RECURRENCE RISKS IN OFFSPRING OF ADULTS WITH MAJOR HEART-DEFECTS - RESULTS FROM FIRST COHORT OF BRITISH COLLABORATIVE STUDY

Background Congenital heart defects are generally assumed to have a mu ltifactorial aetiology. We have tested this hypothesis by studying adu lts with heart defects and their families. Methods We identified 1094 patients who survived surgery for major cardiac defects before 1970. W e chose individuals with disturbance of situs or segmental connection, with atrioventricular septal defect or with tetralogy of Fallot. Afte r exclusion and non-participation, 727 individuals were traced. Each w as visited by an investigator and completed a detailed questionnaire. If possible, all ''normal'' offspring were examined by a paediatric ca rdiologist. Findings The 727 individuals had 393 live offspring. There were 71 miscarriages and five terminated pregnancies. Overall, we fou nd 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 af fected women than in those of affected men (p=0.047); when all malform ations (cardiac and non-cardiac) in the offspring were taken into acco unt the excess was more significant (p=0.032). We found an excess of m iscarriages in the offspring of affected women (p=0.001). In tetralogy of Fallot, heart defects occured 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 fi ndings do not support a polygenic basis for all heart defects. Atriove ntricular septal defect seems to be a single-gene defect and tetralogy of Fallot a polygenic disorder with a small number of interacting gen es. Our data suggest that isolated transposition of the great arteries is a sporadic defect.