Increasing the Yield and Utility of Pediatric Genomic Medicine with Exomiser

利用 Exomiser 提高儿科基因组医学的产量和实用性

• 批准号: 10611970
• 负责人: CHRISTOPHER J MUNGALL
• 金额: $ 70.29万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-10 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611970
• 关键词: Address; Affect; Algorithms; Animal Model; Area; Birth; Case Study; Child; Child Care; Childhood; Clinic; Clinical; Clinical Data; Clinical Management; Clinical Research; Clinical assessments; Cohort Analysis; Collection; Complex; Computational algorithm; Computer Analysis; Computer software; Couples; DNA; DNA sequencing; Data; Databases; Diagnosis; Diagnostic; Disease; England; Evaluation; Finding by Cause; Frustration; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Diseases; Genetic Materials; Genetically Modified Animals; Genome; Genomic medicine; Genomics; Health; Human; Human Genetics; Individual; Intellectual functioning disability; Intelligence; Knowledge; Laboratories; Literature; Medical; Medicine; Mendelian disorder; Methods; Modeling; Molecular; Morbidity - disease rate; Ontology; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pediatrics; Performance; Phenotype; Population; Predictive Value; Process; Publishing; RNA; RNA Splicing; RNA analysis; Rare Diseases; Records; Research; Resources; Role; Running; Scanning; Series; Specialist; Spliced Genes; Symptoms; Techniques; Technology; Testing; Time; Tissue-Specific Gene Expression; United States National Institutes of Health; Variant; Visit; causal variant; clinical care; clinical decision-making; clinical diagnostics; clinical phenotype; cohort; cost; diagnostic tool; diagnostic value; disease diagnostic; exome; exome sequencing; gene discovery; genetic disorder diagnosis; genome sequencing; genomic data; human disease; improved; meter; new technology; next generation sequencing; novel; novel strategies; pediatrician; personalized management; phenomics; rare genetic disorder; support tools; tool; transcriptome sequencing; uptake; whole genome

PROJECT SUMMARY As much as 10% of the population suffers from a rare disease (RD); 80% of these diseases are caused by gene mutations and up to 75% are present at birth or begin in childhood. Diagnosis of genetic diseases is often problematic: roughly 25% of RD patients must wait between 5 and 30 years for a diagnosis, and about half of the initial diagnoses are wrong. For many affected children, definitive diagnosis comes only after a protracted and frustrating odyssey of visits to different specialists. Emerging genetic sequencing techniques offer the possibility of shortening this long and costly path to diagnosis. Methods for determining the changes in gene sequences across all genes (exome sequencing) or all genetic material (genome sequencing), collectively referred to as Next-Generation Sequencing (NGS), and which were first used to identify the genetic cause of a disease in 2010, are now becoming routine in the clinic. The ability to make a diagnosis with NGS has more than doubled since 2010 for children with suspected genetic diseases. The diagnostic analysis of NGS data involves the assessment of tens of thousands (exome) or even millions (genome) of changes in the DNA (variants), which requires sophisticated computer algorithms that can sift through these/this data to find the cause. Our group has developed the Human Phenotype Ontology (HPO), a resource widely used around the world for the computational analysis of clinical data in human genetics and pediatrics, allowing algorithms to match the symptoms of a patient with database records of over 7,000 genetic diseases. Our Exomiser software compares the clinical phenotypes of patients with known human diseases and genetically modified animal models, and couples this with an analysis of the disease-causing potential of DNA variants, greatly reducing the search space to identify the causal variant. Exomiser efficiently processes both exome and genome data. In this proposal, we plan to extend Exomiser to utilize new genomic data types including long-read genome sequencing and NGS-based analysis of RNA data, which will improve pathogenicity prediction for structural variants (SVs) and for variants affecting gene expression or splicing. We will also predict novel disease genes through characterization of networks of clinical phenotypes and the molecular functions (pathways) of affected genes. We plan to use these algorithms to assess collections (cohorts) of unsolved cases in projects such as the 100,000 Genomes Project. Our algorithmic approach will be applied to intelligently reanalyze unsolved cases periodically as new information is added to the medical literature. And finally, we will develop tools to integrate Exomiser into a large range of settings by adding support for standards generated by the Global Alliance for Genomics and Health (GA4GH). The proposed advances will make Exomiser more efficient, more accurate, and easier for non-specialist pediatricians to use, bringing genomic diagnostics to routine pediatric clinical care.

项目总结

项目成果

Phenotype-aware prioritisation of rare Mendelian disease variants.

• DOI: 10.1016/j.tig.2022.07.002
• 发表时间: 2022-12
• 期刊: TRENDS IN GENETICS
• 影响因子: 11.4
• 作者: Kelly, Catherine;Szabo, Anita;Pontikos, Nikolas;Arno, Gavin;Robinson, Peter N.;Jacobsen, Jules O. B.;Smedley, Damian;Cipriani, Valentina
• 通讯作者: Cipriani, Valentina

Evaluation of phenotype-driven gene prioritization methods for Mendelian diseases.

• DOI: 10.1093/bib/bbac188
• 发表时间: 2022-09-20
• 期刊: Briefings in bioinformatics
• 影响因子: 9.5

The RD-Connect Genome-Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases.

• DOI: 10.1002/humu.24353
• 发表时间: 2022-06
• 期刊: HUMAN MUTATION
• 影响因子: 3.9
• 作者: Laurie, Steven;Piscia, Davide;Matalonga, Leslie;Corvo, Alberto;Fernandez-Callejo, Marcos;Garcia-Linares, Carles;Hernandez-Ferrer, Carles;Luengo, Cristina;Martinez, Ines;Papakonstantinou, Anastasios;Pico-Amador, Daniel;Protasio, Joan;Thompson, Rachel;Tonda, Raul;Bayes, Monica;Bullich, Gemma;Camps-Puchadas, Jordi;Paramonov, Ida;Trotta, Jean-Remi;Alonso, Angel;Attimonelli, Marcella;Beroud, Christophe;Bros-Facer, Virginie;Buske, Orion J.;Canada-Pallares, Andres;Fernandez, Jose M.;Hansson, Mats G.;Horvath, Rita;Jacobsen, Julius O. B.;Kaliyaperumal, Rajaram;Lair-Preterre, Severine;Licata, Luana;Lopes, Pedro;Lopez-Martin, Estrella;Mascalzoni, Deborah;Monaco, Lucia;Perez-Jurado, Luis A.;Posada de la Paz, Manuel;Rambla, Jordi;Rath, Ana;Riess, Olaf;Robinson, Peter N.;Salgado, David;Smedley, Damian;Spalding, Dylan;'t Hoen, Peter A. C.;Topf, Ana;Zaharieva, Irina;Graessner, Holm;Gut, Ivo G.;Lochmuller, Hanns;Beltran, Sergi
• 通讯作者: Beltran, Sergi

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.

• DOI: 10.1056/nejmoa2035790
• 发表时间: 2021-11-11
• 期刊: The New England journal of medicine
• 作者: 100,000 Genomes Project Pilot Investigators;Smedley D;Smith KR;Martin A;Thomas EA;McDonagh EM;Cipriani V;Ellingford JM;Arno G;Tucci A;Vandrovcova J;Chan G;Williams HJ;Ratnaike T;Wei W;Stirrups K;Ibanez K;Moutsianas L;Wielscher M;Need A;Barnes MR;Vestito L;Buchanan J;Wordsworth S;Ashford S;Rehmström K;Li E;Fuller G;Twiss P;Spasic-Boskovic O;Halsall S;Floto RA;Poole K;Wagner A;Mehta SG;Gurnell M;Burrows N;James R;Penkett C;Dewhurst E;Gräf S;Mapeta R;Kasanicki M;Haworth A;Savage H;Babcock M;Reese MG;Bale M;Baple E;Boustred C;Brittain H;de Burca A;Bleda M;Devereau A;Halai D;Haraldsdottir E;Hyder Z;Kasperaviciute D;Patch C;Polychronopoulos D;Matchan A;Sultana R;Ryten M;Tavares ALT;Tregidgo C;Turnbull C;Welland M;Wood S;Snow C;Williams E;Leigh S;Foulger RE;Daugherty LC;Niblock O;Leong IUS;Wright CF;Davies J;Crichton C;Welch J;Woods K;Abulhoul L;Aurora P;Bockenhauer D;Broomfield A;Cleary MA;Lam T;Dattani M;Footitt E;Ganesan V;Grunewald S;Compeyrot-Lacassagne S;Muntoni F;Pilkington C;Quinlivan R;Thapar N;Wallis C;Wedderburn LR;Worth A;Bueser T;Compton C;Deshpande C;Fassihi H;Haque E;Izatt L;Josifova D;Mohammed S;Robert L;Rose S;Ruddy D;Sarkany R;Say G;Shaw AC;Wolejko A;Habib B;Burns G;Hunter S;Grocock RJ;Humphray SJ;Robinson PN;Haendel M;Simpson MA;Banka S;Clayton-Smith J;Douzgou S;Hall G;Thomas HB;O'Keefe RT;Michaelides M;Moore AT;Malka S;Pontikos N;Browning AC;Straub V;Gorman GS;Horvath R;Quinton R;Schaefer AM;Yu-Wai-Man P;Turnbull DM;McFarland R;Taylor RW;O'Connor E;Yip J;Newland K;Morris HR;Polke J;Wood NW;Campbell C;Camps C;Gibson K;Koelling N;Lester T;Németh AH;Palles C;Patel S;Roy NBA;Sen A;Taylor J;Cacheiro P;Jacobsen JO;Seaby EG;Davison V;Chitty L;Douglas A;Naresh K;McMullan D;Ellard S;Temple IK;Mumford AD;Wilson G;Beales P;Bitner-Glindzicz M;Black G;Bradley JR;Brennan P;Burn J;Chinnery PF;Elliott P;Flinter F;Houlden H;Irving M;Newman W;Rahman S;Sayer JA;Taylor JC;Webster AR;Wilkie AOM;Ouwehand WH;Raymond FL;Chisholm J;Hill S;Bentley D;Scott RH;Fowler T;Rendon A;Caulfield M
• 通讯作者: Caulfield M

The Clinical Variant Analysis Tool: Analyzing the evidence supporting reported genomic variation in clinical practice.

• DOI: 10.1016/j.gim.2022.03.013
• 发表时间: 2022-07
• 期刊: GENETICS IN MEDICINE
• 影响因子: 8.8
• 作者: Chin, Hui-Lin;Gazzaz, Nour;Huynh, Stephanie;Handra, Iulia;Warnock, Lynn;Moller-Hansen, Ashley;Boerkoel, Pierre;Jacobsen, Julius O. B.;du Souich, Christele;Zhang, Nan;Shefchek, Kent;Prentice, Leah M.;Washington, Nicole;Haendel, Melissa;Armstrong, Linlea;Clarke, Lorne;Li, Wenhui Laura;Smedley, Damian;Robinson, Peter N.;Boerkoel, Cornelius F.
• 通讯作者: Boerkoel, Cornelius F.