The etiology of congenital cardiovascular malformations: observations on genetic risks with implications for further birth defects research.

The previously reported hypothesis of an etiologic association of heart and blood abnormalities was further investigated in a population based study of congenital cardiovascular malformations (CCVM). Three presumed genetic risk factors (CCVM in parents and siblings, heritable blood disorders and maternal mitral valve prolapse) were found to occur significantly more often in cases than in normal controls, irrespective of the presence in the proband of chromosomal or Mendelian lesions. This suggests a specific etiologic origin of the CCVM; the excess of maternal risk components raises the possibility of X-linked inheritance. Observed constellations of heart, blood, and connective tissue disorders within members of a nuclear family may indicate variability of phenotypic expression of a similar biosynthetic defect. A schematic model of abnormal cardiogenesis is presented which supports the above observations with the results of biochemical studies on endothelium, platelets and collagen disorders. It is suggested that teratogenesis results from subtle interactions of genetic sequelae with extrinsic metabolic and xenobiotic effects. This conclusion harmonizes with those derived from experimental animal studies.