Genetic and environmental factors can also act in concert to disrupt normal development. A classic example is the varied array of clefting syndromes - the failure of the lip or palate to fuse properly. Clefting can involve cleft lip with or without cleft palate (CL/P) or cleft palate alone (CP). Clefting can be the principal birth defect (non-syndromic) or be one symptom in literally hundreds of different syndromes (syndromic). Cleft palate as the only defect may in itself be a separate entity, with a unique origin.
nidcr grantees have mapped the gene for Van der Woude syndrome, the most common form of syndromic clefting, to a narrow band on chromosome 1. However, the genes for non-syndromic clefting have been more elusive targets.
Although CL/P is the most common form of non-syndromic clefting and makes up almost half of all facial malformations, progress has been slow in identifying the many components that are thought to be involved. Yet these are hardly static times in human developmental genetics. Already, the technological advances of the past few years have considerably quickened the pace of the clefting hunt.
In human studies, CL/P has been associated with genes on several different chromosomes. These include the gene for transforming growth factor alpha, the gene for the cell receptor that binds retinoic acid, and several genes involved in basic cellular metabolism. In addition, there are associations with specific regions on chromosomes 4, 6, and 19 that contain both known and unknown genes.
Several environmental influences have also been strongly implicated in CL/P. nidcr-supported researchers found links with maternal cigarette smoking and alcohol consumption. Another risk factor that has emerged is the anti-convulsant drug, Dilantin®, a compound that interferes with cell metabolism. On the positive side, vitamins such as folic acid appear to favor suppression of clefting.
Less is known about the underlying causes of cleft palate (CP) as an independent disorder. Scientists are closing in on the gene for a form of CP transmitted on the X chromosome. Many of the other leads have come from animal studies. Animal models produced by altering or destroying certain genes have produced several suspects, including the gene for transforming growth factor-beta3, the homeobox gene MSX1, and a gene for susceptibility to steroid-induced clefting.
Much of the animal data that points to potential clefting genes is limited by the relatively small portion of the genome that has been analyzed. Scientists at nidcr have embarked on a novel project designed to analyze the entire genomes of mouse lines in which clefting can be chemically induced. The lines were produced by crossbreeding a clefting-resistant and clefting-susceptible mouse line. This breeding experiment produced several "mosaic" lines, which, depending on the combination of inherited genes, varied in their susceptibility to clefting. The researchers then looked for the unique combinations of chromosomes that transmitted clefting susceptibility. Several chromosomal regions, containing numerous candidate genes, were linked to chemically induced clefting. These data, combined with the results of human linkage studies, will hopefully narrow the field of candidate human genes. Another interesting observation to emerge from this mouse model is evidence that some of the same genes may be involved in both cleft lip/cleft palate and cleft palate alone - a controversial area in human clefting research.
Linkage studies in human populations are crucial to assembling the pieces of the human clefting puzzle. nidcr is funding numerous studies through its craniofacial research centers and individual research grants. These projects are looking at both individual cases and large families with a history of clefting. To find the number of individuals needed to identify positive gene linkages, collaborations have been formed with the Atlanta Birth Defects Risk Factor Surveillance Study, the California Birth Defects Monitoring Board, the Lancaster (PA) Cleft Palate Clinic, and various groups and organizations with access to populations in Maryland, Iowa, Texas and Shanghai, China.
Eventually it should be possible to screen parents and affected children for the presence of predisposing genes, and to identify additional risk factors that could perhaps be avoided or nutrients that could be supplemented during the critical period of early pregnancy.