目的:分析GSDME基因变异耳聋家系的遗传、听力学特点,探索其发病特点和致病机制,以期为患者提供遗传咨询及干预指导。方法:纳入来自中国聋病基因组计划项目的6个迟发性非综合征型听力损失家系,通过纯音测听、声导抗、言语识别率、听性...目的:分析GSDME基因变异耳聋家系的遗传、听力学特点,探索其发病特点和致病机制,以期为患者提供遗传咨询及干预指导。方法:纳入来自中国聋病基因组计划项目的6个迟发性非综合征型听力损失家系,通过纯音测听、声导抗、言语识别率、听性脑干反应和畸变产物耳声发射等听力学检测评估患者听力水平,结合病史采集及体格检查分析先证者及其家系成员间的表型差异。应用二代测序检测先证者致病基因,并使用Sanger测序对家系其他成员进行变异位点验证,依据美国遗传学与基因组医学委员会指南进行致病性分析。同时,结合国内外GSDME研究进展,探讨可能的致聋机制。结果:在6个迟发性非综合征型听力损失家系中,共30例有听力损失表型,发病年龄10~50岁(27.88±9.74岁)。遗传学分析鉴定4个GSDME基因剪切变异,其中2个变异为新发现的变异,分别是c.991-7C>G和c.1183+1G>T,且c.991-7C>G是GSDME新发变异。另外2个变异为已报道的GSDME剪切变异,分别是c.991-1G>C和c.991-15_991-13del,且c.991-15_991-13del在3个家系中检出。基因型-表型相关分析发现携带c.991-7C>G和c.1183+1G>T变异的先证者均表现为高频下降为主的听力损失表型,相同变异的3个家系的先证者听力损失程度不一且听力损失的年下降率高于既往报道的0.94 dB HL/年。此外,随访发现6个家系内的先证者,有4例接受干预(66.67%),但干预效果不一。结论:本研究分析GSDME变异相关的6个迟发性非综合征型听力损失家系,共鉴定4个剪切变异,其中1个为国内外首个GSDME新发变异,听力学分析发现患者多在10岁后出现渐进性听力损失,且不同干预的效果存在差异。展开更多
Background： Nonsyndrornic hearing loss （NSHL） is highly heterogeneous, in which more than 90 causative genes have currently been identified. DFNA5 is one of the deathess genes that known to cause autosomal dominant...Background： Nonsyndrornic hearing loss （NSHL） is highly heterogeneous, in which more than 90 causative genes have currently been identified. DFNA5 is one of the deathess genes that known to cause autosomal dominant NSHL. Until date, only five DFN.45 mutations have been described in eight families worldwide. In this study, we reported the identification of a novel pathogenic mutation causing DFNA5 deafness in a five-generation Chinese family. Methods： Alter detailed clinical evaluations of this family, the genomic DNA of three affected individuals was selected for targeted exome sequencing of 101 known deafness genes, as well as mitochondrial DNA and microRNA regions. Co-segregation analysis between the hearing loss and the candidate variant was confirmed in available family members by direct polymerase chain reaction （PCR）-Sanger sequencing. Real-time PCR （RT-PCR） was pertormed to investigate the potential effect of the pathogenic mutation on messenger RNA splicing. Results： Clinical evaluations revealed a similar deafness phenotype in this family to that of previously reported DFNA5 families with autosomal dominant, late-onset bearing loss. Molecular analysis identified a novel splice site mutation in DFNA5 intron 8 （IVSS＋ 1 delG）. The mutation segregated with the hearing loss of the family and was absent in 120 unrelated control DNA samples of Chinese origin. RT-PCR showed skipping of exon 8 in the mutant transcript. Conclusions： We identified a novel DFNA5 mutation IVS8＋1 delG in a Chinese family which led to skipping ofexon 8. This is the sixth DFNA5 mutation relates to hearing loss and the second one in DFNA5 intron 8. Our findings provide further support to the hypothesis that the DFNA5-associated hearing loss represents a mechanism of gain-of-function.展开更多
文摘目的:分析GSDME基因变异耳聋家系的遗传、听力学特点,探索其发病特点和致病机制,以期为患者提供遗传咨询及干预指导。方法:纳入来自中国聋病基因组计划项目的6个迟发性非综合征型听力损失家系,通过纯音测听、声导抗、言语识别率、听性脑干反应和畸变产物耳声发射等听力学检测评估患者听力水平,结合病史采集及体格检查分析先证者及其家系成员间的表型差异。应用二代测序检测先证者致病基因,并使用Sanger测序对家系其他成员进行变异位点验证,依据美国遗传学与基因组医学委员会指南进行致病性分析。同时,结合国内外GSDME研究进展,探讨可能的致聋机制。结果:在6个迟发性非综合征型听力损失家系中,共30例有听力损失表型,发病年龄10~50岁(27.88±9.74岁)。遗传学分析鉴定4个GSDME基因剪切变异,其中2个变异为新发现的变异,分别是c.991-7C>G和c.1183+1G>T,且c.991-7C>G是GSDME新发变异。另外2个变异为已报道的GSDME剪切变异,分别是c.991-1G>C和c.991-15_991-13del,且c.991-15_991-13del在3个家系中检出。基因型-表型相关分析发现携带c.991-7C>G和c.1183+1G>T变异的先证者均表现为高频下降为主的听力损失表型,相同变异的3个家系的先证者听力损失程度不一且听力损失的年下降率高于既往报道的0.94 dB HL/年。此外,随访发现6个家系内的先证者,有4例接受干预(66.67%),但干预效果不一。结论:本研究分析GSDME变异相关的6个迟发性非综合征型听力损失家系,共鉴定4个剪切变异,其中1个为国内外首个GSDME新发变异,听力学分析发现患者多在10岁后出现渐进性听力损失,且不同干预的效果存在差异。
基金This study was supported by a grant from the Jiangsu Health Administration，by a research grant award from the National Natural Science Foundation of China，by a grant from the Research Special Fund for Public Welfare Industry of Health,Ministry of Health of China
文摘Background： Nonsyndrornic hearing loss （NSHL） is highly heterogeneous, in which more than 90 causative genes have currently been identified. DFNA5 is one of the deathess genes that known to cause autosomal dominant NSHL. Until date, only five DFN.45 mutations have been described in eight families worldwide. In this study, we reported the identification of a novel pathogenic mutation causing DFNA5 deafness in a five-generation Chinese family. Methods： Alter detailed clinical evaluations of this family, the genomic DNA of three affected individuals was selected for targeted exome sequencing of 101 known deafness genes, as well as mitochondrial DNA and microRNA regions. Co-segregation analysis between the hearing loss and the candidate variant was confirmed in available family members by direct polymerase chain reaction （PCR）-Sanger sequencing. Real-time PCR （RT-PCR） was pertormed to investigate the potential effect of the pathogenic mutation on messenger RNA splicing. Results： Clinical evaluations revealed a similar deafness phenotype in this family to that of previously reported DFNA5 families with autosomal dominant, late-onset bearing loss. Molecular analysis identified a novel splice site mutation in DFNA5 intron 8 （IVSS＋ 1 delG）. The mutation segregated with the hearing loss of the family and was absent in 120 unrelated control DNA samples of Chinese origin. RT-PCR showed skipping of exon 8 in the mutant transcript. Conclusions： We identified a novel DFNA5 mutation IVS8＋1 delG in a Chinese family which led to skipping ofexon 8. This is the sixth DFNA5 mutation relates to hearing loss and the second one in DFNA5 intron 8. Our findings provide further support to the hypothesis that the DFNA5-associated hearing loss represents a mechanism of gain-of-function.
