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

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

doi:10.5195/d3000.2021.164

Abstract

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.

Highlights

Orofacial clefts may occur in association with other birth defects or be isolated
The Van der Woude Syndrome (VWS) (Online Mendelian Inheritance in Man [OMIM]119300) is the most common and well-known syndrome associated with orofacial clefts, being present in approximately 2% of orofacial cleft cases [1, 2]
The family did not present a history of consanguineous marriage and from the second generation on, where a family member has a cleft lip and pits, all subsequent generations have more than one affected relative

Summary

Introduction

Orofacial clefts may occur in association with other birth defects or be isolated. The Van der Woude Syndrome (VWS) (Online Mendelian Inheritance in Man [OMIM]119300) is the most common and well-known syndrome associated with orofacial clefts, being present in approximately 2% of orofacial cleft cases [1, 2]. VWS consists of a rare congenital malformation and presents clinical features in addition to orofacial clefts, such as lower lip pits and occasionally, hypodontia. There is a range of associated phenotypes, from the complete absence of visible abnormalities, only the presence of pits in the lower lip, to the combination of these pits with different types of clefts. These types may include aspects such as laterality (unilateral or bilateral), extension (complete and incomplete) and may involve lip, palate or both [2, 5,6,7]

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Conclusion