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How to: When to consider genetic counseling and testing in patients with congenital heart disease?

Gene regulatory networks in cardiac development

Congenital heart disease (CHD) is a heterogeneous group of cardiac disorders for which genetics can explain part of the causality. In the last decades, molecular knowledge about the genetic control of cardiac development has opened doors for genetic evaluation in congenital heart disease. As a milestone, the identification of cardiac transcription factors controlling cardiovascular progenitor specification, differentiation and migration has changed the vision of CHD: coming from a world where anatomical classification of the cardiac lesions was the standard, “molecular reading” of CHD now enters the clinical reality, offering a new vision of the disease and opportunities for alternative disease classification. As an example, the identification of NKX2-5 acting as a central transcription factor helped to understand a spectrum of (sometimes familial) disorders ranging from conduction delay, atrial- and ventricular-septal defects, and tetralogy of Fallot.1,2 Nevertheless, the complexity of the developmental cardiac gene network, and the multiple interactions that exist between the core cardiac transcription factors make the genotype-phenotype correlations in CHD a very hard issue: one cardiac transcription variant can lead to several phenotypes (pleiotropy); and one anatomical lesion can potentially be explained by alterations in several cardiac transcription factors.3 Also, isolated CHD is rarely a pure monogenic disorder, but rather arises from the interplay between genetic, epigenetic, and extrinsic factors, which can modulate disease expressivity and explains a low sibling recurrence risk of isolated CHD of about 3 to 5%. This complex genetic background in sporadic isolated CHD (which represents about 77% of the total CHD population) is reflected by a low diagnostic yield of genomic studies of less than 5%, with (likely-) pathogenic variants in known CHD genes frequently being inherited from unaffected parents (reduced penetrance), and with each of the known CHD genes being responsible for less than 0.1% of the total non-syndromic CHD cohort.

Genetic heterogeneity and variable expression are posing challenges to genetic variant interpretation in isolated CHD. Obviously, the prevalence of monogenic causes of CHD is higher when CHD is familial or associated with extracardiac features.4 In fetuses or newborns with apparently isolated CHD, age-dependent expression of extracardiac features or cognitive development need to be taken into account for genetic testing.2,5,6 Integrating all those aspects, it is now recognized that clinical genetics (studying a reasonable set of genes, exploring copy number variants and single nucleotide variants) can explain about 5% of sporadic isolated CHD, 10-20% of familial CHD, 11% in fetuses with apparently isolated complex CHD, and up to 60% of patients with syndromic CHD.4,7–11 

When to think about genetics in CHD?  

Three red flags can be easily identified. Of course, a positive familial history of CHD will raise attention, and put the clinician on the track of a possible genetic etiology for CHD. For this, it is important to consider the spectrum of lesions that can be associated with a given genetic variant, which should be searched in a multi-generation pedigree.2,5,10 This approach is time-consuming, and raises questions on how to screen relatives for CHD. Also, regarding the low penetrance of genetic variants associated with CHD, the impact of this approach is often limited in daily practice. But when a positive familial history is present, this should be a sufficient trigger to orient the patient towards genetic counseling.

A second red flag is the presence of syndromic features, which are defined by the presence of extracardiac manifestations, including additional congenital anomalies, facial dysmorphism and/or abnormal growth, development or behavior. After exclusion of aneuploidies, pathogenic copy-number variants (CNVs) are identified in about 20% of syndromic-CHD (S-CHD), while pathogenic single-nucleotide variants (SNVs) are found (by trio WES or targeted analysis) in about 30 % of patients with S-CHD, with genetic causes of CHD occurring de novo (not present in the germline of the parents) in about 90%.4,9-11 Therefore, in the presence of syndromic features, and even in apparently isolated cases, a trio approach with DNA from index and unaffected parents is the preferred strategy to identify genetic variants (including CNV) interfering with normal cardiac (and extra-cardiac) development.2,5,10

A third approach, which will constitute the third red flag, will be the recognition of specific lesions or entities, for which gene-causality is established and would justify a genetic confirmation. Some CHD types have a higher likelihood of having a monogenic cause, or being associated with genetic variants in a specific gene, even when sporadic. Examples include supravalvular aortic stenosis with or without peripheral pulmonary stenosis (SNVs in ELN), atrial septal defects with AV block (SNVs in NKX2.5, TBX5, TBX20, or GATA4), and conotruncal heart defects (deletions of chromosomal region 22q11.2, or SNVs in TBX1).2,5,10 

Overall, genetic counseling should be offered to every patient with CHD, isolated, familial or syndromic, with special attention to CHD-couples willing to have children. Genetic testing should be preserved for patients with syndromic CHD, familial CHD, apparently isolated complex CHD in fetuses and newborns, and in patients with specific lesions. Genetic testing in adults with sporadic non-syndromic CHD should not be routinely offered, considering the low diagnostic yield and the prevalence of inherited variants with reduced penetrance. Genomic analyses in CHD should rather be considered in light of the clinical presentation, technology and expertise availability, access to health care, and psycho-social aspects.   

A genetic test in congenital heart disease: why? 

When conclusive, a genetic test in CHD will rarely change the way the congenital heart defect is treated, but will rather influence patient’s management by providing cues on the potential cardiac or extracardiac prognosis, and allowing a better assessment of recurrence risk. Indeed, the result of the genetic test can help clinicians to anticipate complications in patient subgroups, and will influence patient follow-up strategy. Examples of such situations are described here below: 

  • Cardiac outcome:  
    • patients with pathogenic variants in NKX2.5 orTBX5 are at risk of developing an atrioventricular conduction disorder even in the absence of structural heart defects; 
    • CHD-related syndromes can be associated with higher risk of cardiovascular complications, such as pulmonary arterial hypertension in Trisomy 21, hypertrophic cardiomyopathy in Noonan syndrome, or aortic dilatation and arterial hypertension in Turner syndrome. Patients with conotruncal heart defects have a worse perioperative outcome when 22q11 deletion syndrome is present compared to those without.  
  • Extracardiac outcome: 
    • patients with pathogenic variants in genes for syndromic CHD should be timely referred to a multidisciplinary team to assess growth, behavior and neurodevelopment;
    • patients with situs anomalies due to primary ciliary dyskinesia should be referred to a pulmonologist and fertility center (males), given their increased risk of developing bronchiectasis and fertility issues. 

Familial recurrence risk of CHD is about 5-6% with empiric estimates of 3–4% in siblings, and 4–10% in offspring of an affected parent.2 Risk estimates vary by CHD type with the highest risk in first-degree relatives of probands with left-sided heart defects and the lowest in D- transposition of the great arteries. Higher prevalence of autosomal recessive inheritance, and thus higher sibling recurrence risk, is found when CHD is associated with laterality defects. When a parent is diagnosed with a heterozygous pathogenic variant for autosomal dominant CHD, recurrence can reach 50%. However, even when a genetic cause of CHD is found, assessing the recurrence risk at the individual level is extremely challenging in CHD, as reduced penetrance and variable expression are the rule.

From this, a tailored approach should be provided to each patient, and genetic counseling performed in expert centers. When couples have an increased genetic risk of syndromic CHD or isolated CHD in their offspring, reproductive choices, including in vitro fertilization with preimplantation genetic testing, should be offered, after integrating medical, psychological, socio-cultural and technical aspects. 

A genetic test in congenital heart disease: how? 

Regarding the complexity of the genetic architecture of CHD, choosing an adequate test is key to success in CHD genetics. Referral to a multidisciplinary cardiogenetics team is mandatory, and careful assessment of the clinical and familial situation should be provided through pre-test counseling” (see box).  

The choice of the test will depend on the CHD category:  

CHD subtype Causative genetic variant  Diagnostic yield 
CMA  WES (trio)  WGS (trio) 
Syndromic-CHD with extra cardiac anomaly  De novo or inherited CNVs or SNVs  3-25%  25 %*  41% 
Non-syndromic familial CHD**  Inherited CNVs  Unknown  31-46%  36% 
Sporadic***  Multiple   3-10%  2-10%  10%

*targeted analysis could be considered if a clinical diagnostic is made 
**2 family members with concordant complex CHD, or >2 family members with CHD 
***Apparently isolated complex CHD in fetus/newborn: CMA & trio WES can be considered; sporadic CHD in adults: improved yield if specific lesion (e.g. SVAS and PS (ELN); or ASD with AV block (NKX2.5)) 

CMA: chromosomal microarray; WES: whole exome sequencing; WGS: whole genome sequencing. SVAS: supravalvular aortic stenosis; PS: pulmonary stenosis; ASD: atrial septal defect. Reproduced from Wilde et al.10 with permission. 

As sequencing costs are dropping, virtual panel testing using WES or WGS is preferred over custom-designed targeted gene panels for isolated or syndromic CHD.2, 10 WES/WGS data can be re-interrogated when novel genes for CHD are being identified, and, thus, WES or WGS better respond to the rapidly evolving knowledge on CHD genetics. In the field of CHD, a careful interpretation of the variants is mandatory, and their “actionability” has to be weighted  in light of the clinical evidence.12 Also, this implies that in genetic diagnostic labs a policy needs to be in place (1) to systematically reanalyze genomic data from gene-elusive patients, and (2) to deal with the identification of incidental findings (unintentional discovery of pathogenic variants for unrelated medical conditions). These issues underline the importance of post-test counseling, even when genetic tests for CHD are negative.  


The combination of a rapidly growing knowledge in the field of cardiac development with the accessibility to broad genomic data in clinical genetics allows nowadays CHD genetics to enter the clinical arena. Considering the complexity of CHD genetics with variable expression and low penetrance of known genetic determinants being the rule, a careful clinical approach should be provided to CHD patients by offering them genetic counseling in experienced teams.   


1. Biben, C. et al. Cardiac Septal and Valvular Dysmorphogenesis in Mice Heterozygous for Mutations in the Homeobox Gene Nkx2-5. Circ Res 87, 888–895 (2000). 

2. Pierpont, M. E. et al. Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement from the American Heart Association. Circulation 138, e653–e711 (2018). 

3. Sperling, S. R. Systems biology approaches to heart development and congenital heart disease. Cardiovascular Research 91, 269–278 (2011). 

4. Sifrim, A. et al. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet 48, 1060–1065 (2016). 

5. Backer, J. D. et al. Genetic counselling and testing in adults with congenital heart disease: A consensus document of the ESC Working Group of Grown-Up Congenital Heart Disease, the ESC Working Group on Aorta and Peripheral Vascular Disease and the European Society of Human Genetics. Eur J Prev Cardiolog 27, 1423–1435 (2020). 

6. Baumgartner, H. et al. 2020 ESC Guidelines for the management of adult congenital heart disease. Eur. Heart J. 58, 2241–83 (2020). 

7. Breckpot, J. et al. Array Comparative Genomic Hybridization as a Diagnostic Tool for Syndromic Heart Defects. J Pediatrics 156, 810-817.e4 (2010). 

8. Mone, F. et al. Fetal hydrops and the Incremental yield of Next‐generation sequencing over standard prenatal Diagnostic testing (FIND) study: prospective cohort study and meta‐analysis. Ultrasound Obst Gyn 58, 509–518 (2021). 

9. Zaidi, S. et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature 498, 220–223 (2013). 

10. Wilde, A. A. M. et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. Heart Rhythm (2022) doi:10.1016/j.hrthm.2022.03.1225. 

11. Alankarage, D. et al. Identification of clinically actionable variants from genome sequencing of families with congenital heart disease. Genet Med 21, 1111–1120 (2019). 

12. Yang, A. et al. Congenital Heart Disease Gene: a Curated Database for Congenital Heart Disease Genes. Circulation Genom Precis Medicine 101161CIRCGEN121003539 (2022) doi:10.1161/circgen.121.003539.   

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.