Diagnostic yield after next-generation sequencing in pediatric cardiovascular disease

Anne M Slavotinek; Michelle L Thompson; Lisa J Martin; Bruce D Gelb

doi:10.1016/j.xhgg.2024.100286

Diagnostic yield after next-generation sequencing in pediatric cardiovascular disease

HGG Adv. 2024 Mar 23;5(3):100286. doi: 10.1016/j.xhgg.2024.100286. Online ahead of print.

Authors

Anne M Slavotinek¹, Michelle L Thompson², Lisa J Martin³, Bruce D Gelb⁴

Affiliations

¹ Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA; Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, OH, USA; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA. Electronic address: anne.slavotinek@cchmc.org.
² HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA; Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
³ Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, OH, USA; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
⁴ Mindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Abstract

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.

Keywords: arrhythmia; cardiomyopathy; congenital heart disease; diagnostic yield after next-generation sequencing; heart defects.

Abstract

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