Targeting de novo loss-of-function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project.
Targeting de novo loss-of-function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project.
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DOI：
10.1007/s00439-022-02509-x
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发表时间：
2023-03
期刊：
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
--
作者：
基因组测序首先在英国通过100，000基因组计划（100 KGP）提供临床应用。分析仅限于与患者表型相关的预定义基因组。然而，面板依赖于明确表征的表型，并且存在在所应用的面板之外缺失诊断的风险。我们提出了一种补充方法来快速识别致病性变体，包括那些错过了100 KGP方法。功能丧失观察/预期上限分数（LOEUF）评分量化基因约束，低评分与单倍不足相关。我们应用DeNovoLOEUF（一种过滤策略）对来自100 KGP中13,949种罕见疾病三联体的测序数据进行了过滤，过滤了LOEUF评分< 0.2的疾病基因中罕见的、从头开始的、功能丧失的变异。我们将我们的发现与相应患者的诊断报告进行了比较。使用DeNovoLOEUF鉴定的324/332（98%）种变异具有诊断性或部分诊断性（变异导致一些表型）。我们确定了39个被100 KGP标准分析“遗漏”的诊断，这些诊断现在正在返回给患者。我们已经证明了一种高度特异性和快速的方法，具有98%的阳性预测值，与标准分析具有良好的一致性，假阳性率低，并可以识别其他诊断。在全球范围内，随着越来越多的患者接受基因组测序，我们预计DeNovoLOEUF将快速识别新的诊断，并在发现新的疾病基因时促进迭代分析。在线版本包含补充材料，可通过10.1007/s 00439 -022-02509-x获得。
Genome sequencing was first offered clinically in the UK through the 100,000 Genomes Project (100KGP). Analysis was restricted to predefined gene panels associated with the patient’s phenotype. However, panels rely on clearly characterised phenotypes and risk missing diagnoses outside of the panel(s) applied. We propose a complementary method to rapidly identify pathogenic variants, including those missed by 100KGP methods. The Loss-of-function Observed/Expected Upper-bound Fraction (LOEUF) score quantifies gene constraint, with low scores correlated with haploinsufficiency. We applied DeNovoLOEUF, a filtering strategy to sequencing data from 13,949 rare disease trios in the 100KGP, by filtering for rare, de novo, loss-of-function variants in disease genes with a LOEUF score < 0.2. We compared our findings with the corresponding patient’s diagnostic reports. 324/332 (98%) of the variants identified using DeNovoLOEUF were diagnostic or partially diagnostic (whereby the variant was responsible for some of the phenotype). We identified 39 diagnoses that were “missed” by 100KGP standard analyses, which are now being returned to patients. We have demonstrated a highly specific and rapid method with a 98% positive predictive value that has good concordance with standard analysis, low false-positive rate, and can identify additional diagnoses. Globally, as more patients are being offered genome sequencing, we anticipate that DeNovoLOEUF will rapidly identify new diagnoses and facilitate iterative analyses when new disease genes are discovered. The online version contains supplementary material available at 10.1007/s00439-022-02509-x.
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DOI：
10.1126/science.1215040
发表时间：
2012-02-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
MacArthur DG;Balasubramanian S;Frankish A;Huang N;Morris J;Walter K;Jostins L;Habegger L;Pickrell JK;Montgomery SB;Albers CA;Zhang ZD;Conrad DF;Lunter G;Zheng H;Ayub Q;DePristo MA;Banks E;Hu M;Handsaker RE;Rosenfeld JA;Fromer M;Jin M;Mu XJ;Khurana E;Ye K;Kay M;Saunders GI;Suner MM;Hunt T;Barnes IH;Amid C;Carvalho-Silva DR;Bignell AH;Snow C;Yngvadottir B;Bumpstead S;Cooper DN;Xue Y;Romero IG;1000 Genomes Project Consortium;Wang J;Li Y;Gibbs RA;McCarroll SA;Dermitzakis ET;Pritchard JK;Barrett JC;Harrow J;Hurles ME;Gerstein MB;Tyler-Smith C
通讯作者：
Tyler-Smith C
影响因子：
5.3
作者：
Austin-Tse CA;Jobanputra V;Perry DL;Bick D;Taft RJ;Venner E;Gibbs RA;Young T;Barnett S;Belmont JW;Boczek N;Chowdhury S;Ellsworth KA;Guha S;Kulkarni S;Marcou C;Meng L;Murdock DR;Rehman AU;Spiteri E;Thomas-Wilson A;Kearney HM;Rehm HL;Medical Genome Initiative*
通讯作者：
Medical Genome Initiative*
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
82.9
作者：
Rehm HL
通讯作者：
Rehm HL
影响因子：
3.7
作者：
Seaby EG;Rehm HL;O'Donnell-Luria A
通讯作者：
O'Donnell-Luria A