Congenital heart disease: current knowledge about causes and inheritance

Gillian M Blue, Edwin P Kirk, Gary F Sholler, Richard P Harvey and David S Winlaw
Med J Aust 2012; 197 (3): 155-159.
Published online: 6 August 2012


Congenital heart disease (CHD) affects 6–8 babies in every 1000 live births.1 It is the most common cause of death from a congenital structural abnormality in newborns in the Western world, and is often associated with fetal loss. In Australia, over 2000 babies are born with CHD each year, with about half of these requiring surgery or catheter interventions. The other half have minor abnormalities (minor valve lesions or very small ventricular or atrial septal defects) that have no functional impact and rarely affect wellbeing or require intervention.

More patients with CHD require treatment each year than those with other significant conditions such as childhood cancer or cystic fibrosis (with 600 and 70 new cases, respectively, presenting each year in Australia). About a quarter of those requiring treatment will need surgery in the first year of life. Most infants and children requiring single interventions can expect to lead a near-normal life. A small group of infants with complex lesions require multiple surgical procedures, intensive support and close monitoring during the first few years of life, although their quality of life may still be good. With the success of contemporary surgical procedures and improved survival, many patients with complex lesions are reaching adult life, and the population of adults with CHD now exceeds the number of children with structural heart abnormality.2

However, despite the improved treatment and prognosis of these patients, there is still a large gap in our knowledge of the aetiology of CHD. Determining a cause for CHD is important from a psychosocial perspective for the patient and family (whose main questions when faced with a new diagnosis of CHD are “why” and “how”), but also in regard to family planning for both the parents and the affected child as he or she approaches reproductive age. With the growing adult CHD population, information on recurrence risks and aetiology will become increasingly relevant. Understanding the aetiology of CHD will also benefit clinical management of the patient. It may help identify possible complications and risk factors for surgery or treatment, as patients with genetic syndromes or extracardiac anomalies are generally at higher risk of operative mortality and morbidity.3

Novel genetic techniques, such as whole exome and genome sequencing (Box 1), can accelerate gene discovery and assist in identifying causes of diseases of previously unknown aetiology, such as CHD. This review updates our current understanding of the causes and inheritance of CHD in light of the advances being made in genetic technologies.

Multifactorial congenital heart disease

Currently, about 20% of CHD cases can be attributed to known causes such as genetic syndromes and teratogens, but very little is known about the aetiology of most cases (about 80%). It is generally accepted that the group of CHD lesions with unknown aetiology follows a multifactorial inheritance model, which implicates both genetic and environmental factors in disease development.4 The prevailing model involves variations in many different genes, each of which contributes only a small amount to the individual’s susceptibility to a particular condition. These interact with each other and with environmental factors to raise the likelihood that an individual will have CHD. Most sporadic cases of CHD (ie, isolated cases of CHD without a family history of the condition) would fall into this category.

Chromosomal anomalies

Chromosomal anomalies can cause CHD through several different mechanisms. Chromosomal material may be gained, as in Down syndrome, in which individuals have an additional chromosome 21, or it may be lost, as in velocardiofacial syndrome (VCFS), which is caused by loss of part of chromosome 22. Loss or gain of chromosomal material causes abnormality due to the effect on dosage-sensitive genes. For example, haploinsufficiency of TBX1 is responsible for many of the clinical features of VCFS, including the cardiac phenotype.5 Some phenotypic aspects could also be due to epigenetic effects and as yet unknown mechanisms. Chromosomal rearrangements, such as reciprocal translocations, can also cause problems by disrupting genes at the breakpoints on affected chromosomes, or by changing the relationship between a gene and its regulatory elements.

Chromosomal anomalies account for about 8%–10% of presenting cases of CHD.6 Down syndrome is the most common chromosomal anomaly seen in patients with CHD, followed closely by VCFS. About 40%–50% of patients with Down syndrome have a heart defect (Box 2),10 and 80% of patients with VCFS have CHD, which usually includes lesions affecting the outflow tract and great vessels, such as tetralogy of Fallot (TOF).11 Although other syndromes, such as Edwards syndrome, may report higher percentages of patients with CHD presentation (Box 2), the prevalence of these syndromes is lower than Down syndrome and VCFS and therefore not seen as often.

Copy number variations (CNV) — variations in the number of copies of a specific section of DNA present in an individual — are another type of chromosomal anomaly. Specific CNV have in the past been associated with diseases such as autism and schizophrenia and, more recently, with CHD. A recent study found that microduplications of the 1q21.1 region accounted for about 1% of the population attributable risk of TOF and that duplication of the GJA5 gene was associated with a 10-fold increase in risk of TOF.12

Environmental factors and teratogens

Environmental factors influencing CHD can be broadly defined as any “non-genetic” factor with an associated risk of CHD development. These usually occur within a maternal preconceptional or fetal–placental–maternal context. The contribution of specific environmental exposures to the causation of CHD in general is unknown, as most associations have been derived from small observational studies, which have not been replicated and may have been complicated by recall bias and confounding effects.

The best documented maternal risk factor is maternal diabetes, with a reported fivefold increased risk of CHD from pregestational diabetes.16 As the time of greatest risk for development of CHD is before the 7th week of gestation, the types of CHD most commonly associated with maternal diabetes are those due to defects of primary cardiogenesis, such as heterotaxy, atrioventricular septal defect and outflow tract anomalies.17 The exact mechanisms by which diabetes induces CHD are unknown. One theory suggests that abnormal glucose levels may disrupt expression of regulatory genes in the embryo, thereby resulting in cell death. Another hypothesis is that oxidative stress and the production of free radicals resulting from changes in metabolism may be to blame. Strict glycaemic control before conception and during pregnancy has been reported to reduce the risk of infants developing CHD.18

Other environmental factors have been associated with an increased risk of CHD (Box 5), although findings are generally inconclusive. For example, studies providing supportive evidence of a protective effect of periconceptional folate and folic acid-containing multivitamin supplementation were too small to provide definite answers.19 Additional population-based studies and randomised clinical trials are needed to confirm their findings. Maternal febrile illness is also questionable as a risk factor, as most studies were unable to distinguish between possible confounding effects of medications taken to reduce illness. Potential confounding effects have also been seen in studies investigating maternal antidepressant use, specifically selective serotonin reuptake inhibitors (SSRIs), although consistent evidence supporting an increase in CHD after use of some SSRIs warrants further study.20

Despite the inconclusive evidence reported, it seems reasonable to suggest a few basic recommendations aimed at minimising possible CHD risk factors for women who are or intend to become pregnant:

Contribution of “flow”

Normal circulation in the developing fetus is an important promoter of growth and chamber development.21 In complex forms of CHD, where multiple anomalies exist, it is conventionally thought that individual structural defects may explain “downstream” changes. For example, severe mitral stenosis or atresia may be associated with underdevelopment of the left ventricle, aortic valve and ascending aorta. It is likely that the situation is more complex than this, with translational studies suggesting that individual genetic mutations may cause a range of abnormalities affecting both cardiac valves and chamber myocardium.22 Defining the genetic and molecular underpinning of these abnormalities is important in understanding the growth potential of cardiac structures in affected individuals.

Recurrence risks in congenital heart disease

In a minority of cases, it is possible to provide a precise recurrence risk for CHD, based on known Mendelian inheritance in a family or on risk figures related to a chromosomal anomaly. In the absence of such information, empirical risk estimates must be used. For most lesions, the reported recurrence risk in siblings of an affected individual, when neither parent is affected, is in the range of 1%–6% (Box 6).24,25 If more than one sibling is affected, the recurrence risk can increase to 10%.26 The recurrence risk in offspring of affected parents is generally significantly higher than that in siblings of affected individuals with unaffected parents. Further, if the mother is the affected parent, the risk of disease transmission is higher.25 The reason for these differences is unknown, and it is difficult to reconcile them with known genetic mechanisms.

Recurrence risks also vary considerably among different types of CHD. Obstructive left heart lesions, including hypoplastic left heart syndrome, aortic valve stenosis and coarctation of the aorta, generally have noticeably higher recurrence risks in siblings of unaffected parents and/or offspring of affected parents compared with other types of CHD.27 It is reported that up to 20% of the asymptomatic first-degree relatives of patients with obstructive left heart lesions may have undiagnosed CHD, in particular bicuspid aortic valve (BAV).28 Although not classically considered a childhood heart defect, BAV may require treatment later in life, including valve replacement and aortic surgery.

Concordance of recurrent CHD (ie, the same subtype of CHD) within members of the same family can vary substantially between different types of CHD. The overall exact concordance of recurrent CHD is reportedly 37%, with a group concordance (ie, within the same spectrum of CHD) of 47%.29

Future directions

Recent advances in technology provide us with the potential to better understand conditions with a genetic component that have not previously been well understood. Revolutionary techniques such as whole genome and exome sequencing still harbour many challenges, including the analysis of large amounts of data and the difficulty in distinguishing benign variants from disease-causing mutations. However, the prospect of novel gene discovery and possible identification of disease aetiology greatly outweighs these challenges. For conditions with complex, multifactorial inheritance, such as CHD, these novel techniques hold much promise. Unlike traditional research techniques, they provide an unbiased approach, in which both rare and common variants can be identified, making them more suitable to the study of complex diseases.

Accelerated gene discovery in CHD will translate into more individualised genetic counselling for patients and their families, and the role of genetics in the clinical care of patients with CHD should continue to evolve. For now, ensuring an accurate family history is obtained, including detailed cardiac diagnoses for all affected family members, could provide valuable clues about possible causation and inheritance. This is particularly relevant to families with multiple affected individuals, and a referral to a genetics service should be considered.

4 Selected genes associated with non-syndromal congenital heart disease1,15



Associated cardiac lesions


Transcription factor

ASD–AV block, TOF, HLHS, TGA, DORV, Ebstein anomaly, VSD


Transcription factor



Transcription factor



Transcription factor



Transcription factor

IAA, aortic arch anomalies, VSD


Transcription factor

ASD, VSD, AVSD, conduction abnormalities


Transcription factor

ASD, VSD, valve defects, LVOTO


Transcription factor



Transcription factor

Heterotaxy, ASD, AVSD, TGA, VSD, TAPVR, PS


Transcription factor



Transcription factor



Transcription factor

HLHS (somatic mutation)


Transcription factor



Membrane ligand–receptor



Membrane ligand–receptor

Heterotaxy, TGA


Membrane ligand–receptor



Membrane ligand–receptor

Heterotaxy, TGA, DORV, TOF


Sarcomeric protein



Sarcomeric protein

ASD, Ebstein anomaly


Sarcomeric protein



Sarcomeric protein



Gap junction protein

HLHS (somatic mutation)


Gap junction protein



Matricellular protein

AVSD, dextrocardia


Structural protein





ASD = atrial septal defect. AS = aortic stenosis. AV = atrioventricular. AVSD = atrioventricular septal defect. BAV = bicuspid aortic valve. DORV = double outlet right ventricle. HLHS = hypoplastic left heart syndrome. IAA = interrupted aortic arch. LVOTO = left ventricular outflow tract obstruction. PDA = patent ductus arteriosus. PS = pulmonary stenosis. SVAS = supravalvular aortic stenosis. TA = truncus arteriosus. TAPVR = total anomalous pulmonary venous return. TGA = transposition of the great arteries. TOF = tetralogy of Fallot. VSD = ventricular septal defect.

Provenance: Not commissioned; externally peer reviewed.

  • Gillian M Blue1
  • Edwin P Kirk2
  • Gary F Sholler1
  • Richard P Harvey3
  • David S Winlaw1

  • 1 Heart Centre for Children, The Children’s Hospital at Westmead, Sydney, NSW.
  • 2 Department of Medical Genetics, Sydney Children’s Hospital, Sydney, NSW.
  • 3 Victor Chang Cardiac Research Institute, Sydney, NSW.


We thank the New South Wales Cardiovascular Research Network (Heart Foundation of Australia and NSW Office for Science and Medical Research) for funding and support.

Competing interests:

No relevant disclosures.

  • 1. Wessels MW, Willems PJ. Genetic factors in non-syndromic congenital heart malformations. Clin Genet 2010; 78: 103-123.
  • 2. Khairy P, Ionescu-Ittu R, Mackie AS, et al. Changing mortality in congenital heart disease. J Am Coll Cardiol 2010; 56: 1149-1157.
  • 3. Formigari R, Michielon G, Digilio MC, et al. Genetic syndromes and congenital heart defects: how is surgical management affected? Eur J Cardiothorac Surg 2009; 35: 606-614.
  • 4. Nora JJ. Multifactorial inheritance hypothesis for the etiology of congenital heart diseases: the genetic-environmental interaction. Circulation 1968; 38: 604-617.
  • 5. Merscher S, Funke B, Epstein JA, et al. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 2001; 104: 619-629.
  • 6. Roos-Hesselink JW, Kerstjens-Frederikse WS, Meijboom FJ, Pieper PG. Inheritance of congenital heart disease. Neth Heart J 2005; 13: 88-91.
  • 7. Pierpont ME, Basson CT, Benson DW Jr, et al. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007; 115: 3015-3038.
  • 8. Burn J, Goodship J. Congenital heart disease. In: Rimoin DL, Connor JM, Pyeritz RE, Korf BR, editors. Emery and Rimoin’s principles and practice of medical genetics. 4th ed. London: Churchill Livingstone, 2002: 1239-1272.
  • 9. Lin AE, Ardinger HH. Genetic epidemiology of cardiovascular malformations. Prog Pediatr Cardiol 2005; 20: 113-126.
  • 10. American Academy of Pediatrics Committee on Genetics. Health supervision for children with Down syndrome. Pediatrics 2001; 107: 442-449.
  • 11. Botto LD, May K, Fernhoff PM, et al. A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 2003; 112: 101-107.
  • 12. Soemedi R, Topf A, Wilson IJ, et al. Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls. Hum Mol Genet 2012; 21: 1513-1520.
  • 13. van der Bom T, Zomer AC, Zwinderman AH, et al. The changing epidemiology of congenital heart disease. Nat Rev Cardiol 2011; 8: 50-60.
  • 14. Butler TL, Esposito G, Blue GM, et al. GATA4 mutations in 357 unrelated patients with congenital heart malformation. Genet Test Mol Biomarkers 2010; 14: 797-802.
  • 15. Jongbloed JD, Pósafalvi A, Kerstjens-Frederikse WS, et al. New clinical molecular diagnostic methods for congenital and inherited heart disease. Expert Opin Med Diagn 2011; 5: 9-24.
  • 16. Wren C, Birrell G, Hawthorne G. Cardiovascular malformations in infants of diabetic mothers. Heart 2003; 89: 1217-1220.
  • 17. Jenkins KJ, Correa A, Feinstein JA, et al. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007; 115: 2995-3014.
  • 18. Cousins L. Etiology and prevention of congenital anomalies among infants of overt diabetic women. Clin Obstet Gynecol 1991; 34: 481-493.
  • 19. Botto LD, Olney RS, Erickson JD. Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am J Med Genet C Semin Med Genet 2004; 125C: 12-21.
  • 20. Wurst KE, Poole C, Ephross SA, Olshan AF. First trimester paroxetine use and the prevalence of congenital, specifically cardiac, defects: a meta-analysis of epidemiological studies. Birth Defects Res A Clin Mol Teratol 2010; 88: 159-170.
  • 21. Hove JR, Koster RW, Forouhar AS, et al. Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature 2003; 421: 172-177.
  • 22. Kirk EP, Sunde M, Costa MW, et al. Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy. Am J Hum Genet 2007; 81: 280-291.
  • 23. Esposito G, Butler TL, Blue GM, et al. Somatic mutations in NKX2–5, GATA4, and HAND1 are not a common cause of tetralogy of Fallot or hypoplastic left heart. Am J Med Genet A 2011; 155A: 2416-2421.
  • 24. Calcagni G, Digilio M, Sarkozy A, et al. Familial recurrence of congenital heart disease: an overview and review of the literature. Eur J Pediatr 2007; 166: 111-116.
  • 25. Burn J, Brennan P, Little J, et al. Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study. Lancet 1998; 351: 311-316.
  • 26. Nora JJ, Nora AH, Optiz JM, Reynolds JF. Update on counseling the family with a first-degree relative with a congenital heart defect. Am J Med Genet 1988; 29: 137-142.
  • 27. Lewin MB, McBride KL, Pignatelli R, et al. Echocardiographic evaluation of asymptomatic parental and sibling cardiovascular anomalies associated with congenital left ventricular outflow tract lesions. Pediatrics 2004; 114: 691-696.
  • 28. Kerstjens-Frederikse WS, Du Marchie Sarvaas GJ, Ruiter JS, et al. Left ventricular outflow tract obstruction: should cardiac screening be offered to first-degree relatives? Heart 2011; 97: 1228-1232.
  • 29. Gill HK, Splitt M, Sharland GK, Simpson JM. Patterns of recurrence of congenital heart disease: an analysis of 6,640 consecutive pregnancies evaluated by detailed fetal echocardiography. J Am Coll Cardiol 2003; 42: 923-929.


remove_circle_outline Delete Author
add_circle_outline Add Author

Do you have any competing interests to declare? *

I/we agree to assign copyright to the Medical Journal of Australia and agree to the Conditions of publication *
I/we agree to the Terms of use of the Medical Journal of Australia *
Email me when people comment on this article

Online responses are no longer available. Please refer to our instructions for authors page for more information.