title: The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population.
abstract: BACKGROUND
  Congenital hearing loss (CHL) is diagnosed in 1 - 2 newborns in 1000, genetic factors contribute to two thirds of CHL cases in industrialised countries. Mutations of the GJB2 gene located in the DFNB1 locus (13q11-12) are a major cause of CHL worldwide. The aim of this cross-sectional study was to assess the contribution of the DFNB1 locus containing the GJB2 and GJB6 genes in the development of early onset hearing loss in the affected group of participants, to determine the population-specific mutational profile and DFNB1-related HL burden in Lithuanian population.
  
  
  METHODS
  Clinical data were obtained from a collection of 158 affected participants (146 unrelated probands) with early onset non-syndromic HL. GJB2 and GJB6 gene sequencing and GJB6 gene deletion testing were performed. The data of GJB2 and GJB6 gene sequencing in 98 participants in group of self-reported healthy Lithuanian inhabitants were analysed. Statistic summary, homogeneity tests, and logistic regression analysis were used for the assessment of genotype-phenotype correlation.
  
  
  RESULTS
  Our findings show 57.5% of affected participants with two pathogenic GJB2 gene mutations identified. The most prevalent GJB2 mutations were c.35delG, p. (Gly12Valfs*2) (rs80338939) and c.313_326del14, p. (Lys105Glyfs*5) (rs111033253) with allele frequencies 64.7% and 28.3% respectively. GJB6 gene mutations were not identified in the affected group of participants. The statistical analysis revealed significant differences between GJB2(-) and GJB2(+) groups in disease severity (p = 0.001), and family history (p = 0.01). The probability of identification of GJB2 mutations in patients with various HL characteristics was estimated. The carrier rate of GJB2 gene mutations - 7.1% (~1 in 14) was identified in the group of healthy participants and a high frequency of GJB2-related hearing loss was estimated in our population.
  
  
  CONCLUSIONS
  The results show a very high proportion of GJB2-positive individuals in the research group affected with sensorineural HL. The allele frequency of c.35delG mutation (64.7 %) is consistent with many previously published studies in groups of affected individuals of Caucasian populations. The high frequency of the c.313_326del14 (28.3 % of pathogenic alleles) mutation in affected group of participants was an unexpected finding in our study suggesting not only a high frequency of carriers of this mutation in our population but also its possible origin in Lithuanian ancestors. The high frequency of carriers of the c.313_326del14 mutation in the entire Lithuanian population is supported by it being identified twice in the ethnic Lithuanian group of healthy participants (a frequency 2.0 % of carriers in the study group).
  
  
  CONCLUSIONS
  Analysis of the allele frequency of GJB2 gene mutations revealed a high proportion of c. 313_326del14 (rs111033253) mutations in the GJB2-positive group suggesting its possible origin in Lithuanian forebears. The high frequency of carriers of GJB2 gene mutations in the group of healthy participants corresponds to the substantial frequency of GJB2-associated HL in Lithuania. The observations of the study indicate the significant contribution of GJB2 gene mutations to the pathogenesis of the disorder in the Lithuanian population and will contribute to introducing principles to predict the characteristics of the disease in patients.
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. violeta.mikstiene@mf.vu.lt.
authors.forename: Violeta
authors.initials: V
authors.lastname: Mikstiene
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. audrone.jakaitiene@mf.vu.lt.
authors.forename: Audrone
authors.initials: A
authors.lastname: Jakaitiene
authors.affiliation: Centre of Ear, Nose and Throat Diseases, Vilnius University Hospital Santariskiu clinics, Vilnius, Lithuania. jekaterina.byckova@gmail.com.
authors.forename: Jekaterina
authors.initials: J
authors.lastname: Byckova
authors.affiliation: Centre of Ear, Nose and Throat Diseases, Vilnius University Hospital Santariskiu clinics, Vilnius, Lithuania. egle.gradauskiene@vuvl.lt.
authors.forename: Egle
authors.initials: E
authors.lastname: Gradauskiene
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. eglepreiksaitiene@gmail.com.
authors.forename: Egle
authors.initials: E
authors.lastname: Preiksaitiene
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. birute.burnyte@gmail.com.
authors.forename: Birute
authors.initials: B
authors.lastname: Burnyte
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. tumbir@gmail.com.
authors.forename: Birute
authors.initials: B
authors.lastname: Tumiene
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. ausramatuleviciene@gmail.com.
authors.forename: Ausra
authors.initials: A
authors.lastname: Matuleviciene
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. laima.ambrozaityte@mf.vu.lt.
authors.forename: Laima
authors.initials: L
authors.lastname: Ambrozaityte
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. ingrida.uktveryte@mf.vu.lt.
authors.forename: Ingrida
authors.initials: I
authors.lastname: Uktveryte
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. ingrida.domarkiene@mf.vu.lt.
authors.forename: Ingrida
authors.initials: I
authors.lastname: Domarkiene
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. tautvydas.rancelis@mf.vu.lt.
authors.forename: Tautvydas
authors.initials: T
authors.lastname: Rancelis
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. loreta.cimbalistiene@santa.lt.
authors.forename: Loreta
authors.initials: L
authors.lastname: Cimbalistiene
authors.affiliation: Centre of Ear, Nose and Throat Diseases, Vilnius University Hospital Santariskiu clinics, Vilnius, Lithuania. eugenijus.lesinskas@santa.lt.
authors.forename: Eugenijus
authors.initials: E
authors.lastname: Lesinskas
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. vaidutis.kucinskas@mf.vu.lt.
authors.forename: Vaidutis
authors.initials: V
authors.lastname: Kucinskas
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. algirdas.utkus@mf.vu.lt.
authors.forename: Algirdas
authors.initials: A
authors.lastname: Utkus
mesh_terms: D000483:Alleles; D002675:Child, Preschool; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D003430:Cross-Sectional Studies; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D056726:Genetic Association Studies; D056426:Genetic Loci; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008097:Lithuania; D016015:Logistic Models; D008297:Male; D009154:Mutation; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics*
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26