This is a free sample of content from Heart Development and Disease. Click here for more information on how to buy the book. Genetic Basis of Human Congenital Heart Disease Shannon N. Nees1 and Wendy K. Chung1,2 1Department of Pediatrics,2Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, USA Correspondence: [email protected] Congenital heart disease (CHD) is the most common major congenital anomaly with an incidence of ∼1% of live births and is a significant cause of birth defect–related mortality. The genetic mechanisms underlying the development of CHD are complex and remain incompletely understood. Known genetic causes include all classes of genetic variation in- cluding chromosomal aneuploidies, copy number variants, and rare and common single- nucleotide variants, which can be either de novo or inherited. Among patients with CHD, ∼8%–12% have a chromosomal abnormality or aneuploidy, between 3% and 25% have a copy number variation, and 3%–5% have a single-gene defect in an established CHD gene with higher likelihood of identifying a genetic cause in patients with nonisolated CHD. These genetic variants disrupt or alter genes that play an important role in normal cardiac develop- ment and in some cases have pleiotropic effects on other organs. This work reviews some of the most common genetic causes of CHD as well as what is currently known about the underlying mechanisms. ongenital heart disease (CHD) is the most are underdeveloped left-sided cardiac structures Ccommon major congenital anomaly with an and only a single functioning ventricle. The high incidence of ∼1% of live births (Hoffman and concordance in monozygotic twins, the in- Kaplan 2002; Calzolari et al. 2003). CHD is a creased risk of recurrence in first-degree relatives significant cause of birth defect–related mortal- compared with the general population, and ge- ity (Hanna et al. 1994; Lee et al. 2001; Hoffman netic syndromes associated with specific types of and Kaplan 2002; Calzolari et al. 2003; Centers CHD all suggest a genetic component to CHD in for Disease Control and Prevention (CDC) at least some cases (Nora et al. 1988). The genes 2007; van der Linde et al. 2011; Gilboa et al. and genetic mechanisms underlying CHD are 2016). CHD encompasses any malformation of complex and remain incompletely understood, the cardiovascular system present at birth, and but our understanding has improved signifi- there are many subtypes ranging from relatively cantly over the past decade. All classes of genetic simple lesions such as atrial and ventricular sep- variation including chromosomal aneuploidies, tal defects to complex lesions such as hypoplas- copy number variants (CNVs), and rare and tic left heart syndrome (HLHS) in which there common de novo and inherited single-nucleo- Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a036749 283 © 2020 by Cold Spring Harbor Laboratory Press. All rights reserved. This is a free sample of content from Heart Development and Disease. Click here for more information on how to buy the book. S.N. Nees and W.K. Chung tide variants (SNVs) contribute to CHD (Thien- The overall incidence of CHD is similar be- pont et al. 2007; Erdogan et al. 2008; Southard tween males and females; however, there are dif- et al. 2012; Gelb and Chung 2014). These genetic ferences by type of CHD with males having a variants disrupt or alter genes that play an im- slightly higher incidence of more severe lesions portant role in normal cardiac development. Al- (Sampayo and Pinto 1994; Moons et al. 2009). though many of the genes and mutations that There are also differences in incidence of specif- increase the risk of developing CHD have been ic lesions based on race and ethnicity. Patent identified, only ∼20%–30% of individuals with ductus arteriosus (PDA) and ventricular septal CHD have an identifiable single genetic factor, defects (VSDs) are more common in Europeans, and this yield varies significantly by cardiac le- whereas atrial septal defects (ASDs) are more sion and whether there are additional medical common in Hispanics (Fixler et al. 1990; Egbe features besides CHD (Grech and Gatt 1999; et al. 2014). The differences observed based on Gelb 2004; Cowan and Ware 2015; Patel et al. gender and race suggest that genetics play an 2016). This work reviews the most common ge- important role in the development of specific netic causes of CHD as well as the known genetic types of CHD, with certain populations having mechanisms. increased genetic susceptibility. The risk of CHD recurrence in the offspring of an affected parent is between 3% and 20% OVERVIEW OF CHD depending on the lesion. Recurrence risk in the CHD is the most common birth defect affecting offspring of women with CHD is about twice as ∼1% of live births, or up to 3% of live births in high as the recurrence in offspring of men with studies that include bicuspid aortic valve (BAV) CHD (Burn et al. 1998). A study from Northern (Hoffman and Kaplan 2002; Calzolari et al. Ireland found that the risk of recurrence of CHD 2003; Tutar et al. 2005; van der Linde et al. for siblings was 3.1%, and siblings had an in- 2011; Egbe et al. 2014). CHD encompasses a creased risk of extracardiac anomalies even in wide spectrum of defects, with varying physio- the absence of CHD (Hanna et al. 1994). Other logic consequences. More severe lesions that re- studies have shown similar risk of recurrence quire multiple surgeries have an incidence of among siblings; more severe types of CHD ∼0.1% of live births (Bernier et al. 2010). Despite have higher recurrence rates (Calcagni et al. significant advances in clinical care, CHD re- 2006; Øyen et al. 2009; Brodwall et al. 2017). mains the leading cause of birth defect–related Lesions with the highest recurrence risk are het- mortality (Boneva et al. 2001; Lee et al. 2001; erotaxy (HTX), right ventricular outflow tract Marelli et al. 2007; Gilboa et al. 2010; Khairy obstruction, and left ventricular outflow tract et al. 2010). Data from the Metropolitan Atlanta obstruction (Loffredo et al. 2004). Approximate- Congenital Heart Defects Program showed a 1- ly one-half of siblings with recurrent CHD have yr survival of 83% for patients with critical CHD a different lesion, supporting the theory that the (Oster et al. 2013). For those patients who sur- etiology of CHD is multifactorial (Oyen et al. vive through infancy, there are still significant 2010). Table 1 describes the estimated recur- lifelong morbidities (Oster et al. 2013; Agarwal rence risk for CHD by lesion and affected family et al. 2014). member. Overall, twins have an increased risk of CHD compared with singleton pregnancies, which is EVIDENCE FOR THE GENETIC BASIS OF CHD thought to be the result of vascular changes re- The etiology of CHD is multifactorial. A genetic lated to a shared placenta (Manning and Archer or environmental cause can be identified in 2006; Herskind et al. 2013; Best and Rankin ∼20%–30% of all cases, and that number is 2015). A population-based Taiwanese study cal- changing as new methods of testing become culated the adjusted risk ratio for CHD with an available (Grech and Gatt 1999; Gelb 2004; affected relative and found that it was 12.03 for a Cowan and Ware 2015; Patel et al. 2016). twin, 4.91 for a first-degree relative, and 1.21 for 284 Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a036749 © 2020 by Cold Spring Harbor Laboratory Press. All rights reserved. This is a free sample of content from Heart Development and Disease. Click here for more information on how to buy the book. Genetic Basis of Human CHD Table 1. Risk of recurrence for common isolated congenital heart disease Lesion Father affected (%) Mother affected (%) One sibling affected (%) Two siblings affected (%) ASD 1.5–3.5 4–6 2.5–38 AVSD 1–4.5 11.5–14 3–410 VSD 2–3.5 6–10 3 10 AS 3–48–18 2 6 PS 2–3.5 4–6.5 2 6 TOF 1.5 2–2.5 2.5–38 CoA 2–34–6.5 2 6 HLHS 21 21 2–96 D-TGA 2 2 1.5 5 Data adapted from Cowan and Ware (2015). See Nora et al. (1988); Nora (1994); Calcagni et al. (2006); Hinton et al. (2007). (AS) Aortic stenosis, (ASD) atrial septal defect, (AVSD) atrioventricular septal defect, (CoA) coarctation of the aorta, (D-TGA) d-loop transposition of the great arteries, (HLHS) hypoplastic left heart syndrome, (PS) pulmonary stenosis, (TOF) tetralogy of Fallot, (VSD) ventricular septal defect. a second-degree relative. They determined that villus sampling (CVS) at 10–11 wk gestation or the phenotypic variance of CHD was 37.3% for amniocentesis after 15–16 wk gestation to ob- familial transmission and 62.8% for non–shared tain placental/fetal DNA. More recently, nonin- environmental factors (Kuo et al. 2018). In a vasive prenatal testing (NIPT) has been used to large Norwegian birth cohort study, the adjusted obtain fetal cell-free DNA from maternal blood relative risk ratio of CHD for siblings of a child to screen for aneuploidies and common dele- with CHD was 14.0 for same-sex twins, 11.9 for tions or duplications, most notably 22q11.2 de- opposite-sex twins, 3.6 for full siblings, and 1.5 letion syndrome (Wapner et al. 2015; Grace et al. for half siblings (Brodwall et al. 2017). These 2016; Dugoff et al. 2017; Gil et al. 2017).