Cleft lip±cleft palate: An overview of the literature and an analysis of Danish cases born between 1941 and 1968

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Abstract
In recent years there has been some controversy over the analytical designs and the meaning of varying results with regard to studies of facial clefting and other common congenital malformations. Regardless, it is still unclear as to the nature of the genetic and environmental components of the etiology as well as the nature of the relevant pathogenetic mechanisms. Despite claims to the contrary, the predictions of a particular multifactorial/threshold inheritance (MF/T) model delineated by Carter [1977d] and others are not well supported by studies worldwide. The present study population consists of 1,895 persons born in Denmark with cleft lip with or without cleft palate (CL ± P) between 1941 and 1968. A test of the MF/T predictions revealed the following: 1) the incidence of CL ± P in siblings was 40 × greater than that in the general population 2) the risk to siblings of CL ± P females was not significantly different from the risk to siblings of CL ± P males; 3) recurrence risk for siblings of CL ± P probands was dependent upon the proband's cleft type; 4) only 0.4% of the variation in risk to the siblings born after the proband could be accounted for by the number of previously affected siblings; 5) the consanguinity rate was 6 times less than the general population rate; 6) heritability estimates from siblings and parents by sex suggest, either the presence of significant dominance effects, or a common sibling environment component in the etiology of the disorder. Further, testing with a multiple-sex threshold method, designed and provided us by [Kidd and Spence, 1976] revealed that neither the MF/T nor single-major locus with random environmental variation provided a good fit. In light of recent experimental mouse and human data, an alternative model of monogenic-dependent susceptibility to a variety of teratogens is discussed. It is suggested that the genetic basis for diverse kinds of common and uncommon congenital malformations may very well be homogeneous while, at the same, the evironmental basis is heterogeneous.