Novel IRF6 Mutations Detected in Orofacial Cleft Patients by Targeted Massively Parallel Sequencing

Area of Science:

• Genetics
• Developmental Biology
• Craniofacial Anomalies

Background:

• Common IRF6 variants are linked to nonsyndromic cleft lip/palate (NSCL/P) and tooth agenesis (TA), but explain limited heritability.
• IRF6 mutations are a known cause of syndromic orofacial clefting (OFC).
• The potential role of rare IRF6 mutations in nonsyndromic OFC remains underexplored.

Purpose of the Study:

• To investigate rare IRF6 variants in patients with nonsyndromic OFC and TA.
• To identify novel genetic causes for these congenital conditions.

Main Methods:

• Targeted multiplex sequencing using molecular inversion probes (MIPs).
• Analysis of 1,072 OFC patients, 67 TA patients, and 706 controls.
• Identification and characterization of de novo and rare missense variants.

Main Results:

• Three potentially pathogenic de novo IRF6 mutations were identified in OFC patients.
• Three rare missense variants were found, with uncertain pathogenicity.
• One patient with a de novo mutation showed lip pits, suggestive of Van der Woude syndrome (VWS).

Conclusions:

• Rare IRF6 mutations may contribute to nonsyndromic OFC.
• Further investigation is needed to confirm the pathogenicity of identified rare variants.
• The findings expand the spectrum of IRF6-related orofacial clefting phenotypes.