Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort.
Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort.
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DOI：
10.1093/nar/gky372
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发表时间：
2018-09-06
影响因子：
14.9
通讯作者：
Houdayer C
中科院分区：
文献类型：
--
作者：
Leman R;Gaildrat P;Le Gac G;Ka C;Fichou Y;Audrezet MP;Caux-Moncoutier V;Caputo SM;Boutry-Kryza N;Léone M;Mazoyer S;Bonnet-Dorion F;Sevenet N;Guillaud-Bataille M;Rouleau E;Bressac-de Paillerets B;Wappenschmidt B;Rossing M;Muller D;Bourdon V;Revillon F;Parsons MT;Rousselin A;Davy G;Castelain G;Castéra L;Sokolowska J;Coulet F;Delnatte C;Férec C;Spurdle AB;Martins A;Krieger S;Houdayer C
变异的解释是分子诊断中的关键问题。剪接变异体解决了这个问题，因为每个核苷酸变异体通过破坏或产生剪接位点共有序列可能是有害的。因此，变异剪接原性的可靠的计算机预测将是一个重大的改进。由于国际上的努力，在mRNA水平上研究了一组395个变异，这些变异发生在5′和3′共有区（分别定义为外显子/内含子连接周围的11和14个碱基），用于11个不同的基因，包括BRCA 1，BRCA 2，CFTR和RHD，并用于训练和验证一种新的预测方案，称为剪接预测一致性元件（SPiCE）。SPiCE结合了来自SpliceSiteFinder-like和MaxEntScan的计算机预测，并使用逻辑回归来定义最佳决策阈值。它显示出前所未有的灵敏度和特异性分别为99.5%和95.2%，并且正确预测了98.8%的变体对剪接的影响。因此，我们建议SPiCE作为预测变异剪接原性的新工具。它可以很容易地在任何诊断实验室中实施，作为常规决策工具，帮助遗传学家面对下一代测序时代的大量变异。SPiCE可在（https：//sourceforge.net/projects/spicev2-1/）访问。
Variant interpretation is the key issue in molecular diagnosis. Spliceogenic variants exemplify this issue as each nucleotide variant can be deleterious via disruption or creation of splice site consensus sequences. Consequently, reliable in silico prediction of variant spliceogenicity would be a major improvement. Thanks to an international effort, a set of 395 variants studied at the mRNA level and occurring in 5′ and 3′ consensus regions (defined as the 11 and 14 bases surrounding the exon/intron junction, respectively) was collected for 11 different genes, including BRCA1, BRCA2, CFTR and RHD, and used to train and validate a new prediction protocol named Splicing Prediction in Consensus Elements (SPiCE). SPiCE combines in silico predictions from SpliceSiteFinder-like and MaxEntScan and uses logistic regression to define optimal decision thresholds. It revealed an unprecedented sensitivity and specificity of 99.5 and 95.2%, respectively, and the impact on splicing was correctly predicted for 98.8% of variants. We therefore propose SPiCE as the new tool for predicting variant spliceogenicity. It could be easily implemented in any diagnostic laboratory as a routine decision making tool to help geneticists to face the deluge of variants in the next-generation sequencing era. SPiCE is accessible at (https://sourceforge.net/projects/spicev2-1/).
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DOI：
10.1038/gim.2013.176
发表时间：
2014-07
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
14.9
作者：
Desmet FO;Hamroun D;Lalande M;Collod-Béroud G;Claustres M;Béroud C
通讯作者：
Béroud C
影响因子：
3.5
作者：
Callebaut, Isabelle;Joubrel, Rozenn;Le Gac, Gerald
通讯作者：
Le Gac, Gerald
影响因子：
14.9
作者：
SHAPIRO, MB;SENAPATHY, P
通讯作者：
SENAPATHY, P
影响因子：
3.9
作者：
Houdayer, Claude;Caux-Moncoutier, Virginie;Stoppa-Lyonnet, Dominique
通讯作者：
Stoppa-Lyonnet, Dominique