Genetics of Human Congenital Heart Disease


Congenital heart disease (CHD) affects 0.9% of babies born in the United Kingdom. With improvements in medical and surgical treatments, individuals are surviving longer, and there are now more adults surviving with CHD than children. Prospective parents may ask about the chances of any children they have being affected. Unfortunately, the rate of genetic diagnosis in CHD is relatively low. CHD is likely to result from a complex interaction of genes and the environment. Recent sequencing studies in large cohorts of individuals with CHD have started to decipher the genetic contribution. There is a role for de novo and inherited mutations in CHD, in addition to chromosomal abnormalities, copy number variation, somatic mutations and epigenetics. Whole exome sequencing studies have identified novel CHD genes and expanded the phenotype of known CHD genes, but researchers and clinicians must also consider how to deal with secondary findings which are unrelated to the primary research aim.

Key Concepts

  • Congenital heart disease is the most common birth defect. Some individuals have complex health needs requiring lifelong follow‐up.
  • Mendelian inheritance is rare in CHD, and it is likely that CHD results from a complex interaction between genes and the environment.
  • Reduced penetrance and variable expressivity are common in CHD.
  • Most individuals have CHD in isolation (nonsyndromic CHD). Syndromic CHD affects a smaller proportion of people, and is the combination of CHD with another extracardiac congenital abnormality and/or neurodevelopmental disability.
  • A genetic diagnosis is more likely to be identified in syndromic CHD, but the majority of individuals have nonsyndromic CHD.
  • Untargeted sequencing in large cohorts with CHD can identify novel genes and expand the phenotypic spectrum of known genes.
  • There may be a shared pathogenesis between CHD and neurodevelopmental disability.
  • Collaboration between researchers will be required to fully understand the genetic causes of CHD.
  • Sequencing will generate secondary findings that are not related to the primary aim of the research. Clinicians and researchers have a duty of care to their research participants and should consider the methods to deal with these.

Keywords: congenital heart disease; genetics; secondary findings; incidental findings; sequencing

Figure 1. Representation of the normal heart, a patent ductus arteriosus (PDA), a ventricular septal defect (VSD) and valvular pulmonary stenosis (PS). RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle; Ao, aorta; PA, pulmonary arteries. See also: Noonan Syndrome.
Figure 2. An echocardiogram showing the four chambers of the heart. An atrial septal defect can be seen and is confirmed using Doppler imaging which shows flow between the atria through the defect (left). Courtesy of Dr F. Bu'Lock.


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Further Reading

NHS Fetal Anomaly Screening,‐_HP_‐_FASP76.pdf

Syndrome without a name,

The 100 000 Genomes Project,‐100000‐genomes‐project/

The Deciphering Developmental Disorders Study,

Zaidi S and Brueckner M (2017) Genetics and genomics of congenital heart disease. Circulation Research 120 (6): 923–940.

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Wilsdon, Anna(Oct 2018) Genetics of Human Congenital Heart Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028207]