Open Access

ARTICLE

Factors Affecting the Genetic Diagnostic Rate in Congenital Heart Disease

Jun Sung Park¹, Go Hun Seo², Yunha Choi¹, Soojin Hwang¹, Minji Kang³, Hyo-Sang Do³, Young-Hwue Kim⁴, Jeong Jin Yu⁴, Ellen Ai-Rhan Kim⁵, Euiseok Jung⁵, Byong Sop Lee⁵, Jae Suk Baek⁴, Beom Hee Lee^1,6,*

1 Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
2 3 Billion, Inc., Seoul, Korea
3 Genome Research Center for Birth Defects and Genetic Diseases, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea
4 Division of Cardiology, Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
5 Division of Neonatology, Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
6 Medical Genetics Center, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea

* Corresponding Author: Beom Hee Lee. Email:

Congenital Heart Disease 2022, 17(6), 653-673. https://doi.org/10.32604/chd.2022.021580

Received 24 February 2022; Accepted 20 June 2022; Issue published 11 October 2022

Abstract

Background: Over 400 genes contribute to the development of congenital heart disease (CHD). Additionally, multisystemic manifestations accompanying syndromic CHD pose a higher risk of genetic diseases. This study investigated the diagnostic yield of whole-exome sequencing (WES) in patients with sporadic syndromic CHD and the phenotypic factors affecting the genetic diagnostic rate. Methods: Sixty-four patients with sporadic syndromic CHD aged <18 years underwent WES between May 2018 and December 2020 in a single tertiary center, and the association between genetic testing data and extracardiac phenotypes was analyzed. Results: Extracardiac phenotypes were measured as 3.66 ± 3.05 (standard deviation, interquartile range: 2–5) items per patient. WES detected diagnostic variants in 19 (29.7%) patients: seven (36.8%), seven (36.8%), and five (26.3%) with pathogenic variants, likely pathogenic variants, and variants of unknown significance, respectively. Post-diagnosis surveillance identified the extracardiac phenotype in 54.5% (6/11) of patients. De novo variants accounted for 76.2% (15/19) of variants and autosomal dominant inheritance for 94.7% (18/19). Most diseases were ultra-rare. No significant differences were noted in cardiac and extracardiac phenotypes, single or combined (all P > 0.05), between the groups with and without a diagnostic variant. However, patients with ≥3 extracardiac phenotypes had a significantly higher likelihood of having a diagnostic variant than those with ≤2 (38.3% vs. 5.9%, odds ratio = 9.93, 95% confidence interval = 1.21–81.44, P = 0.013). Conclusions: The number of extracardiac phenotypes is important in predicting the possibility of genetic diagnosis. Physicians will be able to select patients with a high probability of genetic diagnosis and provide appropriate genetic counseling based on the results of this study.

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