title: The controversial p.Met34Thr variant in GJB2 gene: Two siblings, one genotype, two phenotypes.
abstract: BACKGROUND
  Recent advances in molecular genetics have increased the identification of genes and mutations responsible for inherited forms of hearing loss (HL), enabling early detection of these cases. Approximately, 60% of early-onset HL cases are due to genetic causes, of which 70% are non-syndromic. Of these, 75-80% are inherited in an autosomal recessive pattern (DFNB). Mutations in GJB2 gene, coding for connexin 26 (Cx26), are the major cause of autosomal recessive hereditary HL, but some GJB2 mutations are yet of unclear or controversial significance.
  
  
  OBJECTIVE
  The aim of the present study was to identify the etiology of hearing loss, and correlate genotype-phenotype, in two Portuguese siblings with profound and moderate non-syndromic sensorineural bilateral HL.
  
  
  METHODS
  The affected subjects and their parents underwent audiological and genetic study. Molecular analysis of GJB2 gene was performed, searching for mutations in the coding region and receptor splicing site by automated sequencing.
  
  
  RESULTS
  The onset and the degree of HL were different in the two affected subjects. However, the same GJB2 genotype [p.Met34Thr]+[p.Arg184Pro] was identified in both siblings. The c.551G>C (p.Arg184Pro) and c.101T>C (p.Met34Thr) missense variants were inherited from the father and mother, respectively, both heterozygous carriers of these variants.
  
  
  CONCLUSIONS
  The clinical and genetic data here presented suggest that the non-syndromic sensorineural HL of these two Portuguese siblings might be due to the presence of p.Met34Thr and p.Arg184Pro variants in compound heterozygosity. If so, p.Met34Thr variant could have function as a hypomorphic allele that may cause HL depending on the opposing GJB2 allele. The observed phenotypic variability may not, however, be solely explained by variable expression of this genotype. A putative modifier gene or mutations in another HL-associated gene could probably be contributing to the severe HL in one of the siblings.
authors.affiliation: ENT-CHLO, HEM, ENT Service, Centro Hospitalar de Lisboa Ocidental EPE, Egas Moniz Hospital, Lisbon, Portugal; NMS/UNL, Department of Otorhinolaryngology, Nova Medical School, New University of Lisbon, Lisbon, Portugal.
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Lameiras
authors.affiliation: BioISI - Biosystems & Integrative Sciences Institute, Faculty of Science of the University of Lisbon, Lisbon, Portugal. Electronic address: Claudiagoncalves030@gmail.com.
authors.forename: Ana Cláudia
authors.initials: AC
authors.lastname: Gonçalves
authors.affiliation: ENT-CHLO, HEM, ENT Service, Centro Hospitalar de Lisboa Ocidental EPE, Egas Moniz Hospital, Lisbon, Portugal; NMS/UNL, Department of Otorhinolaryngology, Nova Medical School, New University of Lisbon, Lisbon, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Santos
authors.affiliation: ENT-CHLO, HEM, ENT Service, Centro Hospitalar de Lisboa Ocidental EPE, Egas Moniz Hospital, Lisbon, Portugal; NMS/UNL, Department of Anatomy, Nova Medical School, New University of Lisbon, Lisbon, Portugal.
authors.forename: Assunção
authors.initials: A
authors.lastname: O'Neill
authors.affiliation: ENT-CHLO, HEM, ENT Service, Centro Hospitalar de Lisboa Ocidental EPE, Egas Moniz Hospital, Lisbon, Portugal; NMS/UNL, Department of Otorhinolaryngology, Nova Medical School, New University of Lisbon, Lisbon, Portugal.
authors.forename: Luís Roque Dos
authors.initials: LR
authors.lastname: Reis
authors.affiliation: BioISI - Biosystems & Integrative Sciences Institute, Faculty of Science of the University of Lisbon, Lisbon, Portugal.
authors.forename: Tiago Daniel
authors.initials: TD
authors.lastname: Matos
authors.affiliation: BioISI - Biosystems & Integrative Sciences Institute, Faculty of Science of the University of Lisbon, Lisbon, Portugal.
authors.forename: Graça
authors.initials: G
authors.lastname: Fialho
authors.affiliation: BioISI - Biosystems & Integrative Sciences Institute, Faculty of Science of the University of Lisbon, Lisbon, Portugal; ESS/IPS, School of Health, Polytechnic Institute of Setúbal, Setúbal, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Caria
authors.affiliation: ENT-CHLO, HEM, ENT Service, Centro Hospitalar de Lisboa Ocidental EPE, Egas Moniz Hospital, Lisbon, Portugal; NMS/UNL, Department of Otorhinolaryngology, Nova Medical School, New University of Lisbon, Lisbon, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Escada
mesh_terms: D000328:Adult; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006312:Hearing Loss, Bilateral / Q000175:diagnosis / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D035781:Siblings
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D005819:Genetic Markers; D000072259:Connexin 26
keywords: GJB2 p.Met34Thr pathogenesis; Non-syndromic hearing loss