BMJ雜志上發(fā)表的一項(xiàng)新研究，商業(yè)基因檢測公司廣泛使用的技術(shù)在鑒定非常罕見的變異體時(shí)“極其不可靠”，這意味著結(jié)果表明人們攜帶罕見的致病遺傳變異體通常是錯(cuò)誤的。

《Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation.》

       Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108?574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. However, the likelihood of a true positive result decreased dramatically with decreasing variant frequency; for variants that are very rare in the population, with a frequency below 0.001% in UK Biobank, the positive predictive value was very low and only 16% of 4757 heterozygous genotypes from the SNP chips were confirmed with sequencing data. Results were similar for SNP chip data from the Personal Genome Project, and 20/21 individuals analysed had at least one false positive rare pathogenic variant that had been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, which are individually very rare, the overall performance metrics for the SNP chips versus sequencing in the UK Biobank were: sensitivity 34.6%, specificity 98.3%, positive predictive value 4.2%, and negative predictive value 99.9%. Rates of BRCA related cancers in UK Biobank participants with a positive SNP chip result were similar to those for age matched controls (odds ratio 1.31, 95% confidence interval 0.99 to 1.71) because the vast majority of variants were false positives, whereas sequence positive participants had a significantly increased risk

       當(dāng)埃克塞特大學(xué)的研究人員聽說，婦女被誤認(rèn)為BRCA1基因非常罕見的遺傳變異會大大增加患乳腺癌的風(fēng)險(xiǎn)后便計(jì)劃進(jìn)行手術(shù)時(shí)，他們進(jìn)行了一項(xiàng)大規(guī)模的研究。這項(xiàng)技術(shù)使用了來自英國生物庫近50,000名參與者的數(shù)據(jù)。

       研究小組發(fā)現(xiàn)，在大多數(shù)情況下，該技術(shù)無法準(zhǔn)確地檢測到非常罕見的遺傳變異。

研究人員檢查了SNP芯片，該芯片通常測試整個(gè)基因組中成千上萬個(gè)特定位點(diǎn)的遺傳變化。盡管SNP芯片在識別可能會增加各種疾病（包括2型糖尿?。╋L(fēng)險(xiǎn)的常規(guī)遺傳變化方面表現(xiàn)出色，但遺傳學(xué)家早就知道它們在識別罕見變異方面的一致性較低。

       SNP技術(shù)：首先，用聚合酶鏈反應(yīng)（PCR）擴(kuò)增含單核苷酸多態(tài)性的基因組片段,然后用序列特異性引物進(jìn)行單堿基擴(kuò)增。然后將樣品分析物與芯片基體共結(jié)晶，在真空管中用瞬時(shí)納秒（10-9s）激光進(jìn)行激發(fā)。SNP芯片被直接向消費(fèi)者提供基因檢測的商業(yè)公司廣泛采用。研究人員將來自SNP芯片的數(shù)據(jù)與從更一致的下一代測序工具中獲得的數(shù)據(jù)進(jìn)行了比較，共有49,908名英國生物銀行參與者以及另外21個(gè)人通過“個(gè)人基因組計(jì)劃”分享了他們的消費(fèi)者基因測試結(jié)果。

       這項(xiàng)新研究推測，SNP芯片在鑒定常見遺傳變異方面表現(xiàn)出色。但是，較少的變化會導(dǎo)致結(jié)果可靠性降低。在十分罕見的變體中，每10萬人中有不到1個(gè)人發(fā)現(xiàn)了導(dǎo)致罕見遺傳病的特征，其中84％是UK Biobank參與者中的假陽性。

       在從商業(yè)客戶那里獲得的數(shù)據(jù)中，接受檢查的21個(gè)人中有20個(gè)人至少有一個(gè)假陽性罕見罕見病致病變異體，其基因型已被錯(cuò)誤地定型。

       埃克塞特大學(xué)基因組醫(yī)學(xué)研究合著者兼講師Leigh Jackson博士說“SNP芯片產(chǎn)生的罕見遺傳變異的假陽性數(shù)量驚人地高。需要明確的是：使用SNP芯片檢測到的非常罕見的致病變異很可能是錯(cuò)誤的，而不是正確的。盡管一些消費(fèi)者基因組學(xué)公司在將重要結(jié)果發(fā)布給消費(fèi)者之前會進(jìn)行測序以驗(yàn)證重要結(jié)果，但大多數(shù)消費(fèi)者還下載了其“原始” SNP芯片數(shù)據(jù)以進(jìn)行二次分析，并且這些原始數(shù)據(jù)仍然包含這些錯(cuò)誤結(jié)果。我們的發(fā)現(xiàn)的含義非常簡單：SNP芯片在檢測非常罕見的遺傳變異方面表現(xiàn)不佳，除非經(jīng)過驗(yàn)證，否則其結(jié)果不得用于指導(dǎo)患者的醫(yī)療服務(wù)?！?/span>