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. Author manuscript; available in PMC: 2021 Jun 17.
Published in final edited form as: Am J Med Genet C Semin Med Genet. 2019 Dec 26;184(1):97–106. doi: 10.1002/ajmg.c.31763

The Genetics of Isolated Congenital Heart Disease

Shannon N Nees 1, Wendy K Chung 1,2
PMCID: PMC8211463  NIHMSID: NIHMS1710298  PMID: 31876989

Abstract

The genetic mechanisms underlying congenital heart disease (CHD) are complex and remain incompletely understood. The majority of patients with CHD have an isolated heart defect without other organ system involvement, but the genetic basis of isolated CHD has been even more difficult to elucidate compared to syndromic CHD. Our understanding of the genetics of isolated CHD is advancing in large part due to advances in next generation sequencing, and the list of genes associated with CHD is rapidly expanding. Variants in hundreds of genes have been identified that may cause or contribute to CHD, but a genetic cause can still only be identified in about 20–30% of patients. Identifying a genetic cause for CHD can have an impact on clinical outcomes and prognosis and thus it is important for clinicians to understand when and what to test in patients with isolated CHD. This chapter reviews some of the known genetic mechanisms that contribute to isolated inherited and sporadic CHD as well as recommendations for evaluation and genetic testing in patients with isolated CHD.

Keywords: Congenital Heart Disease, Genetics

Introduction

The genetic mechanisms underlying congenital heart disease (CHD) are complex and remain incompletely understood, but our understanding has improved significantly over the past decade. All classes of genetic variation including chromosomal aneuploidies, copy number variants (CNVs), and rare and common de novo and inherited single nucleotide variants contribute to CHD[Thienpont et al., 2007; Southard et al., 2012; Erdogan et al., 2008; Gelb and Chung, 2014]. These genetic variants disrupt or alter genes that play an important role in normal cardiac development. Although many of the genes and mutations that increase the risk of developing CHD have been identified, only ~20–30% of individuals with CHD have an identifiable single genetic factor, and this yield is even lower for patients with isolated or non-syndromic CHD [Grech and Gatt, 1999; Gelb, 2004; Cowan and Ware, 2015; Patel et al., 2016].

The majority of patients with CHD have an isolated heart defect without evidence of other affected organ systems[Garg, 2006]. However, the genetic basis of isolated or non-syndromic CHD has been difficult to determine due to genetic heterogeneity, incomplete penetrance, polygenics and other non-genetic contributions. As sequencing technology has improved, next generation sequencing (NGS) has been used to help elucidate the genetic mechanisms underlying the development of isolated CHD, and there have been hundreds of genes identified that may cause or contribute to the pathogenesis of CHD. As NGS technologies improve and become more cost effective, even more genetic variants are likely to be identified.

Many genes that play an important role in syndromic forms of CHD can also be implicated in cases of isolated CHD. For example, specific variants in PTPN11 cause Noonan syndrome and associated forms of CHD. However, other variants in PTPN11 have been identified in rare cases of isolated CHD[Weismann et al., 2005]. TBX5 is a transcription factor that is associated with Holt-Oram syndrome, a syndrome with both cardiac and limb anomalies. One study demonstrated that a homozygous non-coding variant in an enhancer of TBX5 led to CHD without the limb defects[Smemo et al., 2012]. Thus, our understanding of the genetic basis of syndromic CHD has allowed the identification of some of the genetic causes of isolated CHD.

Determining the genetic factors underlying isolated CHD can have important clinical implications. Patients with isolated CHD and a large CNV containing multiple genes have worse post-operative outcomes compared to similar patients without a large CNV. Genes that predispose to isolated CHD such as NKX2.5 can be associated with complete heart block or other rhythm disturbances and have a significant impact on prognosis [Ellesøe et al., 2016; Perera et al., 2014]. Thus, it is important to understand the most common genetic causes of isolated CHD and the clinical significance of these findings.

This chapter reviews some of the known genetic mechanisms that contribute to isolated inherited and sporadic CHD as well as recommendations for evaluation and genetic testing in patients with isolated CHD.

Evidence for a genetic basis for CHD

The etiology of CHD is multifactorial. A genetic cause can be identified in about 20–30% of all cases, and that number is increasing as new methods of genetic assessment become available[Grech and Gatt, 1999; Gelb, 2004; Cowan and Ware, 2015; Patel et al., 2016]. Several observations support a genetic basis for CHD even in isolated cases. The overall incidence of CHD is similar between males and females; however, there are differences by type of CHD with males having a slightly higher incidence of more severe lesions [Moons et al., 2009; Sampayo and Pinto, 1994]. There are also differences in the incidence of specific lesions based on ancestry and ethnicity. Patent ductus arteriosus and ventricular septal defects (VSDs) are more common in Europeans while atrial septal defects (ASDs) are more common in Latinas [Egbe et al., 2014; Fixler et al., 1990]. The differences observed based on sex and ancestry suggest that genetics play an important role in the development of specific types of CHD, with certain populations having increased genetic susceptibility.

Families containing multiple members with similar types of CHD led to early studies on the genetics of CHD using linkage analysis. The risk of CHD recurrence in the offspring of an affected parent is between 3 and 20% depending on the lesion. Lesions with the highest recurrence risk are heterotaxy (HTX), right ventricular outflow tract obstruction and left ventricular outflow tract obstruction[Loffredo et al., 2004]. Recurrence in families suggests a genetic basis even for isolated cases of CHD. Approximately half of siblings with recurrent CHD have a different lesion, supporting the theory that the etiology of CHD is multifactorial[Oyen et al., 2010]. There are known environmental factors, such as maternal diabetes, rubella, maternal phenylketonuria, and certain medications such as thalidomide and indomethacin that are thought to account for 2% of isolated CHD cases[Kuciene and Dulskiene, 2008]. For many cases of isolated CHD, there is no identifiable genetic or environmental cause.

Monogenic causes of isolated CHD

De novo sequence variants in single genes have been identified using exome sequencing (ES) in patients with CHD, both in syndromic and non-syndromic cases and in inherited and sporadic cases. Patients with CHD have an excess burden of de novo protein altering variants in genes that are expressed during cardiac development compared to controls[Zaidi et al., 2013]. A European study using ES in 1,891 patients found that in patients with non-isolated CHD, there were an increased number of de novo protein truncating variants and deleterious missense variants in known autosomal dominant CHD-associated genes as well as in non-CHD genes associated with neurodevelopmental disorders. In isolated CHD patients, there was a much lower frequency of de novo deleterious variants, but there was an increase in rare, inherited protein truncating variants in CHD-associated genes, likely representing mutations that cause isolated CHD but are incompletely penetrant[Sifrim et al., 2016]. This suggests that some of the genetic mechanisms contributing to isolated CHD are distinct from those causing syndromic CHD.

If there is family history of a syndrome that involves CHD, testing for single gene defects can be targeted based on family member test results or clinical suspicion. In patients with a strong suspicion for a genetic cause of CHD, ES can be used effectively to identify single gene defects.

Variants in an increasing number of genes have been identified in individuals with isolated CHD, initially through studies of familial CHD and later through the use of genomic sequencing approaches. Among the genes that have been identified, most fall into one of the following functional categories and play an important role in normal cardiac development: transcription factors, signaling molecules and structural proteins[Fahed et al., 2013]. Select examples in each of these functional categories are described below. Table 1 contains additional genes associated with isolated CHD that have sufficient evidence supporting this association. The list of genes associated with isolated CHD is rapidly expanding and is still incomplete. In addition to these categories, abnormal levels of folic acid and homocysteine have been detected in infants with CHD, and mutations in genes responsible for regulating these metabolites may also contribute to isolated CHD. One study recently demonstrated that a functional variant in the cystathionine β-synthase gene promoter which is involved in homocysteine metabolism significantly reduces congenital heart disease susceptibility in a Han Chinese population, suggesting that homocysteine plays a role in the development of CHD[Zhao et al., 2013]. Further studies are needed to determine if other genes in the homocysteine metabolic pathway contribute to CHD.

Table 1.

Selected Monogenic Causes of Isolated Congenital Heart Disease

Gene Loci Mode of Inheritance Cardiac Disease References
ACTC1 15q14 AD ASD, HCM, DCM, LVNC [Matsson et al., 2008]
CITED2 6q24.1 AD ASD, VSD [Sperling et al., 2005]
CRELD1 3p25.3 AD ASD, AVSD [Guo et al., 2010]
GATA4 8p23.1 AD ASD, VSD, AVSD, PS, TOF [Zhang et al., 2017]
GATA5 20q13.33 AD/AR ASD, BAV, TOF, VSD, DORV [Shan et al., 2014; Jiang et al., 2013]
GATA6 18q11.2 AD TA, TOF [Kodo et al., 2009; Xu et al., 2018; Zhang et al., 2018]
HAND1 5q33.2 AD SV, VSD [Reamon-Buettner et al., 2008, 2009]
HAND2 4q34.1 AD PS, TOF, VSD [Sun et al., 2016; Shen et al., 2010; Töpf et al., 2014]
MEIS2 15q14 AD ASD, VSD, CoA [Verheije et al., 2019]
MYBPC3 11p11.2 AD ASD, PDA, VSD, MR [Wessels et al., 2015; Wells et al., 2011]
MYH6 14q11.2 AD, AR ASD, HCM, DCM, HLHS [Jin et al., 2017; Theis et al., 2015]
MYH7 14q11.2 AD for CM EA, LVNC, HCM, DCM [Hanchard et al., 2016; Postma et al., 2011]
NODAL 10q22.1 AD D-TGA, DORV, TOF, VSD [Mohapatra et al., 2009; Roessler et al., 2008]
NOTCH1 9q34.3 AD ASD, VSD, CoA, HLHS, DORV [Garg et al., 2005; Kerstjens-Frederikse et al., 2016]
NKX2–5 5q35.1 AD ASD, TOF, HLHS [Stallmeyer et al., 2010; Schott et al., 1998; Benson et al., 1999]
NR2F2 15q26.2 AD AVSD, AS, CoA, VSD, HLHS, TOF, DORV [Al Turki et al., 2014; Qiao et al., 2018; Bashamboo et al., 2018]
SMAD2 18q21.1 AD HTX, DORV, ASD, VSD, PDA [Zaidi et al., 2013; Granadillo et al., 2018]
SMAD6 15q22.31 AD BAV, CoA, AS [Gillis et al., 2017]
TAB2 6q25.1 AD BAV, AS, TOF [Thienpont et al., 2010]
TBX1 22q11.2 AD Conotruncal defects, VSD, IAA, ASD [Yagi et al., 2003]
TBX5 12q24.1 AD VSD, ASD, AVSD, conduction defects [Basson et al., 1999]
TBX20 7p14.2 Unknown ASD, VSD, MS, DCM [Kirk et al., 2007]
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Genes in this table are associated with congenital heart disease based on criteria established by Clinical Genome Resource[The Clinical Genome Resource Gene Curation Working Group, 2018]. AS: aortic stenosis; ASD: atrial septal defect; AVSD: atrioventricular septal defect; BAV: bicuspid aortic valve; CoA: coarctation of the aorta; DCM: dilated cardiomyopathy; DORV: double outlet right ventricle; D-TGA: d-loop transposition of the great arteries; EA: Ebstein’s anomaly of the tricuspid valve; HCM: hypertrophic cardiomyopathy; HLHS: hypoplastic left heart syndrome; HTX: heterotaxy syndrome; IAA: interrupted aortic arch; LVNC: left ventricular non-compaction; MR: mitral regurgitation; PDA: patent ductus arteriosus; PS: pulmonary stenosis; SV: single ventricle; TA: truncus arteriosus; TOF: tetralogy of Fallot; VSD: ventricular septal defect.

Transcription factors

There is a set of highly conserved transcription factors that are critical for cardiac development[Olson, 2006; Kodo et al., 2012]. Mutations in the homeobox transcription factor NKX2–5 have been reported in both familial and sporadic cases of CHD associated with cardiac conduction defects [Schott et al., 1998]. Genome-wide linkage analysis demonstrated linkage to 5q35 which included NKX2.5, a gene that had already been implicated in cardiac morphogenesis in other species[Lyons et al., 1995]. The most common phenotype in individuals with NKX2–5 mutations is ASD with conduction delay[Stallmeyer et al., 2010; Benson et al., 1999]. Identification of NKX2–5 mutations in individuals with these cardiac findings is clinically relevant because they are at increased risk of progressive conduction disease and sudden cardiac death, and the genetic information is considered in decisions regarding pacemakers and implantable cardiac defibrillators[Ellesøe et al., 2016; Perera et al., 2014]. NKX2.5 mutations explain about 1–4% of sporadic, isolated ASD and up to 12.5% of familial cases[Yuichi et al., 2002].

Other transcription factors that have been associated with structural heart disease in both human and mouse models include members of the GATA family [Wei et al., 2013; Kodo et al., 2009; Rajagopal et al., 2007; Qian et al., 2017; Garg et al., 2003] and members of the Tbox family which have been implicated in both syndromic and isolated forms of CHD[Griffin et al., 2010; Kirk et al., 2007; Huang et al., 2017; Smemo et al., 2012]. GATA4 encodes a zinc finger transcription factor with activity modulated by its interaction with other proteins such as those in the NKX2 family. Missense and frameshift mutations throughout the GATA4 gene have been identified in secundum ASD without conduction defects and are also frequently associated with VSD and pulmonary stenosis among other outflow tract lesions [Rajagopal et al., 2007; Yang et al., 2012; Xiang et al., 2014; Garg et al., 2003].

Recent work has identified SOX17 as a contributor to CHD associated with pulmonary hypertension as well as isolated and familial pulmonary hypertension[Zhu et al., 2018]. SOX17 is a transcriptional target of GATA4, and it inhibits signaling in the WNT/B-catenin pathway involved in cardiac development[Holtzinger et al., 2010; Zorn et al., 1999].

Cell signaling and adhesion models

Many signaling pathways are involved in cardiac development, and genes in these pathways are frequently disrupted in patients with CHD. Notch signaling is important for cellular differentiation and is involved in the pathogenesis of both isolated and syndromic CHD [Stittrich et al., 2014; McDaniell et al., 2006; Li et al., 1997; Kamath et al., 2012; Meester et al., 2019]. Mutations in NOTCH1 have been identified in autosomal dominantly inherited CHD consisting primarily of bicuspid aortic valve and are associated with abnormalities of the outflow tracts and semilunar valves [Kerstjens-Frederikse et al., 2016; Preuss et al., 2016; Garg et al., 2005]. Mutations in NOTCH1 in patients with isolated tetralogy of Fallot (TOF) were noted to be the most frequent site of genetic variants accounting for 4.5% of patients in one study[Page et al., 2019].

Another cell signaling family that is crucial for cardiac development is the TGF-β cytokine superfamily. Several genes in this family are implicated in heart development including BMP-2, BMP-4, TGF- β 2 and TGF- β 3[Armstrong and Bischoff, 2004; Nakajima et al., 2000]. The TGF-β superfamily also includes Nodal, a secreted signaling ligand that has been implicated in laterality defects including HTX as well as isolated CHD[Mohapatra et al., 2009; Roessler et al., 2008]. Isolated CHD lesions associated with NODAL mutations include D-transposition of the great arteries (D-TGA), double outlet right ventricle, TOF and isolated VSDs. Over-expression of TGF- β1 seems to play a role in the development of pulmonary hypertension in patients with CHD, suggesting that alterations in this pathway may have pleotropic effects on the heart as well as the pulmonary vasculature[Yuan, 2018; Gao et al., 2005].

Structural proteins

Mutations in structural cardiac proteins also contribute to CHD in some patients. Mutations in cardiac sarcomere proteins are associated with cardiomyopathies, and recently have been reported in some types of CHD. MYH6 encodes myosin heavy chain 6 and dominant mutations have been associated with ASDs in addition to dilated cardiomyopathy[Posch et al., 2011; Granados-Riveron et al., 2010]. Recently, recessive MYH6 missense mutations were identified in two patients with hypoplastic left heart syndrome and decreased ventricular function, suggesting a role in the development of the normal ventricular myocardium[Theis et al., 2015]. Mutations in MYH7, another sarcomeric protein, have been associated with Ebstein’s anomaly of the tricuspid valve and left ventricular non-compaction[Postma et al., 2011]. ACTC1 encodes a cardiac actin and mutations have been identified in familial cases of ASDs [Matsson et al., 2008].

Histone modifiers

ES has identified several monogenic causes of isolated and non-isolated CHD. Zaidi et al used ES in 362 severe cases of CHD and demonstrated an excess of likely damaging de novo variants in genes expressed during cardiac development. This study demonstrated significant enrichment of genes involved in the modification of histone 3 lysine 4 (H34K)[Zaidi et al., 2013; Homsy et al., 2015; Jin et al., 2017]. Methylated H34K is an important regulator of developmental genes. Other genes in this pathway including MLL2, KDM6A and CHD7 have been previously associated with CHD[Lederer et al., 2012; Vissers et al., 2004]. Histone modifications are important regulators of gene expression. These data suggest that the H34K pathway is important for appropriate gene regulation during cardiac development and that other epigenetic mechanisms may play a role in the pathogenesis of CHD. In addition, this demonstrates the utility of using ES to identify new genes and mechanisms in cases of CHD of unknown etiology.

Heterotaxy and ciliopathies

The heart is an asymmetric organ, and left-right patterning is critical for normal cardiac development. Disorders of left-right patterning include HTX, in which there is abnormal sidedness of multiple organs and situs inversus totalis (SIT) in which the organs are in a mirror-image pattern. Data from the National Birth Defects Prevention study demonstrated that among patients with laterality defects, 68% had complex CHD and another 9% has simple CHD. Those with HTX were much more likely to have complex CHD compared to those with SIT[Lin et al., 2014]. The association between CHD and laterality defects suggests a common developmental mechanism, perhaps due to defects in cilia as the primary cause of these abnormalities.

Cilia are organelles that have a crucial role in cellular signaling during in development, particularly in the proper formation of the left-right axis in the developing embryo[Yoshiba and Hamada, 2014]. Abnormal ciliary structure or function is associated with syndromic ciliopathies which include primary ciliary dyskinesia (PCD) and HTX, both of which are associated with CHD[Sutherland and Ware, 2009]. However, there is evidence that mutations in cilia genes are also involved in isolated CHD, especially atrioventricular septal defects and D-TGA[Versacci et al., 2018]. In patients with CHD but no HTX, there is a high incidence of ciliary motion defects, up to 51% in one study[Garrod et al., 2014].

GDF1 and founder Ashkenazi mutation

Given the heterogeneity of CHD, there are likely to be genes involved in the pathogenesis of CHD in specific populations. One such gene is GDF1, which is associated with CHD in the Ashkenazi Jewish population. A study screening 375 unrelated patients identified loss-of-function mutations in GDF1 among cases with various types of CHD including conotruncal defects and atrioventricular canal defects. These were heterozygous mutations, and they hypothesized that GDF1 represented a susceptibility gene[Karkera et al., 2007]. Linkage analysis in a family with right atrial isomerism led to the identification of compound heterozygous recessively inherited truncating mutations in GDF1 [Kaasinen et al., 2010]. A large study using ES data for 2,871 CHD cases demonstrated an increase in homozygous mutations in GDF1 among cases with evidence of Ashkenazi Jewish ancestry based on PCA analysis. One specific mutation, c.1091T>C (encoding p.Met364Thr), accounted for ~5% of severe CHD cases among those with Ashkenazi descent[Jin et al., 2017]. Although the overall contribution to CHD is likely low, GDF1 is an important contributor in this specific population and could be included in routine preconception carrier screening[Sun et al., 2013].

Common variants and CHD

Given that the majority of CHD cases do not yet have a known genetic cause, several authors have hypothesized that common variants may play a role in the risk of CHD. Genome wide association studies (GWAS) have been used to identify common variants associated with specific types of CHD. A large study of patients with CHD found a region on chromosome 4p16 that was associated with risk of ASD, and genotype at this locus accounted for ~9% of the population-attributable risk [Cordell et al., 2013a]. A GWAS in the Han Chinese population identified two loci, 1p12 and 4q13.1 associated with CHD. Another study in the Han Chinese using a compound heterozygous model identified four additional loci that explained 7.8% of the CHD variance in the population, suggesting that multiple modes of inheritance are contributing[Jiang et al., 2018]. Several studies have examined specific groups of CHD including left-sided lesions and TOF and have identified susceptibility loci that account for a small proportion of the genetic variation in each case[Hanchard et al., 2016; Mitchell et al., 2015; Cordell et al., 2013b]. Although common variants likely have a role in CHD susceptibility, these account for only a small proportion of the genetic risk, and large studies of individuals with similar CHD lesions are needed to identify additional susceptibility loci.

Copy Number Variation

CNVs consist of deletions or duplications of contiguous regions of DNA that affect about 12% of the genome and can impact either a single gene or multiple contiguous genes[Redon et al., 2006]. Pathogenic CNVs tend to be de novo, large, and disrupt coding portions of genes that are dosage sensitive. These are found more frequently in patients with CHD compared to controls. There is wide variation in the reported prevalence of CNVs between 3 and 25% depending on the method of detection and the cohort characteristics. CNVs are observed more frequently in patients with CHD and extra-cardiac features compared to those with isolated CHD for which the prevalence is reported to be between 3 and 17%[Southard et al., 2012; Zhu et al., 2016; Soemedi et al., 2012; Goldmuntz et al., 2011; Wu et al., 2017].

Although CNVs tend to be associated with syndromic forms of CHD, they can be found in isolated CHD as well. In one study of patients with isolated, sporadic TOF, several rare, recurrent, de novo CNVs were identified. These regions contain genes known to be involved in cardiac development including TBX1, JAG1 and NOTCH1. Based on these data, the authors predicted that at least 10% of sporadic, non-syndromic cases of TOF could be due to CNVs in these regions suggesting that CNVs play an important role in the development of some types of isolated CHD[Greenway et al., 2009].

Recent data have demonstrated that CNVs are not only causative of CHD, but they also impact clinical outcomes. In 2013, Carey et. al compared neurocognitive and growth outcomes in patients with single ventricle physiology and found that patients with pathogenic CNVs had decreased linear growth [Carey et al., 2013]. Kim et. al examined CNVs in 422 cases of isolated CHD and found that the presence of a likely pathogenic CNV was associated with a significantly lower transplant-free survival after surgery[Kim et al., 2016]. The increased risk of morbidity in patients with large CNVs may be due to additional genes that are impacted or due to pleiotropic effects of single genes within the region.

Mosaicism and CHD

Mosaicism refers to the presence of two or more genetically distinct cell lineages within an individual. Mosaicism is thought to contribute to many dominant genetic diseases[Taylor et al., 2014; Youssoufian and Pyeritz, 2002]. Advances in next generation sequencing have allowed for increased sensitivity to detect mosaic variants and additional studies are necessary to fully assess mosaicism as a contributor to CHD. Cytogenetic studies have demonstrated that individuals with mosaic trisomies can have CHD without associated syndromic features [Fiot et al., 2019; Yokoyama et al., 1992]. The Leipzig heart collection was used to study mosaicism in cardiac tissue from patients with CHD. Several studies from that group demonstrated increased frequency of mutations in cardiac transcription factors including NKX2-5, GATA4, TBX5, MEF2C and HEY2 in cardiac tissue sampled from the area of the heart defect compared to unaffected cardiac tissue from the same patient, suggesting that mosaicism plays a role in isolated CHD [Reamon-Buettner and Borlak, 2006; Reamon-Buettner et al., 2004; Reamon-Buettner and Borlak, 2004; Reamon-Buettner et al., 2006]. Manheimer et al recently described a method to identify mosaic variants from whole exome sequencing in individuals with CHD. Overall, mosaic mutations were not significantly enriched in the patients with CHD, so they concluded that somatic mosaic mutations likely account for only a small proportion of CHD[Manheimer et al., 2018]. However, mosaic mutations isolated to the cardiac tissue are difficult to assess without cardiac tissue, so our estimates of the frequency of mosaicism in isolated CHD may be underestimates.

Recommendations for clinical genetic testing

Recommendations for clinical genetic testing in CHD are evolving and although it is recommended that patients with CHD and extra-cardiac manifestations routinely undergo genetic testing, recommendations for patients with isolated CHD are still evolving. Genetic evaluation should include assessment by a clinical geneticist to thoroughly assess for dysmorphic features and other syndromic characteristics. If there is a family history of congenital anomalies or multiple miscarriages, genetic testing should be offered[Pierpont et al., 2007, 2018]. In neonates and young infants, it can be difficult to appreciate dysmorphic features, cognitive delays and extracardiac anomalies. Testing should be considered for these patients if they have a type of CHD that is frequently associated with genetic syndromes including TOF, IAA, truncus arteriosus and left-sided obstructive lesions, even in the absence of other features[Ito et al., 2017]. For fetuses diagnosed with CHD, there is a higher chance of identifying genetic abnormalities. One study using prenatal chromosome microarray (CMA) in fetuses with CHD found that 20.8% of fetuses with CHD had a pathogenic chromosomal abnormality and among those with isolated CHD, there was a 14.3% diagnostic yield[Wang et al., 2018]. For this reason, genetic testing and counseling should be offered in all cases of prenatally diagnosed CHD since a positive test may help identify additional anomalies and affect pregnancy management, delivery, and neonatal care[Donofrio et al., 2014; Bensemlali et al., 2016; Lazier et al., 2016].

CMA is used to detect CNVs across the genome and can reliably detect deletions or duplications as small as 100,000 nucleotides. CMA is the appropriate first-line test for most individuals and has been shown to be cost-effective[Geddes et al., 2017; Manning and Hudgins, 2010]. In cases when rapid results will have a clinical benefit, fluorescence in situ hybridization for aneuploidy or 22q11.2 deletion can be considered. The limitation of CMA is that balanced chromosomal rearrangements cannot be detected and if this is suspected, karyotype is needed. If CMA is negative and a genetic cause of CHD is strongly suspected, ES can be considered and should include pre- and post-test counseling due the difficulty in interpreting some variants as well as the potential for secondary findings [Zahavich et al., 2017]. As sequencing becomes less expensive and we develop a better understanding of the genetics of isolated CHD and the clinical implications of testing, it is likely that testing will be recommended for an expanded group of patients. The diagnostic yield of whole genome sequencing in patients with isolated CHD is not yet known and there may be non-coding variants that contribute to CHD. In the future studies may demonstrate increasing diagnostic yield of whole genome sequencing over exome sequencing.

Concluding remarks

Our understanding of the genetics of isolated CHD is advancing in large part due to advances in NGS, and the list of genes associated with CHD is rapidly expanding. Variants in genes previously thought to be associated with syndromic forms of CHD have been found in cases of isolated CHD too. However, all of the known genes still only account for a small portion of isolated CHD cases. A given genetic variant can cause different types of CHD in different patients due to genetic and other modifiers. In addition, for each type of CHD, there is a long list of possible genetic causes. A more complete understanding of the complex genetics of CHD will require continued large, collaborative efforts and further work is needed to understand how genetic variants helps predict clinical outcomes.

Acknowledgements

Shannon Nees received salary support through a Ruth L. Kirschstein National Research Service Award of the NIH under award number 5T32HL007854–22. Wendy Chung received support under U01 HL131003. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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