高频突变外显子测序发现GJA8突变所致先天性白内障的家系分析
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摘要
目的:鉴定一个先天性白内障家系的致病基因及位点。方法:对该先天性白内障家系的先证者进行高频突变外显子直接测序,通过生物信息学分析鉴定的致病基因及位点,利用ACMG标准对突变致病性进行分级。结果:在先证者的GJA8基因上存在1个杂合变异位点,c.569A>G (p.N190S)。该位点在家系中符合遗传共分离规律。结论:GJA8基因上的c.569A>G位点是引起该先天性白内障家系临床病变的可能致病位点。该突变位点是引起先天性白内障发生的致病位点为首次报道。
Objective: To investigate the disease-causing mutation in a Chinese family with congenital cataract. Methods: Direct sequencing on hotspot exons was applied to examine the DNA sample of the proband from a Chinese family with congenital cataract. Disease-causing mutation was identified by bioinformatics analysis and followed by ACMG classification. Results: A compound heterozygous mutation, c.569 A>G(p.N190 S) locus on GJA8 of the proband were found, which conformed to the law of genetic cosegregation in the family. Conclusion: c.569 A>G(p.N190 S) locus on in GJA8 maybe cause congenital cataract of patients in a Chinese family, and it is the first reported.
Objective: To investigate the disease-causing mutation in a Chinese family with congenital cataract. Methods: Direct sequencing on hotspot exons was applied to examine the DNA sample of the proband from a Chinese family with congenital cataract. Disease-causing mutation was identified by bioinformatics analysis and followed by ACMG classification. Results: A compound heterozygous mutation, c.569 A>G(p.N190 S) locus on GJA8 of the proband were found, which conformed to the law of genetic cosegregation in the family. Conclusion: c.569 A>G(p.N190 S) locus on in GJA8 maybe cause congenital cataract of patients in a Chinese family, and it is the first reported.
引文
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[2] Lian-Hong Pi,Lin Chen,Qin Liu,et al.Prevalence of eye diseases and causes of visual impairment in school-aged children in Western China [J].J Epidemiol,2012,22:37-44.
[3] Huang B,He W.Molecular characteristics of inherited congenital cataracts [J].Eur J Med Genet,2010,53:347-357.
[4] Chen Q,Ma J,Yan M,et al.A novel mutation in CRYAB associated with autosomal dominant congenital nuclear cataract in a Chinese family [J].Mol Vis,2009,15:1359-1365.
[5] Arora A,Minogue PJ,Liu X,et al.A novel connexin50 mutation associated with congenital nuclear pulverulent cataracts [J].J Med Genet,2008,45:155-160.
[6] Bremond-Gignac D,Bitoun P,Reis LM,et al.Identification of dominant FOXE3 and PAX6 mutations in patients with congenital cataract and aniridia [J].Mol Vis,2010,16:1705-1711.
[7] Aldahmesh MA,Khan AO,Mohamed J,et al.Novel recessive BFSP2 and PITX3 mutations:insights into mutational mechanisms from consanguineous populations [J].Genet Med,2011,13:978-981.
[8] 曹宗富,王雷,喻浴飞,等.中国人群先天性白内障突变谱的建立 [J].中国计划生育学杂志,2018,26:545-550.
[9] Cao Z,Zhu Y,Liu L,et al.Novel mutations in HSF4 cause congenital cataracts in Chinese families [J].BMC Med Genet,2018;19(1):150.
[10] Ng PC,Henikoff S.SIFT:Predicting amino acid changes that affect protein function [J].Nucleic Acids Res,2003,31:3812-3814.
[11] 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.
[12] Li Q,Wang K.InterVar:clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines [J].Am J Hum Genet,2017,100:267-280.
[13] Sellitto C,Li L,White TW.Connexin50 is essential for normal postnatal lens cell proliferation[J].Invest Ophthalmol Vis Sci,2004,45:3196-3202.
[14] Dang FT,Yang FY,Yang YQ,et al.A novel mutation of p.F32I in GJA8 in human dominant congenital cataracts[J].Int J Ophthalmol,2016,9:1561-1567.
[15] Liang C,Liang H,Yang Y,et al.Mutation analysis of two families with inherited congenital cataracts[J].Mol Med Rep,2015,12:3469-3475.
[16] Arora A,Minogue PJ,Liu X,et al.A novel connexin50 mutation associated with congenital nuclear pulverulent cataracts[J].J Med Genet,2008,45:155-160.
[17] Berry V,Mackay D,Khaliq S,et al.Connexin 50 mutation in a family with congenital "zonular nuclear" pulverulent cataract of Pakistani origin[J].Hum Genet,1999,105:168-170.
[18] Mohebi M,Chenari S,Akbari A,et al.Mutation analysis of connexin 50 gene among Iranian families with autosomal dominant cataracts[J].Iran J Basic Med Sci,2017,20:288-293.
[19] Hansen L,Yao W,Eiberg H,et,al.Genetic heterogeneity in microcornea-cataract:five novel mutations in CRYAA,CRYGD,and GJA8 [J].Invest Ophthalmol Vis Sci,2007,48:3937-3944.
[20] Tong JJ,Minogue PJ,Guo W,et al.Different consequences of cataract-associated mutations at adjacent positions in the first extracellular boundary of connexin50 [J].Am J Physiol Cell Physiol,2011,300:1055-1064.