What genes are associated with oral clefts (orofacial clefts)?

From the Guidelines

Oral clefts are primarily associated with genetic variants in IRF6, MSX1, and other genes involved in craniofacial development pathways, and their risk can be mitigated through folic acid supplementation, avoidance of tobacco and alcohol, and good nutrition. The genetic basis of oral clefts is complex, involving multiple genes and environmental factors 1. Key genes associated with oral clefts include IRF6, which causes Van der Woude syndrome and is linked to non-syndromic clefts, and MSX1, which plays a role in facial development. Other important genes include FOXE1, MAFB, PAX9, BMP4, and TGFA, all involved in craniofacial development pathways. Variants in CRISPLD2, TBX22, and FGFR genes have also been implicated 1.

Genetic Factors and Environmental Influences

The interaction between genetic factors and environmental influences, such as maternal smoking, alcohol consumption, poor nutrition (particularly folate deficiency), and certain medications during pregnancy, contributes to the development of oral clefts 1. For families with a history of clefting, genetic counseling is recommended to assess recurrence risk, which varies from 3-5% with one affected child to 10-15% with two affected children.

Prevention Strategies

Prevention strategies include folic acid supplementation (400-800 mcg daily) before and during pregnancy, avoiding tobacco and alcohol, and maintaining good nutrition 1. Understanding these genetic factors helps explain why clefts often run in families and supports the multifactorial inheritance pattern observed in most cases. The application of pathway analysis, such as GWASPA, can help identify larger genetic effects and accommodate genetic heterogeneity among different pathways and ethnic groups 1.

Key Genes and Pathways

Some of the key genes and pathways involved in oral clefts include:

• IRF6: Interferon Regulatory Factor 6, associated with Van der Woude syndrome and non-syndromic clefts
• MSX1: involved in facial development
• FOXE1, MAFB, PAX9, BMP4, and TGFA: involved in craniofacial development pathways
• CRISPLD2, TBX22, and FGFR: variants implicated in oral clefts These genes and pathways play a crucial role in the development of oral clefts, and their interaction with environmental factors contributes to the complexity of the condition 1.

From the Research

Genetic Factors Influencing Oral Clefts

• Oral clefts, including cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP), have a strong familial aggregation, suggesting a major genetic component to their etiology 2.
• Genome-wide association studies have identified almost two dozen different genes achieving genome-wide significance, and there are broad classes of 'causal genes' for orofacial clefts 2.
• Genetic studies have identified several genes influencing risk, but these differ across families and across populations 2, 3.

Gene-Environment Interactions

• Both genetics and environmental factors are involved in the etiology of oral clefts 3, 4.
• The prevention of oral clefts is not possible without knowing the precise etiology, and genetic counseling can now identify high-risk families 3.
• Folic acid supplementation during the periconceptional period has been found effective in the prevention of neural tube defects, and may also play a role in the prevention of oral clefts 5, 4.

Specific Genes Associated with Oral Clefts

• More than 350 genes have syndromic and/or nonsyndromic oral cleft associations in humans 6.
• Genes related to genetic disorders associated with oral cleft phenotypes are known, but a gap between detecting these associations and interpretation of their biological importance has remained 6.
• The transforming growth factors alpha and beta (TGF alpha, TGF beta 2, TGF beta 3), the retinoic acid receptor (RARA), and the methylenetetrahydrofolate reductase receptor (MTHFR) are examples of genes that may be associated with oral clefts 4.

Complexity of Oral Cleft Etiology

• The etiology of oral clefts is complex and heterogeneous, with causes linked to environment, genetics, and gene-environment interaction 3, 4.
• Understanding the different causative etiologies of oral clefts is important, as it may lead to improvements in diagnosis, counseling, and prevention 6.
• Further investigation is required to study in depth how the genotype would modify the role of environmental factors like folic acid 4.