Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: a cross-sectional, multi-center next-generation sequencing study.
Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: a cross-sectional, multi-center next-generation sequencing study.
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DOI：
10.1186/1750-1172-8-172
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发表时间：
2013-10-28
影响因子：
3.7
通讯作者：
Matsunaga T
中科院分区：
文献类型：
--
作者：
Mutai H;Suzuki N;Shimizu A;Torii C;Namba K;Morimoto N;Kudoh J;Kaga K;Kosaki K;Matsunaga T
遗传性听力损失的基因测试为患者的临床治疗提供了信息，并为治疗学的发展提供了第一步。然而，通过桑格测序对耳聋基因进行全面的基因测试是极其昂贵和耗时的。下一代测序(NGS)技术有利于对涉及众多致病基因的异质性疾病进行基因诊断。对来自15个没有血缘关系的日本家庭的58名听力损失患者的基因组DNA样本进行了NGS，以确定听力损失的遗传原因。受试者没有致病的GJB2突变(该基因最常与遗传性听力损失有关)、线粒体m.1555A>；G或3243A>；G突变、前庭导水管扩大或听神经病。受试者的临床特征从病历中获得。基因组DNA用定制设计的SureSelect Target富集系统捕获84个与非综合征性或综合征性听力损失有关的基因的编码外显子和近侧内含子序列，并用Illumina GAIIx(配对末端读取)进行DNA测序。使用程序BWA、NovoAlign、Picard和GATK绘制和质量检查这些序列，并通过Avadis NGS进行分析。在15个家系中有7个发现了候选基因。这些基因是ACTG1、DFNA5、POU4F3、SLC26A5、SIX1、MYO7A、CDH23、PCDH15和USH2A，这表明多种基因导致了日本儿童早期听力损失。在3个家系中检测到Usher综合征相关基因的突变，其中包括1个CDH23和PCDH15双杂合突变。有针对性的NGS分析揭示了日本受试者中罕见耳聋基因的不同谱系，并强调了高效基因测试的意义。
Genetic tests for hereditary hearing loss inform clinical management of patients and can provide the first step in the development of therapeutics. However, comprehensive genetic tests for deafness genes by Sanger sequencing is extremely expensive and time-consuming. Next-generation sequencing (NGS) technology is advantageous for genetic diagnosis of heterogeneous diseases that involve numerous causative genes. Genomic DNA samples from 58 subjects with hearing loss from 15 unrelated Japanese families were subjected to NGS to identify the genetic causes of hearing loss. Subjects did not have pathogenic GJB2 mutations (the gene most often associated with inherited hearing loss), mitochondrial m.1555A>G or 3243A>G mutations, enlarged vestibular aqueduct, or auditory neuropathy. Clinical features of subjects were obtained from medical records. Genomic DNA was subjected to a custom-designed SureSelect Target Enrichment System to capture coding exons and proximal flanking intronic sequences of 84 genes responsible for nonsyndromic or syndromic hearing loss, and DNA was sequenced by Illumina GAIIx (paired-end read). The sequences were mapped and quality-checked using the programs BWA, Novoalign, Picard, and GATK, and analyzed by Avadis NGS. Candidate genes were identified in 7 of the 15 families. These genes were ACTG1, DFNA5, POU4F3, SLC26A5, SIX1, MYO7A, CDH23, PCDH15, and USH2A, suggesting that a variety of genes underlie early-childhood hearing loss in Japanese patients. Mutations in Usher syndrome-related genes were detected in three families, including one double heterozygous mutation of CDH23 and PCDH15. Targeted NGS analysis revealed a diverse spectrum of rare deafness genes in Japanese subjects and underscores implications for efficient genetic testing.
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影响因子：
12.3
作者：
Brownstein Z;Bhonker Y;Avraham KB
通讯作者：
Avraham KB
影响因子：
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作者：
Shearer AE;Smith RJ
通讯作者：
Smith RJ
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作者：
Delmaghani, Sedigheh;Aghaie, Asadollah;Petit, Christine
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Petit, Christine
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作者：
Matsunaga, T;Kumanomido, H;Usami, S
通讯作者：
Usami, S
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作者：
Pettersen, EF;Goddard, TD;Ferrin, TE
通讯作者：
Ferrin, TE