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Identification of a SNP in a Regulatory Region of GJB2 Associated With Idiopathic Nonsyndromic Autosomal Recessive Hearing Loss in a Multicenter Study

Ramsebner, Reinhard*; Ludwig, Martin*; Lucas, Trevor; de Jong, Daniëlle; Hamader, Gertrude; del Castillo, Ignacio§; Parzefall, Thomas*; Baumgartner, Wolf-Dieter*; Schoefer, Christian; Szuhai, Karoly; Frei, Klemens*†

doi: 10.1097/MAO.0b013e31828d6501
Sensorineural Hearing Loss

Hypothesis Additional genetic changes in the regulatory region of the human GJB2 gene encoding the gap junction protein (Connexin 26) may contribute to sensorineural hearing loss.

Background Mutations in GJB2 cause up to 50% of autosomal recessive nonsyndromic hearing impairment (NSHI).

Methods In the present study, we screened the putative 5’ GJB2 regulatory region for novel alterations.

Results In idiopathic familial cases of NSHI lacking known pathogenic alterations in GJB2, we identified a T→C transition (refSNP: rs117685390) in a putative transcription factor binding sequence 228 bp proximal to the transcriptional start site at a homozygous frequency of 0.125 (n = 40), significantly overrepresented in comparison to the homozygous allele frequencies of 0.043 in the normal-hearing Caucasian population (n = 211; p < 0.001). In a NSHI family, inheritance of the rs117685390 C allele segregated on independent chromosomes with NSHI in conjunction with heterozygous inheritance of c.35delG, the most common Caucasian mutation in the GJB2 coding region. In a patient group (n = 32) bearing heterozygous pathogenic c.35delG mutations, - rs117685390 C allele homozygosity was also highly overrepresented (0.25; p < 0.001) and not exclusively linked to the c.35delG mutation in cis in patients homozygous for c.35delG. However, in the majority of NSHI homozygous c.35delG chromosomes examined (91/94), c.35delG homozygosity was linked to the rs117685390 C allele in cis.

Conclusion These results suggest that the rs117685390 C allele could represent a biomarker for the development of NSHI in Caucasian populations and may be included in risk assessment for the development of NSHI.

*Department of Otorhinolaryngology, and †Centre of Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria; ‡Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands; and §Unidad de Genética Molecular, Hospital Ramón y Cajal, Madrid, Spain

Address correspondence and reprint requests to Klemens Frei, M.D., Department of Otorhinolaryngology, Medical University of Vienna, AKH-8J, Waehringer Guertel 18-20, Vienna, A-1090, Austria; E-mail:

The authors disclose no conflicts of interest.

This project was supported by funds of the Oesterreichische Nationalbank (Anniversary Fund, project number AP14058ONB) and the Medical Electronics Corporation, Innsbruck, Austria.

Copyright © 2013 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company