Clinical, radiographic, and genetic evaluation of a novel form of autosomal-dominant oligodontia

A frameshift mutation recently identified within the paired domain of the t ranscription factor, PAX9, has been linked to a unique form of oligodontia in a single, multigenerational family (Stockton et al., 2000). We now descr ibe the phenotypic and segregation analyses of this remarkable kindred, the initial approach taken to identify a candidate gene involved in this form of oligodontia, and the power of this single-family pedigree to generate si gnificant linkage in a genome search. Of the 43 family members enrolled in this study, 21 individuals were affected with several congenitally missing permanent teeth. The pattern of inheritance of the oligodontia trait sugges ted the involvement of a single gene bearing a dominant mutation. To variou s degrees, affected members lacked permanent first, second, and third molar s in all four quadrants. Several individuals with missing molars also lacke d second premolars-most commonly, maxillary second premolars and mandibular central incisors. To the best of our knowledge, this pattern of non-syndro mic, familial tooth agenesis has not been previously described in the liter ature. Since a missense mutation in the homeobox gene, MSX1, was previously linked to tooth agenesis in a single family lacking second premolars and t hird molars, we performed a mutational analysis of MSX1 by PCR. The absence of a mutation in exons 1 and 2 of MSX1 suggested that allelic mutations in the coding region of MSX1 are not associated with this phenotypically dist inct form of oligodontia. Computer simulation of linkage analysis Further p roved that this pedigree alone was sufficient to generate a significant res ult for a total genome scan.