Genetic studies of craniofacial anomalies: clinical implications and applications

Abstract

The objective of the study was to overview the role of genetic research in fostering translational studies of craniofacial diseases of dental interest. Background information is presented to illustrate influences affecting genetic research studies of Mendelian diseases. Genetic studies of amelogenesis imperfecta, dentinogenesis imperfecta, hereditary gingival fibromatosis and Papillon Lefèvre syndrome are reviewed. Findings are presented to illustrate how translational applications of clinical and basic research may improve clinical care. Clinical and basic science research has identified specific genes and mutations etiologically responsible for amelogenesis imperfecta, dentinogenesis imperfecta, hereditary gingival fibromatosis and Papillon Lefèvre syndrome. These findings are enabling researchers to understand how specific genetic alterations perturb normal growth and development of dental tissues. Identification of the genetic basis of these conditions is enabling clinicians and researchers to more fully understand the etiology and clinical consequences of these diseases of dental importance. Findings from genetic studies of dental diseases provide a basis for diagnostic genetic testing and development of therapeutic intervention strategies directed at the underlying disease etiology. These studies are advancing our understanding of the development of dental tissues in health and disease. The dental community must consider how to incorporate these developments into effective disease prevention paradigms to facilitate the diagnosis and treatment of individuals with genetic diseases.

Fig. 1

Clinical implications of understanding the genetic basis of disease.

Fig. 2

Amelogenesis imperfecta summary. Genes for which mutations have been identified for each of the Mendelian modes of transmission are illustrated. Clinical photographs illustrating representative examples for each form of Mendelian transmission for AI are shown. The genetic mutation responsible for each case is indicated directly below each photograph. ARAI, autosomal recessive AI; ADAI, autosomal dominant AI; XLAI, X-linked AI).

Fig. 3

PLS pedigree illustrating phenotype, CTSC genotype and CTSC enzyme activity. Filled symbols indicate individuals with a clinical diagnosis of PLS. Half shaded and open symbols are carriers and non carriers, respectively, based upon biochemical and/or mutational analyses. The CTSC protease activity (μmol/min/mg protein) in leukocytes is given below each individual. Mutated CTSC alleles associated with PLS have no enzyme activity. Heterozygote individuals demonstrate approximately 50% enzyme activity levels found in individuals with 2 normal CTSC alleles. The affected individual is homozygous for a c.267_268delGG mutation.

Fig. 4

Disease prevention paradigm for Mendelian diseases. Mendelian diseases reviewed in text are listed in the left column. Specific gene(s) for which etiologic mutations have been identified for each condition are listed in the second column, with the associated Online Mendelian Inheritance in Man (OMIM) catalogue number (1). Third column lists primary pathologic findings associated with mutations of each gene. Fourth column lists clinical complications that commonly result due to the underlying disease pathology. Possible points of treatment intervention (primary, secondary and tertiary) are indicated above.