What genes are associated with isolated cleft lip and cleft lip and palate?

Genes Associated with Isolated Cleft Lip and Cleft Lip and Palate

Multiple genes have been identified in association with isolated cleft lip and cleft lip with palate, with IRF6, MSX1, PVRL1, and TBX22 being the most strongly implicated genes with established evidence.

Key Genes in Nonsyndromic Cleft Lip and Palate

Primary Genes with Strong Evidence

• IRF6 (Interferon Regulatory Factor-6)

  • Most widely studied gene for nonsyndromic cleft lip/palate
  • Also causes Van der Woude syndrome (accounts for ~2% of all CL/P cases) 1
  • Mutations in this gene affect both syndromic and nonsyndromic forms 1

• MSX1 (Muscle Segment Homeobox 1)

  • Associated with OFC5 locus 2
  • Involved in craniofacial development and palate formation
  • Mutations lead to isolated cleft lip with or without cleft palate

• PVRL1 (Poliovirus Receptor-Like-1)

  • Associated with OFC7 locus 2
  • Causes cleft lip/palate-ectodermal dysplasia syndrome
  • Also implicated in nonsyndromic forms 3

• TBX22 (T-box Transcription Factor-22)

  • Primary gene identified for isolated cleft palate 2
  • Causes X-linked cleft palate
  • Also involved in nonsyndromic cleft palate 3

Additional Significant Genes

• TGFB3 (Transforming Growth Factor Beta 3)

  • Important role in palate development 2
  • Involved in cell signaling during craniofacial development

• PAX9 (Paired Box 9)

  • Part of the gene regulatory network for palate and lip development 4
  • Interacts with IRF6 in craniofacial development

• JAG2 (Jagged 2)

  • Functions in the IRF6-related gene regulatory network 4
  • Critical for proper palate formation

• RARA (Retinoic Acid Receptor Alpha)

  • Involved in cleft onset 2
  • Part of the IRF6 gene network 4

Genetic Loci Associated with Cleft Lip/Palate

Several loci have been identified and designated as OFC (Orofacial Cleft) loci:

• OFC1: Mapped to chromosome 6p24 2
• OFC2: Mapped to 2p13 2
• OFC3: Mapped to 19q13.2 2
• OFC4: Mapped to 4q 2
• OFC9: Maps to 13q33.1-q34 2
• OFC10: Associated with haploinsufficiency of the SUMO1 gene 2

Genetic Associations in Syndromic Forms

• CDC45: Associated with craniosynostosis, cleft lip/palate, and other anomalies (CGS syndrome) 5
• TANGO2: Associated with multiple disorders including cleft lip/palate 5
• CDH1: Mutations associated with cleft lip/cleft palate and gastric cancer (HDGC) 5

Clinical Implications and Genetic Testing

• Genetic testing should be considered for individuals with:

  • Personal or family history of cleft lip/palate with gastric cancer 5
  • Cleft lip/palate as part of multiple congenital anomalies
  • Family history of cleft lip/palate suggesting Mendelian inheritance

• Genetic counseling is essential for families with:

  • Known genetic mutations associated with cleft lip/palate
  • Multiple affected family members
  • Cleft lip/palate as part of a recognized syndrome

Environmental Interactions

• Certain medications during pregnancy may increase risk of cleft lip/palate:

  • Systemic corticosteroids in first trimester (3-fold increased risk) 5
  • Some anticonvulsants

• Gene-environment interactions are significant:

  • Genetic susceptibility may be triggered by environmental factors
  • Multifactorial inheritance pattern in most nonsyndromic cases 3

Diagnostic Approach

For patients with cleft lip/palate:

1. Determine if isolated or syndromic (look for associated anomalies)
2. Collect detailed family history (3-generation pedigree)
3. Consider genetic testing based on clinical presentation:
   • Targeted gene panels for suspected syndromes
   • Broader testing for complex presentations
4. Refer to multidisciplinary cleft team for comprehensive management

Understanding the genetic basis of cleft lip and palate continues to evolve, with new genes being identified through advanced genetic technologies. The complex interplay between genetic and environmental factors makes this a challenging but important area for continued research.