Aetiology, genes, and environment

Abstract

Genetic factors predisposing to congenital heart disease (CHD) are characterized by extreme heterogeneity, comprising changes to the genome at all levels of variation from chromosomal aneuploidy to single nucleotide mutations. About 15–20% of patients with CHD have underlying genetic causes identifiable by currently standard clinical genetics laboratory testing, including patients with Down syndrome, Turner syndrome, 22q11 deletion syndrome, other chromosomal rearrangements, and multisystem conditions mediated by single nucleotide changes in particular genes (e.g. Noonan’s syndrome). Extracardiac malformations and/or neurodevelopmental abnormalities characteristic of these conditions are important diagnostic cues. Mendelian families with isolated non-syndromic CHD are very rare. In the remaining 80% of cases, CHD is apparently ‘sporadic’ and the empirical recurrence risk to a sibling of an index case in such families is approximately 3%. This low recurrence risk suggests that de novo events, that is, new mutations in affected offspring absent in the parents, are an important potential genetic cause of CHD. De novo copy number variations such as 1q21.1 duplication have been shown to contribute to aetiology in 5–10% of apparently sporadic patients. Recent studies have also shown that approximately 20% of patients without recognized syndromic presentations, but with CHD accompanied by extracardiac malformations and/or neurodevelopmental delay, may have pathogenic de novo single nucleotide changes discoverable by exome sequencing. Continuing advances in genomic technologies present the prospect of substantial progress in the understanding of the genetic predisposition to CHD, but further research in large cohort studies is required.