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GENETIC INFORMATION AND CLEFTS:
New Horizons in Understanding and Prevention
by Dr Jeffrey Murray
Cleft lip and/or palate is an easily recognized, yet complicated disorder with important implications for normal nutritional, dental, speech, hearing and psychological development. A majority of cases of clefting are referred to as "non-syndromic". That means they lack an association with other features commonly found in so-called syndromes. Although statistical analysis of such non-syndromic cases of clefting suggests that genetics plays a strong role in these, it is likely there are different causes, including not only genetic factors, but also environmental and random ones as well.
Syndromic forms of clefting, or those associated with other abnormalities, are also caused by a variety of different factors. There are, in fact, more than 300 known disorders that can involve clefting, with a number of others involving abnormalities of the development of the facial regions. A large number of these have also been identified as being caused by genetic factors. Environmental agents (i.e., drugs, infections, etc) as well as a variety of unknown causes also play a role in this group. As a result, talking about the genetics of cleft lip and palate can be a daunting undertaking.
Human genetic material is made up of a series of components which can be broken down at several different levels. Most of the cells of the body contain packages of genetic material called chromosomes. Each chromosome contains approximately 1,000 genes. Each gene is a specific set of instructions to carry out a specific function of the body. Genes control everything from muscle proteins and the oxygen-carrying molecule hemoglobin, to the determinants of hair and eye color. Each gene is comprised of several thousand base pairs of the molecule, DNA (Deoxyribonucleic Acid). DNA is made up of four independent chemical structures referred to as mic;eptodes (commonly thought of as the letters of the DNA alphabet: A, G, C, or T). An abnormality in even one of these letters can result in enough damage to the inherited material that a significant birth defect, such as a cleft lip or palate, can arise. The entire set of chromosomes contains approximately three BILLION such nucleotides, or letters. Understanding the nature and position of each one of these individual nucleotides presents a challenging goal for science in an attempt to obtain a complete understanding of the human inherited material.
Substantial progress has been made in understanding the nature and position of many different genes and several hundred thousand different nucleotides, but an enormous amount of work is still ahead for a complete understanding of this genetic material. Each of the possibly several hundred different genetic causes of cleft lip and palate may be underlined by different changes in the basic DNA structure. Therefore, the problem of understanding the nature each individual form of cleft lip or palate can take is, again, an extremely difficult one. It is nonetheless underway in many of the laboratories around the world.
In recent years, sophisticated techniques of molecular biology, coupled with improved statistical analysis have allowed physicians, scientists, genetic counselors, developmental biologists and others to gain insight into at least some of the genetic causes of clefting. Several different approaches have been used, including those that involve detailed studies of families that contain more than one individual with cleft.
Information developed form studies of animal models suggests a group of so-called candidate genes that may play a role in normal facial development. These candidate genes can then be studied in greater detail as we look for evidence of specific genetic rearrangements that may underlie disturbances in the normal process of facial development.
The long range goals of such studies are several fold. These goals include obtaining a better understanding of not only the abnormal developmental process, but the normal process as well. A better understanding of the specific genetic factors involved in such processes will hopefully lead to improvements in the ways in which cleft lip and palate may be potentially prevented. For example, it has recently been demonstrated that a usually unrelated birth defect called spina bifida can in some cases have its recurrence risk in families decreased by the use of appropriate vitamin supplementation in the pregnant mother. While as yet there is not confirmed evidence that such vitamin supplementation will play a role in preventing occurrences of cleft, it is hoped that by obtaining a better understanding of the development of the face, we will be better able to identify such factors and target ways to then prevent or decrease the occurrence of clefting disorders.
A second, more immediate goal of such projects is to obtain improvements in our ability to identify the specific genetic components of the many different forms of clefting with the hope that identification of these factors will lead to an improvement in our ability to identify individuals at risk of having a child with a cleft, and to provide those individuals with better information about what the risks are, and how they can then best plan their families in light of a better known and specific risk. In the last several years, progress has been made using these techniques in a variety of inherited disorders, which significant breakthroughs being made in either localizing the genes causing these disorders to specific chromosomes, or identifying the specific gene on a chromosome involved in a particular disorder. some of these successes have been reported in the area of cleft lip and palate and craniofacial development.
---------------------------------Dr Jeffrey Murray is a pediatrician, clinical geneticist and molecular biologist with an interest in the molecular genetics of human craniofacial development. Besides working with families who have children with cleft lip and palate in the US and overseas, he has a laboratory effort to understand genetic components of Van Der Voude Syndrome. He is a member of the Department of Pediatrics at the University of Iowa.