IRF6 Missense Mutations and Oral Clefts in Puerto Rican Hispanics

Objectives: Approximately 15 babies/10,000 live births are born with cleft lip with or without palate (CL/P) in Puerto Rico (PR). Van der Woude syndrome (VWS) is the most common type of syndromic cleft, accounting for 2% of all CL/P with variable phenotypic expression. IRF6 mutations have been previously identified in individuals with VWS. This study aims to identify IRF6 functional variant mutations in Puerto Ricans with CL/P.
Methods: Children with CL/P, ages 0-14 years, were recruited. Mothers were interviewed for maternal exposures and a blood sample (2-5ml) from child/mother/father was collected. We carried out Sanger sequencing using DNA samples from the probands (n=111) to study IRF6 variants. Results were confirmed by reverse and sequenced DNA of those probands’ parents with missense mutations. Families were clinically re-examined to identify presence of lip pits/VWS.
Results: Three missense mutations were found in IRF6. Two were known mutations and one was unknown or novel. The two previously reported missense variants were found in exons 3 and 7 in CL/P cases but parents did not present lip pits/family history of VWS. The novel Q438L glutamine to leucine missense variant was located in exon 9 on proband with absence of lip pits/VWS characteristics. We identified the same variant in father and absence of lip pits/VWS characteristics in the family. The IRF6 novel variant present in this Puerto Rican family has not been previously reported in dbSNP nor 1,000 genomes databases.
Conclusions: IRF6 missense mutations are important since they are associated with VWS etiology, an autosomal dominant form of CL/P that can be a phenocopy of non-syndromic CL/P. Our findings contribute to the list of IRF6 mutations in VWS etiology. It is important to identify these mutations for genetic counseling since the recurrence rate for VWS is 50%.