Multifactorial Inheritance Hypothesis for the Etiology of Congenital Heart Diseases: The Genetic-Environmental Interaction

Abstract

A systematic investigation into the etiology of congenital heart diseases (CHD) has been undertaken through the testing of four alternative hypotheses. Data was obtained for six common congenital heart lesions from the investigation of familial aggregates, twin studies, and chromosomal evaluations. Animal homologies were also considered in the evaluation of the hypotheses. Hypothesis 1—no genetic basis for the etiology of congenital heart diseases—was tested and rejected. Then in an effort to define the possible genetic basis of congenital cardiovascular malformations hypothesis 2—the genetic basis of CHD is determined by gross chromosomal aberrations—was evaluated by reviewing karyotypes of nonsyndrome CHD patients in the literature as as well as 104 personal cases. Rejection of hypothesis 2 is required by all available evidence. Hypothesis 3—the genetic basis of common isolated congenital heart lesions is determined by single mutant genes—was also tested and rejected. Hypothesis 4—congenital heart diseases are a heterogeneous category of developmental anomalies, representing in most cases the multifactorial inheritance of threshold characters, the expression of which is the product of a genetic-environmental interaction—was tested by the same criteria. On the basis of these criteria this hypothesis could not be rejected. Therefore the multifactorial hypothesis is proposed as a working hypothesis which encompasses both the genetic and environmental factors known to participate in the etiology of congenital heart diseases. It is hoped that through the testing of this hypothesis investigation into new areas will be stimulated, which ultimately will lead to active methods of prevention.