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

Authors

  • Rosany de Oliveira Lisboa Laboratory of Inborn Errors of Metabolism, Institute of Biological Sciences, Federal University of Pará, Pará, Brazil. Oncology and Medical Sciences Graduate Program, Federal University of Pará, Pará, Brazil. Department of Oral Biology and Pediatric Dentistry and Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. https://orcid.org/0000-0002-1513-1148
  • Cláudia Maria da Rocha Martins Department of Speech therapy, Ophir Loyola Hospital, Pará, Brazil.
  • Maria Elisabete Silva Santos Laboratory of Inborn Errors of Metabolism, Institute of Biological Sciences, Federal University of Pará, Pará, Brazil. Genetics and Molecular Biology Postgraduate Studies Program, Federal University of Pará, Pará, Brazil.
  • Danilo Leôncio Aguiar Pereira Laboratory of Inborn Errors of Metabolism, Institute of Biological Sciences, Federal University of Pará, Pará, Brazil. Genetics and Molecular Biology Postgraduate Studies Program, Federal University of Pará, Pará, Brazil.
  • Flávia Martinez de Carvalho ECLAMC at LEMC (Laboratory of Congenital Malformation Epidemiology), Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
  • Ieda Maria Orioli Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. ECLAMC (Latin‐American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil.
  • João Farias Guerreiro Laboratory of Human and Medical Genetics, Federal University of Pará, Pará, Brazil. Genetics and Molecular Biology Postgraduate Studies Program, Federal University of Pará, Pará, Brazil.
  • Alexandre Rezende Vieira Departments of Oral Biology and Pediatric Dentistry and Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • Luiz Carlos Santana-da-Silva Laboratory of Inborn Errors of Metabolism, Institute of Biological Sciences, Federal University of Pará, Pará, Brazil. Oncology and Medical Sciences Graduate Program, Federal University of Pará, Pará, Brazil. National Institute on Population Medical Genetics, Institute of Biological Sciences, Federal University of Pará, Pará, Brazil.

DOI:

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

Keywords:

Van der Woude syndrome, Orofacial clefts, IRF6 gene

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.

Author Biography

Luiz Carlos Santana-da-Silva, Laboratory of Inborn Errors of Metabolism, Institute of Biological Sciences, Federal University of Pará, Pará, Brazil. Oncology and Medical Sciences Graduate Program, Federal University of Pará, Pará, Brazil. National Institute on Population Medical Genetics, Institute of Biological Sciences, Federal University of Pará, Pará, Brazil.

Laboratory of Inborn Errors of Metabolism, Institute of Biological Sciences, Federal University of Pará.

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Published

2021-11-04

Issue

Vol. 9 No. 1 (2021)

Section

Development of Craniofacial Structures

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