ß 2008 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 146A:2879–2884 (2008) Strong Linkage Disequilibrium for the Frequent GJB2 35delG Mutation in the Greek Population Haris Kokotas, 1 Lut Van Laer, 2 Maria Grigoriadou, 1 Vassiliki Iliadou, 3 John Economides, 4 Stella Pomoni, 1 Andreas Pampanos, 1 Nikos Eleftheriades, 5 Elisabeth Ferekidou, 6 Stavros Korres, 6 Aglaia Giannoulia-Karantana, 7 Guy Van Camp, 2 and Michael B. Petersen 1 * 1 Department of Genetics, Institute of Child Health, Athens, Greece 2 Department of Medical Genetics, University of Antwerp, Antwerp, Belgium 3 Department of Psychoacoustics-Neurootology, AHEPA Hospital, C’ Psychiatric Clinic, Aristotle University of Thessaloniki, Thessaloniki, Greece 4 Department of Audiology-Neurootology, ‘Aghia Sophia’ Children’s Hospital, Athens, Greece 5 Department of Otorhinolaryngology, St. Loukas Hospital, Thessaloniki, Greece 6 Department of Otorhinolaryngology, Athens University, Hippokration Hospital, Athens, Greece 7 Department of Pediatrics, Athens University Medical School, Athens, Greece Received 26 March 2008; Accepted 22 June 2008 Approximately one in 1,000 children is affected by severe or profound hearing loss at birth or during early childhood (prelingual deafness). Up to 40% of congenital, autosomal recessive, severe to profound hearing impairment cases result from mutations in a single gene, GJB2, that encodes the connexin 26 protein. One specific mutation in this gene, 35delG, accounts for the majority of GJB2 mutations detected in Caucasian populations. Some previous studies have assumed that the high frequency of the 35delG mutation reflects the presence of a mutational hot spot, while other studies support the theory of a common founder. Greece is among the countries with the highest carrier frequency of the 35delG mutation (3.5%), and a recent study raised the hypothesis of the origin of this mutation in ancient Greece. We genotyped 60 Greek deafness patients homozygous for the 35delG mutation for six single nucleotide poly- morphisms (SNPs) and two microsatellite markers inside or flanking the GJB2 gene. The allele distribution in the patients was compared to 60 Greek normal hearing controls. A strong linkage disequilibrium was found between the 35delG mutation and markers inside or flanking the GJB2 gene. Furthermore, we found a common haplotype with a previous study, suggesting a common founder for the 35delG mutation. ß 2008 Wiley-Liss, Inc. Key words: recessive deafness; nonsyndromic; GJB2; 35delG; founder effect; ancient Greece; SNP How to cite this article: Kokotas H, Van Laer L, Grigoriadou M, Iliadou V, Economides J, Pomoni S, Pampanos A, Eleftheriades N, Ferekidou E, Korres S, Giannoulia-Karantana A, Van Camp G, Petersen MB. 2008. Strong linkage disequilibrium for the frequent GJB2 35delG mutation in the Greek population. Am J Med Genet Part A 146A:2879 – 2884. INTRODUCTION Mutations in the GJB2 gene represent a major cause of prelingual, nonsyndromic, recessive deafness, as they are responsible for as much as 40% of such cases in many populations [Zelante et al., 1997; Denoyelle et al., 1997; Rabionet et al., 2000; Kenneson et al., 2002]. The GJB2 gene has a single coding exon, and the protein belongs to the large family of connexins which have been implicated in gap-junctional intercellular communication. Loss or malfunction of these gap junctions, as resulting from mutations in the GJB2 gene, may disrupt potassium movement from the hair cells through the supporting cell network back to the endolymph, leading to hearing impairment. Deafness can also be caused by defective permeation of inositol-1,4,5-triphosphate (InsP(3)) through gap junctions [Hernandez et al., 2007]. A limited number of GJB2 mutations lead to autosomal dominant hearing loss, and others lead to syndromic hearing loss with skin disorders as the accompanying symptom, such as palmoplantar keratoderma with hearing loss [Rabionet et al., 2000] and keratitis-ichthyosis-deafness (KID) syndrome Grant sponsor: Oticon Foundation (MBP). *Correspondence to: Dr. Michael B. Petersen, Department of Genetics, Institute of Child Health, ‘Aghia Sophia’ Children’s Hospital, Thivon & Levadias, 115 27 Athens, Greece. E-mail: inchildh@otenet.gr Published online 16 October 2008 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.a.32546