特大常染色体显性遗传聋家系听力学特征及候选致病基因突变筛查

Audiological and genetic characteristics of a large Chinese pedigree with dominantly inherited non-syndromic hearing impairment

目的探讨一中国常染色体显性遗传聋大家系的听力学特征,进行已知致聋基因已知突变位点的筛查。方法经知情同意,对家系成员进行全身检查及听力学检测,获得血样标本;整理分析家系资料并绘制系谱图;用基因组DNA抽提试剂盒提取外周血DNA。对2例家系患者DNA进行GJB2和GJB3基因全部编码区突变检测,对其余23个已知常染色体显性遗传性耳聋(DFNA)基因的74个已知突变位点所涉及的50个外显子进行PCR扩增和直接测序分析。结果该家系共7代199人,现存4代176人,耳聋患者54人。系谱分析显示,耳聋表型代代相传,男女患病人数分别为24和30,符合常染色体显性遗传特征。听力学表现为:迟发性、进行性、双侧对称性、感音神经性听力损失,首先是高频区受损,并快速向中、低频扩展。GJB2、GJB3基因全部编码区及其余23个DFNA基因已知突变位点的序列分析均无阳性发现。结论该家系是一个非综合征型常染色体显性遗传聋大家系,耳聋表型为迟发性、进行性、双耳对称性感音神经性听力损失;初步分子遗传学分析提示可能由新基因或已知基因的新突变致病。

Objective To investigate the audiological features of a large Chinese family with autosomal dominant hereditary hearing loss and to perform a mutational analysis of candidate genes. Methods After obtaining informed consent from all participants, medical and audiological examinations were performed to rule out any syndromic hearing impairment, and the inheritance mode of the family was evaluated. Genomic DNA was isolated from the peripheral leukocytes of the sub-jects using the Puregene DNA Isolation Kits. The DNA fragments spanning the entire coding regions of GJB2 and GJB3 genes, and 50 exons in other 23 cloned autosomal dominant deafness genes were PCR amplified using specific primers. Each fragment was purified and subsequently analyzed by direct sequencing. Results The family had 199 members in 7generations, in which 176 members in 4 generations were alive. Fifty four subjects, including 24 males and 30 females, were found to be hearing-impaired. The mode of inheritance of the family was consistent with the autosomal dominant pattern ac- cording to the pedigree. Hearing impairment was found in the second or third decade. Audiograms showed bilateral symmet- ric, progressive and sensorineural hearing loss which started from high frequencies and quickly expended to mid and low frequencies. We failed to detect any known deafness-associated gene mutations by PCR amplification and direct sequenceanalysis. Conclusions Pedigree analysis suggested an autosomal dominant hereditary pattern in this family. Hearing loss was bilateral symmetric, progressive and sensorineural with late onset. The known deafness loci seem not contributing to the pathogenesis of the hearing loss in this Chinese family, suggesting new gene（s） or mutation（s） involvement.