expression associated with calcium handling and pacemaker-nodal expression., Results: ACMs harboring HRAS variants displayed higher beating rates compared with healthy controls. The hyperpolarization activated cyclic nucleotide gated potassium channel inhibitor ivabradine and the Na v 1.5 blocker flecainide significantly decreased beating rates in mutant ACMs, whereas voltage-gated calcium channel 1.2 blocker verapamil attenuated their irregularity. Electrophysiological assessment revealed an increased number of pacemaker-like cells with elevated funny current densities among mutant ACMs. Mutant ACMs demonstrated elevated gene expression (ie, ISL1 , TBX3 , TBX18 ) related to intracellular calcium homeostasis, heart rate, RAS signaling, and induction of pacemaker-nodal-like transcriptional programming. Immunoblotting confirmed increased protein levels for genes of interest and suppressed MAPK (mitogen-activated protein kinase) activity in mutant ACMs., Conclusions: CS-associated gain-of-function HRAS G12 mutations in induced pluripotent stem cells-derived ACMs trigger transcriptional changes associated with enhanced automaticity and arrhythmic activity consistent with multifocal atrial tachycardia. This is the first human-induced pluripotent stem cell model establishing the mechanistic basis for multifocal atrial tachycardia in CS., Competing Interests: Disclosures None.

Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Motivation: Structural variants (SVs) play a causal role in numerous diseases but can be difficult to detect and accurately genotype (determine zygosity) with short-read genome sequencing data (SRS). Improving SV genotyping accuracy in SRS data, particularly for the many SVs first detected with long-read sequencing, will improve our understanding of genetic variation., Results: NPSV-deep is a deep learning-based approach for genotyping previously reported insertion and deletion SVs that recasts this task as an image similarity problem. NPSV-deep predicts the SV genotype based on the similarity between pileup images generated from the actual SRS data and matching SRS simulations. We show that NPSV-deep consistently matches or improves upon the state-of-the-art for SV genotyping accuracy across different SV call sets, samples and variant types, including a 25% reduction in genotyping errors for the Genome-in-a-Bottle (GIAB) high-confidence SVs. NPSV-deep is not limited to the SVs as described; it improves deletion genotyping concordance a further 1.5 percentage points for GIAB SVs (92%) by automatically correcting imprecise/incorrectly described SVs., Availability and Implementation: Python/C++ source code and pre-trained models freely available at https://github.com/mlinderm/npsv2., (© The Author(s) 2024. Published by Oxford University Press.)

Rare coding mutations cause ∼45% of congenital heart disease (CHD). Noncoding mutations that perturb cis-regulatory elements (CREs) likely contribute to the remaining cases, but their identification has been problematic. Using a lentiviral massively parallel reporter assay (lentiMPRA) in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we functionally evaluated 6,590 noncoding de novo variants (ncDNVs) prioritized from the whole-genome sequencing of 750 CHD trios. A total of 403 ncDNVs substantially affected cardiac CRE activity. A majority increased enhancer activity, often at regions with undetectable reference sequence activity. Of ten DNVs tested by introduction into their native genomic context, four altered the expression of neighboring genes and iPSC-CM transcriptional state. To prioritize future DNVs for functional testing, we used the MPRA data to develop a regression model, EpiCard. Analysis of an independent CHD cohort by EpiCard found enrichment of DNVs. Together, we developed a scalable system to measure the effect of ncDNVs on CRE activity and deployed it to systematically assess the contribution of ncDNVs to CHD., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Persons with congenital heart disease (CHD) are at increased risk of neurodevelopmental disabilities, including impairments to executive function. Sulcal pattern features correlate with executive function in adolescents with single-ventricle heart disease and tetralogy of Fallot. However, the interaction of sulcal pattern features with genetic and participant factors in predicting executive dysfunction is unknown., Methods: We studied sulcal pattern features, participant factors, and genetic risk for executive function impairment in a cohort with multiple CHD types using stepwise linear regression and machine learning., Results: Genetic factors, including predicted damaging de novo or rare inherited variants in neurodevelopmental disabilities risk genes, apolipoprotein E genotype, and principal components of sulcal pattern features were associated with executive function measures after adjusting for age at testing, sex, mother's education, and biventricular versus single-ventricle CHD in a linear regression model. Using regression trees and bootstrap validation, younger participant age and larger alterations in sulcal pattern features were consistently identified as important predictors of decreased cognitive flexibility with left hemisphere graph topology often selected as the most important predictor. Inclusion of both sulcal pattern and genetic factors improved model fit compared to either alone., Interpretation: We conclude that sulcal measures remain important predictors of cognitive flexibility, and the model predicting executive outcomes is improved by inclusion of potential genetic sources of neurodevelopmental risk. If confirmed, measures of sulcal patterning may serve as early imaging biomarkers to identify those at heightened risk for future neurodevelopmental disabilities., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)