The multifactorial/threshold concept -- uses and misuses

F Clarke Fraser


The common congenital malformations have familial distributions that cannot be accounted for by simple Mendelian models, but can be explained in terms of a continuous variable, "liability," with a threshold value beyond which individuals will be affected. Both genetic and environmental factors determine liability, making the system multifactorial. Cleft palate is a useful experimental model, illustrating a number of factors that contribute to palate closure, the nature of a developmental threshold, and how genes and teratogens can alter the components of liability to increase the probability of cleft palate. The nature of the genetic component to liability in human malformations in not clear, and various possibilities, ranging from polygenic in the strict sense to a major gene with reduced penetrance are compatible with the data -- but the important feature is the threshold. Much of the confusion over the concept results from inconsistent use of terminology. The term "multifactorial" should be used for "determined by a combination of genetic and environmental factors," without reference to the nature of the genetic factor(s). "Polygenic" should be reserved for "a large number of genes, each with a small effect, acting additivel...Continue Reading


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Cleft Palate, Isolated
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