Genetics of congenital heart malformations: a stochastic model

A stochastic model is proposed to explain how alterations in the properties of developing endocardial cells could control the outgrowth of endocardial cushions in normal persons, in subjects from families with a predisposition to congenital heart defects, and in subjects with trisomy 21. Normal and abnormal outgrowth of the endocardial cushions of the atrioventricular (AV) canal were modeled by computer simulations. Computer simulations depicted not only the sequence of normal AV valve development, but also illustrated how increased cellular adhesiveness of fibroblasts from the endocardial cushions of the AV canal--which we have observed in vitro among cultured cells from Down syndrome abortuses--may result in AV canal defects. The stochastic model so elaborated demonstrates how single gene changes may result in abnormalities in only a proportion of subjects carrying mutant alleles, yielding inheritance patterns characterized previously as being "multifactorial" in origin.