Current knowledge about causes and inheritance

Article from The Medical Journal of Australia. Full article can be viewed here.


  • About 80% of congenital heart disease (CHD) is multifactorial and arises through various combinations of genetic and environmental contributors.
  • About 20% of cases can be attributed to chromosomal anomalies, Mendelian syndromes, non-syndromal single gene disorders or teratogens. Down syndrome and velocardiofacial syndrome are the most commonly seen syndromes in patients with CHD.
  • To date, more than 30 genes have been linked to non-syndromal forms of CHD. Their contribution to CHD remains unknown but is presumed to be relatively small.
  • There is limited evidence for the contribution of specific environmental factors to CHD causation. However, folic acid supplementation in the pre- and peri-conception period, ensuring rubella vaccination has been completed before pregnancy, and maintaining good glycaemic control in mothers with diabetes may reduce the risk of CHD in infants.
  • Recurrence risks vary between different types of non-syndromal CHD with multifactorial inheritance, and can be as high as 10% when two or more siblings are affected. Generally, the recurrence risk increases if a parent rather than a sibling is affected, particularly when the affected parent is the mother.
  • Individualised recurrence risks can be generated for members of families affected by CHD after obtaining a detailed family history, including accurate cardiac diagnoses for all affected members.
  • High-throughput genetic techniques can accelerate gene discovery and improve our ability to provide individualised genetic counselling.

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.

Victoria & Tasmania