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A Seventh Locus for Otosclerosis, OTSC7, Maps to Chromosome 6Q13–16.1

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A Seventh Locus for Otosclerosis, OTSC7, Maps to Chromosome 6Q13–16.1 European Journal of Human Genetics (2007) 15, 362–368 & 2007 Nature Publishing Group All rights reserved 1018-4813/07 $30.00 www.nature.com/ejhg ARTICLE A seventh locus for otosclerosis, OTSC7, maps to chromosome 6q13–16.1 Melissa Thys1, Kris Van Den Bogaert1, Vassiliki Iliadou2, Kathleen Vanderstraeten1, Nele Dieltjens1, Isabelle Schrauwen1, Wenjie Chen3, Nikolaos Eleftheriades4, Maria Grigoriadou5, Robert Jan Pauw6, Cor RWJ Cremers6, Richard JH Smith3, Michael B Petersen5 and Guy Van Camp*,1 1Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, Antwerp, Belgium; 2Clinical Psychoacoustics and Neurootology Laboratory, Neuroscience Department, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece; 3Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, University of Iowa, 200 Hawkins Drive, Iowa City, IA, USA; 4Otolaryngology Departement, St Lucas Clinic, Thessaloniki, Greece; 5Department of Genetics, Institute of Child Health, ‘Aghia Sophia’ Children’s Hospital, Athens, Greece; 6Department of Otorhinolaryngology, University Medical Center St Radboud, Philips van Leydenlaan 15, Nijmegen, The Netherlands Otosclerosis is a common form of hearing impairment among white adults with a prevalence of 0.3–0.4%. It is caused by abnormal bone homeostasis of the otic capsule that compromises free motion of the stapes in the oval window. Otosclerosis is in most patients a multifactorial disease, caused by both genetic and environmental factors. In some cases, the disease is inherited as a monogenic autosomal dominant trait, sometimes with reduced penetrance. However, families large enough for genetic linkage studies are extremely rare. To date, five loci (OTSC1-5) have been reported, but none of the responsible genes have been cloned yet. An additional locus, OTSC6, has been reported to the HUGO nomenclature committee but the relevant linkage study has not been published. In this study, a genome-wide linkage study was performed in a large Greek pedigree segregating autosomal dominant otosclerosis. A seventh locus, OTSC7, was localized on chromosome 6q13–16.1 with a multipoint LOD score of 7.5 in the 13.47 cM region defined by markers D6S1036 (centromeric) and D6S300 (telomeric). Linkage analysis of this new locus in 13 smaller Belgian and Dutch families has identified one family from The Netherlands in which allele segregation suggests linkage to this region. The overlap between the critical regions of these two families is a 1.06 Mb interval between the genetic markers D6S1036 (centromeric) and D6S406 (telomeric) on chromosome 6q13. European Journal of Human Genetics (2007) 15, 362–368. doi:10.1038/sj.ejhg.5201761; published online 10 January 2007 Keywords: otosclerosis; genetic linkage analysis; OTSC7 Introduction *Correspondence: Professor G Van Camp, Department of Medical Otosclerosis is a form of progressive hearing loss due to Genetics, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, an abnormal bone homeostasis of the otic capsule that Belgium. leads to a bony fixation of the stapedial footplate in Tel: þ 323 820 2491; Fax: þ 323 820 2566; the oval window. This fixation disturbs transmission of E-mail: [email protected] Received 24 March 2006; revised 2 November 2006; accepted 16 sound waves through the middle ear ossicles, resulting in November 2006; published online 10 January 2007 a conductive hearing impairment. In about 10% of all OTSC7, a new locus for otosclerosis M Thys et al 363 otosclerosis patients, an additional cochlear component family members, progression of the additional sensorineur- develops that most likely represents the encroachment of al component led to a pure SHL, masking the conductive otosclerotic foci on the labyrinthine capsule, which leads component. The diagnosis in these latter patients was to a mixed or sensorineural hearing loss (SHL).1 Occasion- based on the family history together with the presence of ally, otosclerotic damage to the cochlea produces additional signs, like the absence of stapedial reflexes in all only SHL.2 patients and detailed information about the progression of The prevalence of otosclerosis among white adults is the hearing loss. 0.3–0.4%.3 Although its etiology is unknown, it is All family members with hearing loss were also exam- considered a complex disease caused by both genetic and ined by a clinical geneticist to exclude syndromic forms of environmental factors. Occasionally, otosclerosis is inher- stapes fixation. In particular, movement of finger joints, ited as a monogenic autosomal dominant trait. However, shape of fingers and toes as well as facial characteristics families large enough for a genetic linkage study are rare, were noted. and in these families, factors like reduced penetrance and phenocopies complicate linkage analysis. Dutch and Belgian families To date, five autosomal dominant otosclerosis loci have Thirteen additional families from the Netherlands and been reported: OTSC1 on chromosome 15q25–26,4 OTSC2 Belgium were analyzed, and nine of these families were on chromosome 7q34–36,5 OTSC3 on chromosome 6p21– described previously.10 The clinical diagnosis of the four 22,6 OTSC4 on chromosome 16q21–23.2,7 and OTSC5 on additional families was made in the same way as the other chromosome 3q22–24.8 In addition, a sixth locus, OTSC6, nine families.10 Persons who had stapes microsurgery were has been reported to the Human Genome Organisation considered affected. In non-operated patients, the diag- nomenclature committee but details describing this locus nosis was based on audiologic data, having conductive or have not been published. None of the disease causing mixed hearing loss together with absent stapedial reflexes. genes has been identified. In this study, genome wide Because of variability in the age of onset, only persons linkage analysis was performed in a large Greek pedigree older than 50 and with normal hearing were considered segregating autosomal dominant otosclerosis. This analysis unaffected. The remaining persons were given an ‘uncer- has identified a seventh locus, OTSC7, on chromosome 6q. tain’ affection status. Materials and methods Genotype analysis Clinical diagnosis Blood samples from study participants were obtained after Persons who underwent stapes microsurgery were consid- informed consent and genomic DNA was isolated using ered affected. For the remaining patients, the clinical standard techniques. diagnosis of otosclerosis was based on audiological data. In a large Greek family, consisting of 36 persons, a Pure-tone audiometry was performed on all persons with genome-wide screen was performed by deCODE genetics air conduction at 250, 500, 1000, 2000, 4000 and 8000 Hz, (Reykjavik, Iceland) using approximately 500 micro- and bone conduction at 250, 500, 1000, 2000 and 4000 Hz. satellite markers with an average marker density of 8 cM. Otoscopy and tympanoscopy were performed to rule out For fine mapping of the candidate region, we selected outer or middle ear pathology, respectively, and stapedial additional microsatellite markers from public databases. reflex decay was measured to assess the mobility of the The microsatellite markers used to analyze linkage to stapes. the OTSC7 locus in 10 Belgian and 3 Dutch families were D6S1596, D6S1589 and D6S275. Genotyping was Greek family performed on DNA from 165 persons: 83 were diagnosed The family used for the genome-wide screen is a large as affected, 69 persons were labeled unaffected and 13 were Greek family segregating autosomal dominant otosclerosis. given an uncertain diagnosis. The family originates from a small village in the island For the microsatellite markers we analyzed, polymerase of Rhodes. The clinical details of this family have been chain reaction (PCR) amplification was carried out using described recently.9 The family was expanded for this study standard conditions. One of the primers was synthesized to include 19 affecteds, seven unaffecteds, six spouses and with an M13 sequence at the 50 end. A fluorescently labeled four family members with an unknown or uncertain M13 primer was included in the PCR reaction, thus diagnosis. The hearing loss in this family arises in child- labeling the PCR product. Capillary electrophoresis and hood around the age of 10 as a conductive hearing loss, pattern visualization were performed using an ABI PRISM but soon becomes mixed. The presence of an air-bone 3100 DNA sequencer (Applied Biosystems Inc., Foster City, gap, closing at a frequency of 2000 Hz, together with USA). Allele sizes were determined using the GENESCAN the absence of stapedial reflexes, clinically confirmed the 2.1.1. and Genotyper V3.7 software (Applied Biosystems diagnosis of otosclerosis in these patients. In some of the Inc.). European Journal of Human Genetics OTSC7, a new locus for otosclerosis M Thys et al 364 Linkage analysis strands using an ABI 3130XL sequencer with the BigDyes Two-point LOD scores were calculated using the MLINK Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems computer program.11 For linkage analysis, otosclerosis Inc.). was coded as an autosomal dominant trait with reduced penetrance. The frequency of the otosclerosis gene was set at 0.0001 and the penetrance at 90%. To allow for possible Results and discussion phenocopies, this chance was set at 1%, because without Genetic analysis of the Greek family surgical exploration it is often difficult to exclude hearing Previous analysis in the large Greek family excluded loss of other origin. Equal recombination
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