Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.
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DOI：
10.1038/s41431-020-00713-9
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发表时间：
2021-01
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影响因子：
--
通讯作者：
Bauer P
中科院分区：
文献类型：
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作者：
Bertoli-Avella AM;Beetz C;Ameziane N;Rocha ME;Guatibonza P;Pereira C;Calvo M;Herrera-Ordonez N;Segura-Castel M;Diego-Alvarez D;Zawada M;Kandaswamy KK;Werber M;Paknia O;Zielske S;Ugrinovski D;Warnack G;Kampe K;Iurașcu MI;Cozma C;Vogel F;Alhashem A;Hertecant J;Al-Shamsi AM;Alswaid AF;Eyaid W;Al Mutairi F;Alfares A;Albalwi MA;Alfadhel M;Al-Sannaa NA;Reardon W;Alanay Y;Rolfs A;Bauer P
尽管基因组测序（GS）相对于其他诊断方法（如外显子组测序（ES））具有明显的技术优势，但很少有关于其临床应用优势的研究。我们分析了1007个连续的索引病例，这些病例在2年内的诊断环境中进行了GS。我们报告了致病性和可能致病性（P/LP）变异，解释了1007例病例中212例（21.1%）患者的表型。在另外245例病例（24.3%）中，报告了与表型相关的未知意义变异（VUS）。我们特别调查了没有遗传学诊断的ES患者（n = 358）。该组的GS诊断率为14.5%（358例患者中有52例P/LP）。GS应特别适用于ES阴性病例，因为其中高达29.6%的患者可以从GS检测中受益（P/LP为14.5%，n = 52; VUS为15.1%，n = 54）。大多数ES阴性/GS阳性病例的遗传诊断是由GS的技术优势决定的，即，访问非编码区域和更均匀的覆盖范围。重要的是，我们报告了79个非编码变异，其中41个变异被归类为P/LP。非编码变异的解释仍然具有挑战性，在许多情况下，需要基于直接酶评估，生物标志物检测和RNA分析的补充方法进行变异分类和诊断。我们介绍了迄今为止在临床环境中进行的最大的GS患者队列。本研究的结果应指导GS作为标准二线，甚至一线独立测试的决定。
Despite clear technical superiority of genome sequencing (GS) over other diagnostic methods such as exome sequencing (ES), few studies are available regarding the advantages of its clinical application. We analyzed 1007 consecutive index cases for whom GS was performed in a diagnostic setting over a 2-year period. We reported pathogenic and likely pathogenic (P/LP) variants that explain the patients’ phenotype in 212 of the 1007 cases (21.1%). In 245 additional cases (24.3%), a variant of unknown significance (VUS) related to the phenotype was reported. We especially investigated patients which had had ES with no genetic diagnosis (n = 358). For this group, GS diagnostic yield was 14.5% (52 patients with P/LP out of 358). GS should be especially indicated for ES-negative cases since up to 29.6% of them could benefit from GS testing (14.5% with P/LP, n = 52 and 15.1% with VUS, n = 54). Genetic diagnoses in most of the ES-negative/GS-positive cases were determined by technical superiority of GS, i.e., access to noncoding regions and more uniform coverage. Importantly, we reported 79 noncoding variants, of which, 41 variants were classified as P/LP. Interpretation of noncoding variants remains challenging, and in many cases, complementary methods based on direct enzyme assessment, biomarker testing and RNA analysis are needed for variant classification and diagnosis. We present the largest cohort of patients with GS performed in a clinical setting to date. The results of this study should direct the decision for GS as standard second-line, or even first-line stand-alone test.
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