Congenital heart disease: current knowledge about causes and inheritance

Abstract

Summary 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.

Somatic GATA5 mutations in sporadic tetralogy of Fallot

“…These anomalies may result in degraded quality of life, delayed fetal brain development, cardiac enlargement or hypertrophy, pulmonary hypertension, infective endocarditis, thromboembolism, Eisenmenger's syndrome, congestive heart failure, arrhythmias, as well as sudden cardiac death in the absence of surgical or catheter-based repairs (4)(5)(6)(7)(8)(9)(10). Despite the high prevalence and significant clinical importance, the molecular mechanism of CHD remains poorly understood (11).…”

Cardiovascular Management in Pregnancy

“…For genetic defects such as Marfan syndrome or other autosomal dominant syndromes, the risk of fetal transmission is 50%, although variable penetrance of particular traits may 32,35 Genetic counseling should be offered to all patients with CHD with referral for genetic testing in specific situations.…”

“…For isolated cases of CHD without a family history of CHD (eg, sporadic defects), the recurrence risk of CHD in the offspring is reported to be in the range of 3% to 8%, although the absolute risk varies with the specific type of defect and which parent is affected. [28][29][30][31][32] In general, the risk of recurrence is higher if the mother is the affected parent. If >1 sibling is affected by CHD, the recurrence risk may be as high as 10%.…”

Gestational stress induces the unfolded protein response, resulting in heart defects

“…Genetic factors have been widely investigated (reviewed by Andersen et al, 2014;Fahed et al, 2013). However, only ∼20% of CHD cases can be attributed to a specific genetic cause (Blue et al, 2012). Thus, nongenetic factors are likely to be important in human heart development.…”