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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 Lee1,6,*

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: email

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

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.

Graphical Abstract

Factors Affecting the Genetic Diagnostic Rate in Congenital Heart Disease

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Cite This Article

Park, J. S., Seo, G. H., Choi, Y., Hwang, S., Kang, M. et al. (2022). Factors Affecting the Genetic Diagnostic Rate in Congenital Heart Disease. Congenital Heart Disease, 17(6), 653–673.



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