全外显子组测序对肥厚型心肌病猝死者的基因分析
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摘要
目的在全外显子组水平分析1例肥厚型心肌病(hypertrophic cardiomyopathy,HCM)猝死病例的相关致病性基因突变。方法对1例具有HCM病理学特征的猝死病例样本,利用Illumina~Hi Seq 2500平台进行全外显子组测序(whole exome sequencing,WES)。测序数据分析以hg19为参照序列,筛选可疑的单核苷酸变异位点,通过PhyloP、PolyPhen-2、SIFT等软件进行突变的保守性和功能分析。结果经过筛选,发现该病例的MYBPC3基因发生C719R杂合突变。结论利用二代测序技术进行全外显子组水平的分子解剖(基因突变检测和分析),有助于明确HCM的分子机制,并为死因分析提供新的方法和思路。
Objective To analyze the related pathogenicity gene mutations in a sudden death of hypertrophic cardiomyopathy(HCM) on whole exome level. Methods Whole exome sequencing(WES) was been performed on a sudden death case sample with pathological features of HCM by Illumina~Hiseq2500 platform. Using hg19 as the reference sequences, the sequencing data were analyzed. Suspicious single nucleotide variants(SNV) were screened, and the conservatism and function were analyzed by the software such as Phylo P, Poly Phen-2, SIFT, etc. Results After screening, a heterozygous mutation C719 R was finally identified in the gene MYBPC3 of this case. Conclusion The molecular anatomy on whole exome level by second generation sequencing technology can help to define the molecular mechanism of HCM and provide a new mothed and thought for analysis of death cause.
Objective To analyze the related pathogenicity gene mutations in a sudden death of hypertrophic cardiomyopathy(HCM) on whole exome level. Methods Whole exome sequencing(WES) was been performed on a sudden death case sample with pathological features of HCM by Illumina~Hiseq2500 platform. Using hg19 as the reference sequences, the sequencing data were analyzed. Suspicious single nucleotide variants(SNV) were screened, and the conservatism and function were analyzed by the software such as Phylo P, Poly Phen-2, SIFT, etc. Results After screening, a heterozygous mutation C719 R was finally identified in the gene MYBPC3 of this case. Conclusion The molecular anatomy on whole exome level by second generation sequencing technology can help to define the molecular mechanism of HCM and provide a new mothed and thought for analysis of death cause.
引文
[1]GERSH B J,MARON B J,BONOW R O,et al.2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy:executive summary:a report of the american college of cardiology foundation/american heart association task force on practice guidelines[J].Circulation,2011,124(24):2761-2796.
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[4]王纯,王辉,许心舒,等.外显子组测序对1例青壮年猝死的分子遗传学分析[J].法医学杂志,2015,31(6):436-440,444.
[5]李玉林.病理学[M].8版.北京:人民卫生出版社,2013.
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[7]WINEGRAD S.Cardiac myosin binding protein C[J].Circ Res,1999,84(10):1117-1126.
[8]FLASHMAN E,REDWOOD C,MOOLMANSMOOK J,et al.Cardiac myosin binding protein C:its role in physiology and disease[J].Circ Res,2004,94(10):1279-1289.
[9]NIIMURA H,BACHINSKI L L,SANGWATANAROJ S,et al.Mutations in the gene for cardiac myosinbinding protein C and late-onset familial hypertrophic cardiomyopathy[J].N Engl J Med,1998,338(18):1248-1257.
[10]CARRIER L,MEARINI G,STATHOPOULOU K,et al.Cardiac myosin-binding protein C(MYBPC3)in cardiac pathophysiology[J].Gene,2015,573(2):188-197.
[11]RICHARD P,CHARRON P,CARRIER L,et al.Hypertrophic cardiomyopathy:distribution of disease genes,spectrum of mutations,and implications for a molecular diagnosis strategy[J].Circulation,2003,107(17):2227-2232.
[12]BLAYNEY L M,LAI F A.Ryanodine receptormediated arrhythmias and sudden cardiac death[J].Pharmacol Ther,2009,123(2):151-177.
[13]MEDEIROS-DOMINGO A,BHUIYAN Z A,TESTER D J,et al.Comprehensive open reading frame mutational analysis of the RYR2-encoded ryanodine receptor/calcium channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative,exerciseinduced long QT syndrome[J].J Am Coll Cardiol,2009,54(22):2065-2074.
[14]CHAUVEAU C,ROWELL J,FERREIRO A.A rising titan:ttn review and mutation update[J].Hum Mutat,2014,35(9):1046-1059.
[15]VAN SPAENDONCK-ZWARTS K Y,POSAFALVI A,VAN DEN BERG M P,et al.Titin gene mutations are common in families with both peripartum cardiomyopathy and dilated cardiomyopathy[J].Eur Heart J,2014,35(32):2165-2173.
[16]PUGH T J,KELLY M A,GOWRISANKAR S,et al.The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing[J].Genet Med,2014,16(8):601-608.
[2]ELLIOTT P,MCKENNA W J.Hypertrophic cardiomyopathy[J].Lancet,2004,363(9424):1881-1891.
[3]MARON B J,MARON M S,SEMSARIAN C.Genetics of hypertrophic cardiomyopathy after 20 years:clinical perspectives[J].J Am Coll Cardiol,2012,60(8):705-715.
[4]王纯,王辉,许心舒,等.外显子组测序对1例青壮年猝死的分子遗传学分析[J].法医学杂志,2015,31(6):436-440,444.
[5]李玉林.病理学[M].8版.北京:人民卫生出版社,2013.
[6]MARIAN A J.Hypertrophic cardiomyopathy:from genetics to treatment[J].Eur J Clin Invest,2010,40(4):360-369.
[7]WINEGRAD S.Cardiac myosin binding protein C[J].Circ Res,1999,84(10):1117-1126.
[8]FLASHMAN E,REDWOOD C,MOOLMANSMOOK J,et al.Cardiac myosin binding protein C:its role in physiology and disease[J].Circ Res,2004,94(10):1279-1289.
[9]NIIMURA H,BACHINSKI L L,SANGWATANAROJ S,et al.Mutations in the gene for cardiac myosinbinding protein C and late-onset familial hypertrophic cardiomyopathy[J].N Engl J Med,1998,338(18):1248-1257.
[10]CARRIER L,MEARINI G,STATHOPOULOU K,et al.Cardiac myosin-binding protein C(MYBPC3)in cardiac pathophysiology[J].Gene,2015,573(2):188-197.
[11]RICHARD P,CHARRON P,CARRIER L,et al.Hypertrophic cardiomyopathy:distribution of disease genes,spectrum of mutations,and implications for a molecular diagnosis strategy[J].Circulation,2003,107(17):2227-2232.
[12]BLAYNEY L M,LAI F A.Ryanodine receptormediated arrhythmias and sudden cardiac death[J].Pharmacol Ther,2009,123(2):151-177.
[13]MEDEIROS-DOMINGO A,BHUIYAN Z A,TESTER D J,et al.Comprehensive open reading frame mutational analysis of the RYR2-encoded ryanodine receptor/calcium channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative,exerciseinduced long QT syndrome[J].J Am Coll Cardiol,2009,54(22):2065-2074.
[14]CHAUVEAU C,ROWELL J,FERREIRO A.A rising titan:ttn review and mutation update[J].Hum Mutat,2014,35(9):1046-1059.
[15]VAN SPAENDONCK-ZWARTS K Y,POSAFALVI A,VAN DEN BERG M P,et al.Titin gene mutations are common in families with both peripartum cardiomyopathy and dilated cardiomyopathy[J].Eur Heart J,2014,35(32):2165-2173.
[16]PUGH T J,KELLY M A,GOWRISANKAR S,et al.The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing[J].Genet Med,2014,16(8):601-608.