一个常染色体显性遗传非综合征型聋家系MYO6基因新致病性变异
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摘要
目的分析一个常染色体显性非综合征型听力损失家系的听力学特征,应用外显子测序鉴定该家系的致聋原因。方法通过家系调查、临床听力学和遗传学特征分析,对一个非综合征型听力损失家系的致病原因进行系统研究,对该家系1例听力正常和2例听力损失者进行全外显子组测序确定候选基因,对所有家系成员进行候选基因变异的Sanger测序验证。结果该家系遗传方式为常染色体显性遗传,表现为双侧对称性的感音神经性听力损失,随着年龄增长听力损失呈进行性加重;通过全外显子组测序鉴定出MYO6基因(DFNA22)新的致病性变异c.622A> G(p.K208E),该变异位点在多物种间保守,并与该家系成员的听力损失表型共分离。结论在1个常染色体显性非综合征型听力损失家系中通过全外显子组测序发现了MYO6基因新的c.622A>G(p.K208E)致病性变异。
Objective To analyze the clinical audiological characters and to identify the causative gene of a Chinese family with nonsyndromic autosomal dominant inherited hearing loss using whole-exome sequencing(WES) approach.Methods The family surveys, clinical audiological characteristics and inheritance patterns of this family were evaluated. Whole exome sequencing was conducted using DNA samples of one normal and two affected members of this family. The candidate mutation was confirmed by Sanger sequencing. Furthermore, multiple in silico analysis(SIFT, Polyphen2, PROVEAN and Mutation Taster) were used to assess the potential pathogenicity of the candidate mutations.Results This Chinese family was characterized by a bilaterally symmetrical and progressively worsening sensorineural hearing loss. A novel causative mutation c.622A>G in MYO6(DFNA22) resulting in a p.K208E substitution was identified. This mutation co-segregated with the hearing loss phenotype in extended family members was predicted to be pathogenic by SIFT, PolyPhen2, PROVEAN and Mutation Taster.Conclusion In our study, a novel c.622A>G(p.K208E) mutation in MYO6 was identified in a Chinese family affected with DFNA22 by WES and bioinformatics analysis.
Objective To analyze the clinical audiological characters and to identify the causative gene of a Chinese family with nonsyndromic autosomal dominant inherited hearing loss using whole-exome sequencing(WES) approach.Methods The family surveys, clinical audiological characteristics and inheritance patterns of this family were evaluated. Whole exome sequencing was conducted using DNA samples of one normal and two affected members of this family. The candidate mutation was confirmed by Sanger sequencing. Furthermore, multiple in silico analysis(SIFT, Polyphen2, PROVEAN and Mutation Taster) were used to assess the potential pathogenicity of the candidate mutations.Results This Chinese family was characterized by a bilaterally symmetrical and progressively worsening sensorineural hearing loss. A novel causative mutation c.622A>G in MYO6(DFNA22) resulting in a p.K208E substitution was identified. This mutation co-segregated with the hearing loss phenotype in extended family members was predicted to be pathogenic by SIFT, PolyPhen2, PROVEAN and Mutation Taster.Conclusion In our study, a novel c.622A>G(p.K208E) mutation in MYO6 was identified in a Chinese family affected with DFNA22 by WES and bioinformatics analysis.
引文
1 Sommen M,Wuyts W,Van Camp G,et al.Molecular diagnostics for hereditary hearing loss in children [J].Expert Rev Mol Diagn,2017,17:751.
2 Friedman TB,Griffith AJ.Human nonsyndromic sensorineural deafness [J].Annu Rev Genomics Hum Genet,2003,4:341.
3 Stelma F,Bhutta MF.Non-syndromic hereditary sensorineural hearing loss:review of the genes involved [J].J Laryngol Otol,2014,128:13.
4 Fang Y,Gu MS,Suo F,et al.Application of gene detection technique in the antenatal diagnosis of hereditary hearing loss [J].Eur Rev Med Pharmacol Sci,2017,21:1452.
5 Birkenhager R,Maier W,Kunze M,et al.Rapid umbilical cord diagnostic of hereditary profound hearing loss:how we do it [J].Clin Otolaryngol,2009,34:374.
6 Han GY,Xu Z,Li QS,et al.Detection of hereditary hearing loss gene by DNA microarray [J].Eur Rev Med Pharmacol Sci,2017,21:3538.
7 Sommen M,Schrauwen I,Vandeweyer G,et al.DNA diagnostics of hereditary hearing loss:a targeted resequencing approach combined with a mutation classification system [J].Hum Mutat,2016,37:812.
8 Wei Q,Zhu H,Qian X,et al.Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss [J].J Transl Med,2014,12:311.
9 Hu J,Liu F,Xia W,et al.Exome sequencing identifies a mutation in TMC1 as a novel cause of autosomal recessive nonsyndromic hearing loss [J].J Transl Med,2016,14:29.
10 Mohiddin SA,Ahmed ZM,Griffith AJ,et al.Novel association of hypertrophic cardiomyopathy,sensorineural deafness,and a mutation in unconventional myosin VI (MYO6) [J].J Med Genet,2004,41:309.
11 Oonk AM,Leijendeckers JM,Lammers EM,et al.Progressive hereditary hearing impairment caused by a MYO6 mutation resembles presbyacusis [J].Hear Res,2013,299:88.
12 Aschenbrenner L,Naccache SN,Hasson T.Uncoated endocytic vesicles require the unconventional myosin,Myo6,for rapid transport through actin barriers [J].Mol Biol Cell,2004,15:2253.
13 Hertzano R,Shalit E,Rzadzinska AK,et al.A Myo6 mutation destroys coordination between the myosin heads,revealing new functions of myosin VI in the stereocilia of mammalian inner ear hair cells [J].PLoS Genet,2008,4:e1000207.
14 Masters TA,Tumbarello DA,Chibalina MV,et al.MYO6 regulates spatial organization of signaling endosomes driving AKT activation and actin dynamics [J].Cell Rep,2017,19:2088.
2 Friedman TB,Griffith AJ.Human nonsyndromic sensorineural deafness [J].Annu Rev Genomics Hum Genet,2003,4:341.
3 Stelma F,Bhutta MF.Non-syndromic hereditary sensorineural hearing loss:review of the genes involved [J].J Laryngol Otol,2014,128:13.
4 Fang Y,Gu MS,Suo F,et al.Application of gene detection technique in the antenatal diagnosis of hereditary hearing loss [J].Eur Rev Med Pharmacol Sci,2017,21:1452.
5 Birkenhager R,Maier W,Kunze M,et al.Rapid umbilical cord diagnostic of hereditary profound hearing loss:how we do it [J].Clin Otolaryngol,2009,34:374.
6 Han GY,Xu Z,Li QS,et al.Detection of hereditary hearing loss gene by DNA microarray [J].Eur Rev Med Pharmacol Sci,2017,21:3538.
7 Sommen M,Schrauwen I,Vandeweyer G,et al.DNA diagnostics of hereditary hearing loss:a targeted resequencing approach combined with a mutation classification system [J].Hum Mutat,2016,37:812.
8 Wei Q,Zhu H,Qian X,et al.Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss [J].J Transl Med,2014,12:311.
9 Hu J,Liu F,Xia W,et al.Exome sequencing identifies a mutation in TMC1 as a novel cause of autosomal recessive nonsyndromic hearing loss [J].J Transl Med,2016,14:29.
10 Mohiddin SA,Ahmed ZM,Griffith AJ,et al.Novel association of hypertrophic cardiomyopathy,sensorineural deafness,and a mutation in unconventional myosin VI (MYO6) [J].J Med Genet,2004,41:309.
11 Oonk AM,Leijendeckers JM,Lammers EM,et al.Progressive hereditary hearing impairment caused by a MYO6 mutation resembles presbyacusis [J].Hear Res,2013,299:88.
12 Aschenbrenner L,Naccache SN,Hasson T.Uncoated endocytic vesicles require the unconventional myosin,Myo6,for rapid transport through actin barriers [J].Mol Biol Cell,2004,15:2253.
13 Hertzano R,Shalit E,Rzadzinska AK,et al.A Myo6 mutation destroys coordination between the myosin heads,revealing new functions of myosin VI in the stereocilia of mammalian inner ear hair cells [J].PLoS Genet,2008,4:e1000207.
14 Masters TA,Tumbarello DA,Chibalina MV,et al.MYO6 regulates spatial organization of signaling endosomes driving AKT activation and actin dynamics [J].Cell Rep,2017,19:2088.
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