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Published on: July 18, 2014
Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative
Insights
Recurrent congenital heart defects (CHDs) in families suggest multifactorial causes. This study found higher recurrence risks in offspring of affected mothers, indicating specific genetic influences for certain CHDs.
Area of Science:
- Cardiovascular Genetics
- Developmental Biology
- Medical Genetics
Background:
- Congenital heart defects (CHDs) are commonly believed to arise from multiple genetic and environmental factors.
- This study investigates the etiological basis of CHDs by examining affected individuals and their families.
Purpose of the Study:
- To test the hypothesis of a multifactorial etiology for congenital heart defects.
- To determine recurrence risks and identify potential genetic patterns in families with CHDs.
Main Methods:
- Identified 1094 adult patients with major cardiac defects operated on before 1970.
- Focused on individuals with situs anomalies, atrioventricular septal defects, or tetralogy of Fallot.
- Traced 727 patients, collected data via questionnaires, and examined offspring by pediatric cardiologists.
Main Results:
- A recurrence risk of 4.1% for heart defects was observed in 16 liveborn offspring from 727 patients.
- Recurrence risk was significantly higher than sibling risk (2.1%).
- Affected mothers had a higher incidence of CHDs and miscarriages in their offspring compared to affected fathers.
Conclusions:
- Findings challenge a universal polygenic basis for all CHDs.
- Atrioventricular septal defects may be single-gene disorders.
- Tetralogy of Fallot appears to be polygenic, while isolated transposition of the great arteries may be sporadic.
Background:
Congenital heart defects are generally assumed to have a multifactorial aetiology. We have tested this hypothesis by studying adults with heart defects and their families.
Methods:
We identified 1094 patients who survived surgery for major cardiac defects before 1970. We chose individuals with disturbance of situs or segmental connection, with atrioventricular septal defect or with tetralogy of Fallot. After exclusion and non-participation, 727 individuals were traced. Each was visited by an investigator and completed a detailed questionnaire. If possible, all "normal" offspring were examined by a paediatric cardiologist.
Findings:
The 727 individuals had 393 live offspring. There were 71 miscarriages and five terminated pregnancies. Overall, we found recurrent heart defects in 16 liveborn offspring--a recurrence risk of 4.1%. This result differed significantly from sibling risk (2.1%; p=0.021). More congenital heart defects occurred in the offspring of affected women than in those of affected men (p=0.047); when all malformations (cardiac and non-cardiac) in the offspring were taken into account the excess was more significant (p=0.032). We found an excess of miscarriages in the offspring of affected women (p=0.001). In tetralogy of Fallot, heart defects occurred in seven (3.1%) of 223 offspring, 12 (2.2%) of 539 siblings, five (0.3%) of 1575 second-degree relatives, and eight (0.3%) of 2728 third-degree relatives.
Interpretation:
Our findings do not support a polygenic basis for all heart defects. Atrioventricular septal defect seems to be a single-gene defect and tetralogy of Fallot a polygenic disorder with a small number of interacting genes. Our data suggest that isolated transposition of the great arteries is a sporadic defect.
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