Craniofacial Morphology in familial cases of cleft lip/palate: phenotypic heterogeneity and genetic predisposition in unaffected family members

Abstract

This study investigated familial cases of cleft lip with or without cleft palate to determine whether the unaffected members of each family can be identified as gene carriers for the cleft trait. This research presumes that such carriers will have henotypic features identifiable by cephalometric analysis that are associated with an increased risk to cleft offspring. Using population genetics methodology, a pedigree analysis was made for each family member was assigned to one of four groups: (1) obligate normal, (2) affected, (3) carrier, and (4) unknown. LA and PA cephalographs were taken on each subject and a clinical oral-facial examination carried out on participating family members. Various anatomic landmarks located on the LA and PA films were digitized and from them, a total of 28 linear measurements were made. To eliminate the effect of sex and differential age responses, Z scores were calculated. Through univariate analysis, only one variable, NCR-MO, was shown to be significantly different between the two groups. This variable difference by itself is not adequate to differentiate those in the normal group from the carrier group. Even though only one variable was significant, other differences in the variables between these groups become obvious when the group variables were plotted as Z scores. Since Z scores are pure values with no limits (2--the number of standard deviations in a given variable differs from normal). Thereby, age-related growth differences were minimized. Further information is gained when these Z scores are plotted as pattern profiles, Figures 5-7. These profiles of mean Z scores for each variable pointed out areas of the face in which the differences were so great that specific anatomic areas appeared to be associated with one of the four groups. For example, gene carriers demonstrated specific alterations in facial height that might conceivably be used to discriminate that group from the other three groups. The family normals and carriers were then analyzed by using a stepwise multivariate analysis. By this approach, a discriminant function was generated consisting of six variables (three each from the lateral and frontal headplates), which proved to be significant in distinguishing an individual's phenotype. These variables define facial height, width and depth. The specific findings included a decrease in mid-facial height and depth along with an increased lower facial height and width in the gene carrier population as compared to the normals. The function then was used to predict group membership of the same two groups. Comparing this analytical prediction to that of the grouping system that resulted from the pedigree analysis, all but one individual was classified correctly in both the normal and carrier population. A discriminant score was also determined for the unknown population of family members which were defined as non-cleft blood relatives of cleft probands. Thus, they were a mixture of two types--those unaffected who carried a genetic liability for producing a cleft child and those unaffected who did not. A prediction of their placement into either the normal or carrier group was made with the discriminate function. One-third were classed in the normal group and two-thirds as gene carriers. The results of this study confirm that the phenotype of these unaffected family members designated as obligate gene carriers differs significantly from that of the family normals. This information is not only quite useful for genetic counselling but gives both a better understanding or the genetic control of clefting and can lead to molecular research to identify the specific gene in question.