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From Stem Cells to Populations—Using hiPSC, Next-Generation Sequencing, and GWAS to Explore the Genetic and Molecular Mechanisms of Congenital Heart Defects
Review

Molecular Genetics and Complex Inheritance of Congenital Heart Disease

1
Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA
2
Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065, USA
3
Department of Genetics, School of Medicine, Washington University, St. Louis, MO 63110, USA
4
Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA
5
Department of Computer Science & Engineering, Washington University, St. Louis, MO 63130, USA
6
Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510, USA
7
Department of Pediatrics, Yale School of Medicine, New Haven, CT 06510, USA
8
Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA
9
Department of Pediatrics, School of Medicine, Washington University, St. Louis, MO 63110, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally.
Academic Editor: Cecilia Lo
Genes 2021, 12(7), 1020; https://doi.org/10.3390/genes12071020
Received: 17 May 2021 / Revised: 23 June 2021 / Accepted: 25 June 2021 / Published: 30 June 2021
(This article belongs to the Special Issue Genetics and Epigenetics of Human Congenital Heart Disease)
Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy account for ~23% of cases overall, and high-throughput genomic technologies have revealed additional types of genetic variation in CHD. The first CHD risk genotypes identified through high-throughput sequencing were de novo mutations, many of which occur in chromatin modifying genes. Murine models of cardiogenesis further support the damaging nature of chromatin modifying CHD mutations. Transmitted mutations have also been identified through sequencing of population scale CHD cohorts, and many transmitted mutations are enriched in cilia genes and Notch or VEGF pathway genes. While we have come a long way in identifying the causes of CHD, more work is required to end the diagnostic odyssey for all CHD families. Complex genetic explanations of CHD are emerging but will require increasingly sophisticated analysis strategies applied to very large CHD cohorts before they can come to fruition in providing molecular diagnoses to genetically unsolved patients. In this review, we discuss the genetic architecture of CHD and biological pathways involved in its pathogenesis. View Full-Text
Keywords: congenital heart disease; genetics; genomics; complex inheritance; histone marks; next-generation sequencing; genomic medicine; precision medicine; rare disease congenital heart disease; genetics; genomics; complex inheritance; histone marks; next-generation sequencing; genomic medicine; precision medicine; rare disease
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MDPI and ACS Style

Diab, N.S.; Barish, S.; Dong, W.; Zhao, S.; Allington, G.; Yu, X.; Kahle, K.T.; Brueckner, M.; Jin, S.C. Molecular Genetics and Complex Inheritance of Congenital Heart Disease. Genes 2021, 12, 1020. https://doi.org/10.3390/genes12071020

AMA Style

Diab NS, Barish S, Dong W, Zhao S, Allington G, Yu X, Kahle KT, Brueckner M, Jin SC. Molecular Genetics and Complex Inheritance of Congenital Heart Disease. Genes. 2021; 12(7):1020. https://doi.org/10.3390/genes12071020

Chicago/Turabian Style

Diab, Nicholas S., Syndi Barish, Weilai Dong, Shujuan Zhao, Garrett Allington, Xiaobing Yu, Kristopher T. Kahle, Martina Brueckner, and Sheng C. Jin 2021. "Molecular Genetics and Complex Inheritance of Congenital Heart Disease" Genes 12, no. 7: 1020. https://doi.org/10.3390/genes12071020

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