VarElect: the phenotype-based variation prioritizer of the GeneCards Suite

BMC Genomics

Methodology Article

Doron Lancet¹  Simon Fishilevich¹  Tsviya Olender¹  Anna Alkelai¹  Marilyn Safran¹  Michal Twik¹  Tsippi Iny Stein¹  Shahar Zimmerman¹  Noa Rappaport¹  Danit Oz-Levi¹  Ron Nudel¹  Gil Stelzer²  David Warshawsky³  Asher Kohn³  Yaron Guan-Golan³  Sergey Kaplan⁴  Yaron Mazor⁴  Inbar Plaschkes⁴  Dvir Dahary⁵  Frida Belinky⁶  Hagit N. Baris⁷ 

[1] Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel;Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel;LifeMap Sciences Ltd, Tel Aviv, Israel;LifeMap Sciences Inc, 02050, Marshfield, MA, USA;LifeMap Sciences Ltd, Tel Aviv, Israel;LifeMap Sciences Ltd, Tel Aviv, Israel;Toldot Genetics Ltd, Hod Hasharon, Israel;National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, 20894, Bethesda, MD, USA;The Genetics Institute, Rambam Health Care Campus, Haifa, Israel;Rappaport School of Medicine, Technion, Haifa, Israel;

关键词: Variant selection;    Gene prioritization;    Phenotyping;    Phenotype interpretation;    Next generation sequencing analysis;    Guilt by association;   

DOI  :  10.1186/s12864-016-2722-2

来源: Springer

【 摘 要 】

BackgroundNext generation sequencing (NGS) provides a key technology for deciphering the genetic underpinnings of human diseases. Typical NGS analyses of a patient depict tens of thousands non-reference coding variants, but only one or very few are expected to be significant for the relevant disorder. In a filtering stage, one employs family segregation, rarity in the population, predicted protein impact and evolutionary conservation as a means for shortening the variation list. However, narrowing down further towards culprit disease genes usually entails laborious seeking of gene-phenotype relationships, consulting numerous separate databases. Thus, a major challenge is to transition from the few hundred shortlisted genes to the most viable disease-causing candidates.ResultsWe describe a novel tool, VarElect (http://ve.genecards.org), a comprehensive phenotype-dependent variant/gene prioritizer, based on the widely-used GeneCards, which helps rapidly identify causal mutations with extensive evidence. The GeneCards suite offers an effective and speedy alternative, whereby >120 gene-centric automatically-mined data sources are jointly available for the task. VarElect cashes on this wealth of information, as well as on GeneCards’ powerful free-text Boolean search and scoring capabilities, proficiently matching variant-containing genes to submitted disease/symptom keywords. The tool also leverages the rich disease and pathway information of MalaCards, the human disease database, and PathCards, the unified pathway (SuperPaths) database, both within the GeneCards Suite. The VarElect algorithm infers direct as well as indirect links between genes and phenotypes, the latter benefitting from GeneCards’ diverse gene-to-gene data links in GenesLikeMe. Finally, our tool offers an extensive gene-phenotype evidence portrayal (“MiniCards”) and hyperlinks to the parent databases.ConclusionsWe demonstrate that VarElect compares favorably with several often-used NGS phenotyping tools, thus providing a robust facility for ranking genes, pointing out their likelihood to be related to a patient’s disease. VarElect’s capacity to automatically process numerous NGS cases, either in stand-alone format or in VCF-analyzer mode (TGex and VarAnnot), is indispensable for emerging clinical projects that involve thousands of whole exome/genome NGS analyses.

【 授权许可】

CC BY   
© Stelzer et al. 2016