ß 2006 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 140A:1791–1794 (2006) Research Letter Identification of a Novel COCH Mutation, G87W, Causing Autosomal Dominant Hearing Impairment (DFNA9) Rob W.J. Collin, 1 Robert J. Pauw, 1 Jeroen Schoots, 2 Patrick L.M. Huygen, 1 Lies H. Hoefsloot, 2 Cor W.R.J. Cremers, 1 and Hannie Kremer 1 * 1 Department of Otorhinolaryngology, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands 2 Department of Human Genetics, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands Received 23 February 2006; Accepted 15 May 2006 How to cite this article: Collin RWJ, Pauw RJ, Schoots J, Huygen PLM, Hoefsloot LH, Cremers CWRJ, Kremer H. 2006. Identification of a novel COCH mutation, G87W, causing autosomal dominant hearing impairment (DFNA9). Am J Med Genet Part A 140A:1791 – 1794. To the Editor: Non-syndromic hearing impairment (NSHI) is a very heterogeneous disorder, both clinically and genetically, and can be inherited in a dominant, recessive or mitochondrial fashion. To date, over 50 loci for autosomal dominant NSHI (DFNA) and more than 60 loci for autosomal recessive NSHI (DFNB) have been described, for which a number of causative genes have been identified (Hereditary Hearing Loss Homepage, http://webhost.ua.ac.be/ hhh). The autosomal dominant hearing disorder DFNA9 is caused by mutations in the COCH gene that localizes on chromosome 14q12 [Manolis et al., 1996; Robertson et al., 1997, 1998; de Kok et al., 1999; Fransen et al., 1999]. The COCH gene encodes a 550- aa extracellular protein that contains a signal peptide, an LCCL module, and two von Willebrand factor A (vWFA) domains. Thus far, the majority of mutations found in COCH are missense mutations affecting amino acids located in the LCCL domain, although recently the first missense mutation in the second vWFA domain has been described [Street et al., 2005]. Here, we report on a novel mutation in the COCH gene, resulting in an amino acid change p.G87W within the LCCL domain of the cochlin protein. A Dutch family suffering from autosomal dominant mid-life onset progressive hearing loss affecting mainly high frequencies and concomitant vestibular dysfunction was ascertained. The family pedigree is depicted in Figure 1A. Forty-six individuals partici- pated in this study. The local ethics committee approved this study and written informed consent was obtained from all participants. Figure 1B shows serial audiograms of one of the affected family members (age range 48–72 years). In this particular case, subjective onset of hearing loss was reported to be at approximately 45 years of age. Initially, the hearing loss was mild and mainly affected the high frequencies. Over the course of 24 years it progressed to a severe hearing loss with a flat audiometric configuration and a binaural mean pure tone average at 0.5, 1, and 2 kHz of 80 dB. Concomitant symptoms of vestibular dysfunction were reported to have started at approximately the same age as the hearing loss. These symptoms included instability in the dark, vertigo, and a tendency to fall. Evaluation of the vestibulo-ocular reflex using electronystagmography confirmed a vestibular dysfunction. The clinical characteristics of this family will be described in more detail separately [Pauw et al., manuscript in preparation]. Results of audiometric and vestibular function tests of the affected individuals were consistent with previous reports on DFNA9 families [Kemperman et al., 2005]. Therefore, the COCH gene was analyzed for the presence of a mutation. All 12 exons including their exon-intron boundaries were sequenced in one of the affected individuals. PCRs were performed under standard conditions (primer sequences are available on request). Subsequently, PCR fragments were purified using QiaQuick spin columns (Qiagen, Hilden, Germany) and sequenced using the corre- sponding forward primers with the ABI PRISM Big *Correspondence to: Hannie Kremer, Department of Otorhinolaryn- gology, Radboud University Medical Center Nijmegen, Internal Postal Code 377, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: h.kremer@antrg.umcn.nl DOI 10.1002/ajmg.a.31354