New insights into the genetic and environmental causes of cleft lip and palate

0
0 views

Cleft lip and palate are common birth defects that affect the development of the mouth and face. They occur when the tissues that form the lip or the roof of the mouth do not fuse properly during pregnancy. This can result in a gap or opening in the lip, the palate, or both. Cleft lip and palate can cause difficulties with feeding, speech, hearing, and dental health. They can also affect the appearance and self-esteem of the affected individuals.

The causes of cleft lip and palate are complex and not fully understood. They are thought to involve a combination of genetic and environmental factors. However, the exact genes and environmental exposures that contribute to the risk of clefting are still being identified and studied.

In this article, we will review some of the recent research findings that shed light on the genetic and environmental causes of cleft lip and palate. We will also discuss the implications of these findings for the prevention and treatment of this condition.

Genetic factors

Genetic factors play a significant role in the development of cleft lip and palate. It is estimated that about 70% of the risk of clefting is due to genetic factors, while the remaining 30% is due to environmental factors. However, the genetic factors are not simple or straightforward. There is no single gene that causes cleft lip and palate. Rather, there are many genes that interact with each other and with the environment to influence the risk of clefting.

Some of these genes are known and have been studied extensively. For example, genes that are involved in the signaling pathways that regulate the growth and differentiation of the facial tissues, such as IRF6, MSX1, and SPRY1, have been shown to be associated with cleft lip and palate. Mutations or variations in these genes can disrupt the normal development of the lip and palate and increase the risk of clefting.

cleft lip and palate

However, many other genes that are involved in cleft lip and palate are still unknown or poorly understood. To identify these genes, researchers use various methods, such as genome-wide association studies (GWAS), which scan the entire genome for common variants that are associated with clefting, and whole-genome sequencing (WGS), which analyzes the entire DNA sequence of an individual for rare variants that may cause clefting.

One of the recent studies that used WGS to identify new genes associated with cleft lip and palate was led by Dr. Kerstin U. Ludwig, head of an Emmy Noether group at the Institute of Human Genetics at the University Hospital Bonn. The study analyzed the DNA of more than 200 children with cleft lip and palate and their parents, and compared it with the DNA of families without the condition. The study found that there were more rare variants, especially new mutations, in two regions of the genome that are known to contain common risk variants for clefting. These regions are located near the genes SPRY1 and IRF6. The study also found evidence that another gene, called Musculin, which is a transcription factor that regulates the expression of other genes, is involved in cleft lip and palate. The study suggested that Musculin may influence the development of the facial muscles, which are also affected by clefting.

Another recent study that used WGS to identify new genes associated with cleft lip and palate was led by John Manak, professor in the Department of Biology at the University of Iowa. The study analyzed the DNA of more than 1,000 patients with cleft lip and/or palate from the United States and the Philippines, and looked for copy number variants (CNVs), which are deletions or duplications of small sections of the genome. The study found that there were three genes that were deleted in some of the patients with clefting, but not in their parents or in the control group. These genes are called PAX7, FGF10, and WNT9B. The study confirmed that these genes are directly associated with clefting by reducing their function in two animal models, African clawed frogs and zebrafish. The study showed that these genes are involved in the signaling pathways that regulate the formation of the lip and palate.

These studies demonstrate that there are many genes that contribute to the risk of cleft lip and palate, and that some of these genes are rare or new mutations that are not inherited from the parents. These genes may interact with each other and with the environmental factors to cause clefting.

Environmental factors

Environmental factors are also important in the development of cleft lip and palate. These factors include maternal exposures during pregnancy, such as smoking, alcohol, drugs, infections, nutrition, and stress. These factors may affect the development of the fetus and the expression of the genes that are involved in clefting.

One of the recent studies that investigated the environmental factors associated with cleft lip and palate was led by Dr. Elizabeth Leslie, assistant professor in the Department of Human Genetics at Emory University. The study used data from the National Birth Defects Prevention Study (NBDPS), which is a large, population-based study that collects information on the risk factors and outcomes of various birth defects in the United States. The study analyzed the data of more than 6,000 mothers of children with cleft lip and/or palate and more than 10,000 mothers of children without the condition. The study assessed the maternal exposures to various inflammatory risk factors, such as smoking, infections, fever, and use of anti-inflammatory medications, during the first trimester of pregnancy. The study also genotyped the mothers and the children for common variants in genes that are involved in the inflammatory response, such as IL6, IL10, and TNF.

The study found that there was a significant interaction between the maternal exposures to inflammatory risk factors and the genetic variants in the inflammatory genes. The study showed that the mothers who had both high exposure to inflammatory risk factors and high-risk genetic variants had a higher risk of having a child with cleft lip and/or palate than the mothers who had low exposure or low-risk variants. The study also showed that the effect of the maternal exposures and the genetic variants varied depending on the type of clefting. For example, the study found that smoking increased the risk of cleft lip with or without cleft palate, but not the risk of cleft palate alone. The study also found that fever increased the risk of cleft palate alone, but not the risk of cleft lip with or without cleft palate.

These findings suggest that cleft lip and palate are caused by a combination of genetic and environmental factors that affect the inflammatory response during pregnancy. The findings also suggest that different types of clefting may have different causes and mechanisms.

Implications and future directions

The research on the genetic and environmental causes of cleft lip and palate has important implications for the prevention and treatment of this condition. By identifying the genes and the environmental factors that are associated with clefting, the researchers can develop better ways to screen, diagnose, and counsel the families who are affected by this condition. The researchers can also design interventions that can reduce the risk of clefting by modifying the environmental factors or targeting the genes that are involved in clefting. For example, the researchers can advise the pregnant women to avoid smoking, alcohol, drugs, infections, and stress, and to take folic acid supplements, which have been shown to reduce the risk of clefting. The researchers can also develop gene therapies or gene editing techniques that can correct the mutations or variations in the genes that cause clefting.

However, there are still many challenges and limitations in the research on the genetic and environmental causes of cleft lip and palate. One of the challenges is the complexity and heterogeneity of the condition. Cleft lip and palate can occur in different forms and severities, and can be associated with other syndromes or anomalies. Therefore, it is difficult to find a common cause or mechanism for all types of clefting. Another challenge is the interaction and interplay between the genetic and environmental factors. It is not easy to separate the effects of the genes and the environment, or to measure the exposure and the response accurately. Moreover, there may be other factors that influence the risk of clefting, such as epigenetic factors, which are changes in the gene expression that are not caused by changes in the DNA sequence, but by environmental or developmental factors.

Therefore, more research is needed to understand the genetic and environmental causes of cleft lip and palate. The researchers need to use larger and more diverse samples, more advanced and comprehensive methods, and more integrative and interdisciplinary approaches, to identify and validate the genes and the environmental factors that are involved in clefting. The researchers also need to collaborate and communicate with each other, and with the clinicians, the patients, and the families, to translate the research findings into clinical practice and public health policy. By doing so, the researchers hope to improve the lives and the outcomes of the individuals who are affected by cleft lip and palate.

LEAVE A REPLY

Please enter your comment!
Please enter your name here