应用高通量基因捕获技术筛查Joubert综合征新突变
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摘要
目的诊断Joubert综合征致病基因。方法应用高通量基因捕获技术对曾怀过Joubert综合征胎儿的夫妻进行基因筛查,并采用荧光定量PCR和Sanger测序法对疑似突变进行验证。从生物学意义、遗传学意义及临床特征吻合度三方面预测新突变的致病性。结果夫妻均为表型正常的Joubert综合征6型AHI1致病基因携带者。妻子为AHI1基因(NM-017651.4)Ex5-6del杂合突变,丈夫为AHI1基因c.1799-1802delAACA杂合突变。AHI1基因是已知的Joubert综合征致病基因,与临床症状相符。这两种突变既往未见数据库及文献收录,按照ACMG解读规则属于致病性突变。结论 AHI1基因(NM-017651.4)是该家系的致病基因,Ex5-6del和c.1799-1802delAACA是AHI1基因新的致病突变,对Joubert综合征诊断及病因筛查具有重要的临床价值。
Objective:To identify causative gene of Joubert syndrome. Methods High-throughput gene capture technology was used to screen causative gene in a couple with Joubert syndrome′s fetal. Suspected mutations were verified with Sanger sequencing or Quantitative fluorescence PCR. Pathogenicity of new mutations were predicted according to ACMG,inheritant mode and clinical phenotype. Results:Couple had normal phenotype but carried heterozygous mutation of AHI1 gene(NM-017651.4),including wife with Ex5-6 del and husband with c.1799-1802 delAACA which had not been reported previously. The two mutations were predicted to be harmful. Conclusion:Ex5-6 del and c.1799-1802 delAACA of AHI1 gene are novel mutations associated with Joubert syndrome type Ⅵ,which may facilitate the genetic diagnosis of Joubert syndrome.
Objective:To identify causative gene of Joubert syndrome. Methods High-throughput gene capture technology was used to screen causative gene in a couple with Joubert syndrome′s fetal. Suspected mutations were verified with Sanger sequencing or Quantitative fluorescence PCR. Pathogenicity of new mutations were predicted according to ACMG,inheritant mode and clinical phenotype. Results:Couple had normal phenotype but carried heterozygous mutation of AHI1 gene(NM-017651.4),including wife with Ex5-6 del and husband with c.1799-1802 delAACA which had not been reported previously. The two mutations were predicted to be harmful. Conclusion:Ex5-6 del and c.1799-1802 delAACA of AHI1 gene are novel mutations associated with Joubert syndrome type Ⅵ,which may facilitate the genetic diagnosis of Joubert syndrome.
引文
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[9]Valente EM,Brancati F,Silhavy JL,et al.AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders[J].Ann Neurol,2006,59:527-34.
[10]罗敏娜,等.全外显子测序发现中国Joubert综合征家系C5orf42基因的新突变[J].生殖医学杂志,2017,26(5):464-469.
[2]罗敏娜,刘志敏,沈玥,等.目标外显子组捕获测序发现INPP5E突变致Joubert综合征1例[J].中国计划生育学杂志,2018,26(5):400-404.
[3]周永安,曾红艳,粟向韶,等.应用高通量基因捕获技术寻找非综合征型耳聋新的热点突变[J].中华医学遗传学杂志,2016,33(6):758-761.
[4]Richards S,Aziz N,Bale S,et al.Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J].Genet Med,2015,17:405-424.
[5]Jiang X,Hanna Z,Kaouass M,et al.Ahi-1,a novel gene encoding a modular protein with WD40-repeat and SH3 domains,is targeted by the Ahi-1 and Mis-2 provirus integrations[J].Virol,2002,76:9046-9059.
[6]Smith TF,Gaitatzes C,Saxena K,et al.The WD repeat:a common architecture for diverse functions[J].Trends Biochem.Sci,1999,24:181-185.
[7]Mayer,BJ.SH3 domains:complexity in moderation[J].J Cell Scii,2001,114:1253-1263.
[8]Kroes HY,van Zon PH,Fransen van de Putte D,et al.DNAanalysis of AHI1,NPHP1 and CYCLIN D1 in Joubert syndrome patients from the Netherlands[J].Eur J Med Genet,2008,51:24-34.
[9]Valente EM,Brancati F,Silhavy JL,et al.AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders[J].Ann Neurol,2006,59:527-34.
[10]罗敏娜,等.全外显子测序发现中国Joubert综合征家系C5orf42基因的新突变[J].生殖医学杂志,2017,26(5):464-469.