Genetic Factors and Orofacial Clefting

Abstract

Cleft lip with or without cleft palate is the most common facial birth defect and it is caused by a complex interaction between genetic and environmental factors. The purpose of this review is to provide an overview of the spectrum of the genetic causes for cleft lip and cleft palate using both syndromic and nonsyndromic forms of clefting as examples. Although the gene identification process for orofacial clefting in humans is in the early stages, the pace is rapidly accelerating. Recently, several genes have been identified that have a combined role in up to 20% of all clefts. While this is a significant step forward, it is apparent that additional cleft causing genes have yet to be identified. Ongoing human genome-wide linkage studies have identified regions in the genome that likely contain genes that when mutated cause orofacial clefting, including a major gene on chromosome 9 that is positive in multiple racial groups. Currently, efforts are focused to identify which genes are mutated in these regions. In addition, parallel studies are also evaluating genes involved in environmental pathways. Furthermore, statistical geneticists are developing new methods to characterize both gene-gene and gene-environment interactions to build better models for pathogenesis of this common birth defect. The ultimate goal of these studies is to provide knowledge for more accurate risk counseling and the development of preventive therapies.

Figure 1

Pedigree showing a dominant pattern of inheritance. Dominance means only 1 of the 2 copies of a gene needs to be mutated to cause the disease or trait. Hence at least 1 parent is affected and 50% of descendants from affected parents are also affected. For mapping purposes, in a trait (disease) with high penetrance, every normal person can be assumed to not carry the trait (disease) gene. Thus this pedigree is much more powerful for mapping than a disease with incomplete penetrance as shown in figure 5. Shaded individuals are affected with the trait (disease) of interest.

Figure 2

Pedigree showing a recessive pattern of inheritance. Recessive means that both copies of a gene need to be mutated to cause the disease or trait. In this situation both parents are not affected, but descendants of parents who are both carriers will be affected, unaffected (but trait or disease gene carriers like the parents), or unaffected with normal genes in proportions of 25%:50%:25% on average. These are also the respective likelihoods of a child being one of the three outcomes at conception. Once it is known that a child of carrier parents is not affected, then the chance of the child being a carrier is 2 out of 3. Shaded individuals are affected and individuals with dots are carriers of the specific trait (disease).

Figure 3

Pedigree showing an X-Linked pattern of inheritance. Male descendants from carrier females are usually affected since they only have one X chromosome. Females may be variably affected depending upon the X-inactivation pattern. Shaded individuals are affected and individuals with dots are carriers of the specific trait (disease).

Figure 4

The spectrum of underlying genetic causes for diseases, ranging from single gene to multiple genes. All diseases and traits are also under influence of modifier genes (small arrows) and nongenetic or environmental factors. These influences can be protective or negative and ultimately the balance of all factors determines the outcome. Printed with permission from.

Figure 5

Patient with Van der Woude syndrome with a repaired right cleft lip and two abnormal mounds on the vermilion of the lower lip that are indicative of lower lip pits.

Figure 6

Pedigree showing a complex inheritance pattern. Note that the number of affected descendants in the pedigree does not match expected proportions from any possible Mendelian pattern. One can assume that the linking relatives between affected individuals are disease gene carriers and at least one of the original parents is also a carrier. Because of the reduced penetrance, it is not possible to know for certain that an unaffected person is not a disease gene carrier and hence unaffected people do not add to the mapping power of the pedigree. Therefore this pedigree has significantly reduced power compared to those in figure 1 and figure 2 even though it contains more people. Shaded individuals are affected and individuals with dots are carriers of the specific trait.

Figure 7

Expression of the MSX1 messenger RNA in the medial nasal (MNP), lateral nasal (LNP), and maxillary (MxP) processes at the time of primary palate fusion on gestational day 11.5 in a mouse embryo.