常染色体显性遗传性聋家系的临床表型及候选致病基因分析

目的探讨线粒体DNA 961delT/insC（n）突变与氨基甙类药物性耳聋的相关性。方法对一个耳聋家系11个成员采集氨基甙类抗生素用药史、进行听力学检查、表型分析,采集外周静脉血样本,从白细胞中提取DNA,用聚合酶链反应扩增线粒体DNA（mtDNA）全序列,对扩增片段进行DNA测序,对发现的基因突变与耳聋表型进行分离分析。结果参与研究的所有9例母系成员均检出mtDNA 961delT/insC（n）突变。有明确氨基甙类抗生素用药史的4例中只有2例耳聋患者,其中1例为用药之前出现的先天性聋,另1例为用药后38年出现的轻度耳聋。突变不与耳聋共分离。结论本研究不支持mtDNA 961delT/insC（n）突变是该家系耳聋的致病突变,mtDNA 961位点附近可能是一个多变异的区域,mtDNA 961delT/insC（n）可能是一个与氨基甙类药物性耳聋不明确相关的多态。

Analysis of phenotype and genotype of a large Chinese family with autosomal dominant hereditary nonsyndromic hearing loss

Objective To analyse the phenotype of a Chinese family with late-onset autosomal dominant hereditary nonsyndromic hearing loss and to screen the known causative genes related to autosomal dominant hereditary hearing loss. Methods The pedigree investigation, medical history taking, general medicine examination, and otolaryngological and vestibular examination of the family were performed. The otolaryngological examination comprised pure tone audiometry, acoustic impedance and otoacoustic emission. The proband was carried out computed tomography (CT) scan of the temporal bone to exclude other possible aural disorders. The venous blood sample of the family members was collected to extract DNA. After the investigation of the clinical features, the inheritance mode of the family was evaluated. Linkage analysis of one or two genetic markers near each of the 22 known causative genes of the autosomal dominant hereditary hearing loss with the phenotype of the family was performed. Results The family had eighty-one members in 6 generations, in which seventy-one members in 4 generations were alive and 14 expressed hearing loss. The inheritance mode of the family was consistent with the autosomal dominant according to the pedigree. The phenotypic features were as follow: bilateral, postlingual, progressive, moderate to severe sensorineural hearing impairment involving mainly higher frequencies princi-pally. By linkage analysis, the phenotype of the family did not show linkage with the markers selected. Conclusion The known causative genes related to the autosomal dominant hereditary hearing loss is not the underlying gene of the family. This indicates that the causative gene of the family may be a novel deafness gene. The linkage analysis based on the whole genome should be performed in the future to map the disease locus and clone the causative gene.