Differential expression of the IRF6 gene in the signs of Van der Woude Syndrome: Are distinct genetic modifiers operating?

Rosany de Oliveira Lisboa, Cláudia Maria da Rocha Martins, Maria Elisabete Silva Santos, Danilo Leôncio Aguiar Pereira, Flávia Martinez de Carvalho, Ieda Maria Orioli, João Farias Guerreiro, Alexandre Rezende Vieira, Luiz Carlos Santana-da-Silva


Objective: The purpose of this study was to report a new variant in the Interferon Regulatory Factor 6 gene (IRF6) and to determine phenotype-genotype correlations in a family segregating Van der Woude syndrome.

Methods: A five-generation family of 80 individuals segregating VWS was investigated using a tabulated pedigree but considering that three individuals registered in the pedigree died shortly after birth, the final sample size was 77 individuals.  Five individuals had a complete dental clinical examination and molecular analysis performed using direct sequencing of the exon 4 and an adjacent region with 23 base pairs of the IRF6 gene.

Results: Features of VWS reported in family history were present in 36.4% (28/77) of all family members; of these 57% (16/28) had pits in the lower lip, 36% (10/28) had both pits and orofacial clefts and 7 % (2/28) had only orofacial clefts. Developmental dental anomalies were observed in three individuals. The sequence analysis of exon 4 of the IRF6 gene carried out for 4 family members revealed the presence of the SNP rs7552506 (c.175-5C> G) located in five base pairs before the start of exon. The analysis of exon 4 of the IRF6 gene also revealed a new variant c.269G>C (p.Ser90Thr) which causes exchange of the Serine amino acid residue for the Threonine residue.

 Conclusions: The c.269G>C(p.Ser90Thr) can interfere with multimeric interactions and with protein conformation that will be slightly destabilized, because the mutant residue is bigger than the wild-type residue. The phenotypic variations in the cases studied, despite carrying the same genetic mutation, suggest that distinct genetic modifiers operate on the formation of clefts and dental development.


Van der Woude syndrome; Orofacial clefts; IRF6 gene

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DOI: https://doi.org/10.5195/d3000.2021.164

Copyright (c) 2021 Rosany de Oliveira Lisboa, Cláudia Maria da Rocha Martins, Maria Elisabete Silva Santos, Danilo Leôncio Aguiar Pereira, Flávia Martinez de Carvalho, Ieda Maria Orioli, João Farias Guerreiro, Alexandre Rezende Vieira, Luiz Carlos Santana-da-Silva

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