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Etiologic heterogeneity in the familial aggregation of congenital cardiovascular malformations
N E Maestri1, T H Beaty, J A Boughman
1Department of Epidemiology, Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD.
Insights
Congenital cardiovascular malformations (CCVM) show a simple recessive inheritance pattern. However, genetic heterogeneity exists, with differing familial aggregation patterns observed across races and specific defect types.
Area of Science:
- Genetics
- Cardiovascular Research
- Developmental Biology
Background:
- Congenital cardiovascular malformations (CCVM) are a significant concern, with familial recurrence suggesting genetic components.
- Altered embryonic blood flow (flow lesions) represent a specific subgroup of CCVM with potential unique inheritance patterns.
Purpose of the Study:
- To investigate the inheritance models for CCVM in families with flow lesions.
- To test for etiologic heterogeneity in CCVM based on defect type and race.
Main Methods:
- Utilized regressive models to analyze familial aggregation in 375 flow-lesion families.
- Compared inheritance models, including Mendelian transmission.
- Assessed the effect of race as a covariate in genetic models for different CCVM subgroups (left heart defects, right heart defects, VSD).
Main Results:
- A simple recessive Mendelian model best explained CCVM inheritance when all families were analyzed together, with race not being a significant factor.
- Subgroup analyses for left heart defects, right heart defects, and VSD also initially supported a simple Mendelian recessive model.
- Inclusion of race revealed significant heterogeneity: increased risk for relatives of white probands with right heart defects and black probands with VSD.
Conclusions:
- Etiologic heterogeneity exists in the genetic control of CCVM within flow-lesion families.
- Familial aggregation patterns for CCVM differ significantly between racial groups and specific defect types.
Abstract:
Recent data indicate that there is increased risk of congenital cardiovascular malformations (CCVM) within families of probands diagnosed with congenital cardiovascular malformations that are due to altered embryonic blood flow (flow lesions). In the present study, regressive models recently developed by Bonney were used to compare specific models of inheritance and to test for etiologic heterogeneity among three subgroups of 375 flow-lesion families identified by the Baltimore-Washington Infant Study. When all families were analyzed as a single group, the best-fitting model was a simple recessive model with Mendelian transmission; race did not have a significant effect on estimated risk. Separate analyses of families of probands with left heart defects, right heart defects, and ventricular septal defects (VSD) confirmed this simple Mendelian recessive model as the model of choice. However, when race was included as a covariate in these genetic models, there was evidence for significant heterogeneity among the three subgroups. There was an increased risk to relatives of white probands with right heart defects and to relatives of black probands with VSD, while there was no effect of race among relatives of probands with left heart defects. These results strongly suggest that there is etiologic heterogeneity in the control of CCVM among flow-lesion families and that the patterns of familial aggregation differ among the races.