中国大陆脊髓小脑性共济失调家系和散发病例的最新基因突变分析(英文)

Spinocerebellar ataxias in China's Mainland:an updated genetic analysis among a large cohort of familial and sporadic cases

目的:了解中国大陆汉族人群常染色体显性遗传和散发脊髓小脑性共济失调(SCA)中最新基因频率分布。方法:采用聚合酶链反应(PCR)和DNA直接测序(DNA sequenc ing)方法对430例常染色体显性遗传SCA(AD-SCA)家系先证者和237例散发患者进行了SCA1,SCA2,SCA3/M JD,SCA6,SCA7,SCA8,SCA10,SCA12,SCA17亚型和齿状核红核苍白球路易体萎缩(DRPLA)亚型致病基因核苷酸重复突变检测分析,然后采用聚合酶链反应-变性高效液相色谱(PCR-DHPLC),多重连接探针扩增(MLPA)和DNA直接测序方法对91例排除了以上SCA亚型突变的ADCA家系先证者和196例散发患者进行了SCA5,SCA11,SCA13,SCA14,SCA15/16/29,SCA27,SCA31和SCA35亚型的点突变及插入缺失突变检测。结果:在430个AD-SCA家系中,发现有25个SCA1家系(5.81%)、27个SCA2家系(5.81%)、267个SCA3/M JD家系(62.09%)、8个SCA6家系(1.86%)、8个SCA7家系(1.86%)、1个SCA12家系(0.23%)、1个SCA17家系(0.23%)和2个SCA35家系(0.47%),91个ADCA家系未明确基因分型(21.16%);在237例散发SCA患者中,发现有6例SCA1患者(2.53%)、9例SCA2患者(3.80%)、23例SCA3/M JD患者(9.70%)和3例SCA6患者(1.27%),196例SCA患者未明确基因分型(82.7%);未发现SCA8,SCA10和DRPLA亚型核苷酸重复突变和SCA5,SCA11,SCA13,SCA14,SCA15/16/29,SCA27和SCA31亚型点突变或插入缺失突变。结论:在中国汉族人群中SCA3/M JD为最常见的SCA亚型,其次为SCA2,SCA1,SCA6和SCA7亚型,SCA12,SCA17和SCA35亚型比较少见,SCA5,SCA8,SCA10,SCA11,SCA13,SCA14,SCA15/16/29,SCA27,SCA31和DRPLA亚型罕见。在AD-CA家系和散发患者中存在一定比例基因型暂不明的病例,说明SCA的遗传异质性,可能是由于部分ADCA家系存在其他致病基因的作用,大部分散发SCA患者除遗传因素外还存在其他致病因素。

Objective To undertake an updated genetic spectrum analysis in patients with hereditary spinocerebellar ataxia（SCA） in China's Mainland.Methods SCA 1,2,3,6,7,8,10,12,17 and dentatorubral-pallidoluysian atrophy（DRPLA） nucleotide repeat mutations were detected in 430 families with autosomal dominant SCA（ADCA） and 237 patients with sporadic ataxias by PCR and DNA sequencing.Subsequently,point and Indel（Insertion/deletion） mutation analyses of SCA5,SCA11,SCA13,SCA14,SCA15/16/29,SCA27,SCA31 and SCA35 were detected in 91 families with ADCA and 196 patients with sporadic ataxias excluded from SCA1,2,3,6,7,8,10,12,17 and DRPLA genotypes via PCR and Denaturing High Performance Liquid Chromatography（PCR-DHPLC）,Multiplex ligation-dependent probe amplification and DNA direct sequencing analysis.Results Among the 430 ADCA families,there were 25 SCA1（5.81%）,27 SCA2（6.28%）,267 SCA3/MJD（62.09%）,8 SCA6（1.86%）,8 SCA7（1.86%）,1 SCA12（0.23%）,1 SCA17（0.23%） and 2 SCA35（0.47%）,and the remaining 91 families（21.16%） were genetically unidentified.Among the 237 sporadic SCA patients,there were 6 SCA1（2.53%）,9 SCA2（3.80%）,23 SCA3/MJD（9.70%） and 3 SCA6（1.27%）,and the remaining 196（82.7%） were genetically unidentified.No pathogenic point mutation causing SCA5,SCA11,SCA13,SCA14,SCA27 or SCA31 subtypes was found.Conclusion SCA3/MJD is substantially the most common subtype in patients with ADCA and sporadic forms in China's Mainland,followed by SCA2,SCA1,SCA6 and SCA7.While SCA12,SCA17 and SCA35 are seldom found,SCA5,SCA8,SCA10,SCA11,SCA13,SCA27,SCA31 and DRPLA are very rare.The high proportion of genetically unidentified cases further verify that SCAs are of highly genetic heterogeneity,suggesting that other disease-causing genes might be involved in the negative ADCA pedigrees,and other etiological factors may involve in those sporadic cases other than genetics.