Genome analysis and knowledge-driven variant interpretation with TGex

BackgroundThe clinical genetics revolution ushers in great opportunities, accompanied by significant challenges. The fundamental mission in clinical genetics is to analyze genomes, and to identify the most relevant genetic variations underlying a patient’s phenotypes and symptoms. The adoption of Whole Genome Sequencing requires novel capacities for interpretation of non-coding variants.ResultsWe present TGex, the Translational Genomics expert, a novel genome variation analysis and interpretation platform, with remarkable exome analysis capacities and a pioneering approach of non-coding variants interpretation. TGex’s main strength is combining state-of-the-art variant filtering with knowledge-driven analysis made possible by VarElect, our highly effective gene-phenotype interpretation tool. VarElect leverages the widely used GeneCards knowledgebase, which integrates information from > 150 automatically-mined data sources. Access to such a comprehensive data compendium also facilitates TGex’s broad variant annotation, supporting evidence exploration, and decision making. TGex has an interactive, user-friendly, and easy adaptive interface, ACMG compliance, and an automated reporting system. Beyond comprehensive whole exome sequence capabilities, TGex encompasses innovative non-coding variants interpretation, towards the goal of maximal exploitation of whole genome sequence analyses in the clinical genetics practice. This is enabled by GeneCards’ recently developed GeneHancer, a novel integrative and fully annotated database of human enhancers and promoters. Examining use-cases from a variety of TGex users world-wide, we demonstrate its high diagnostic yields (42% for single exome and 50% for trios in 1500 rare genetic disease cases) and critical actionable genetic findings. The platform’s support for integration with EHR and LIMS through dedicated APIs facilitates automated retrieval of patient data for TGex’s customizable reporting engine, establishing a rapid and cost-effective workflow for an entire range of clinical genetic testing, including rare disorders, cancer predisposition, tumor biopsies and health screening.ConclusionsTGex is an innovative tool for the annotation, analysis and prioritization of coding and non-coding genomic variants. It provides access to an extensive knowledgebase of genomic annotations, with intuitive and flexible configuration options, allows quick adaptation, and addresses various workflow requirements. It thus simplifies and accelerates variant interpretation in clinical genetics workflows, with remarkable diagnostic yield, as exemplified in the described use cases.TGex is available at http://tgex.genecards.org/

[1]  Allyn McConkie-Rosell,et al.  The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders , 2013, Genetics in Medicine.

[2]  Tomas W. Fitzgerald,et al.  Large-scale discovery of novel genetic causes of developmental disorders , 2014, Nature.

[3]  Clara Gaff,et al.  Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions , 2017, JAMA pediatrics.

[4]  Sean V Tavtigian,et al.  Genetic predisposition to colorectal cancer: syndromes, genes, classification of genetic variants and implications for precision medicine , 2019, The Journal of pathology.

[5]  Edward Blair,et al.  “Not pathogenic until proven otherwise”: perspectives of UK clinical genomics professionals toward secondary findings in context of a Genomic Medicine Multidisciplinary Team and the 100,000 Genomes Project , 2017, Genetics in Medicine.

[6]  Antonio Novelli,et al.  Primary muscle involvement in a 15‐year‐old girl with the recurrent homozygous c.362dupC variant in FKBP14 , 2019, American journal of medical genetics. Part A.

[7]  S. Batzoglou,et al.  Distribution and intensity of constraint in mammalian genomic sequence. , 2005, Genome research.

[8]  M. Margaglione,et al.  Mutation of the angiopoietin‐1 gene (ANGPT1) associates with a new type of hereditary angioedema , 2017, The Journal of allergy and clinical immunology.

[9]  François Schiettecatte,et al.  OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders , 2014, Nucleic Acids Res..

[10]  Yiping Shen,et al.  Three additional de novo CTCF mutations in Chinese patients help to define an emerging neurodevelopmental disorder , 2019, American journal of medical genetics. Part C, Seminars in medical genetics.

[11]  Doron Lancet,et al.  Non-redundant compendium of human ncRNA genes in GeneCards , 2013, Bioinform..

[12]  Brett J. Kennedy,et al.  Phevor combines multiple biomedical ontologies for accurate identification of disease-causing alleles in single individuals and small nuclear families. , 2014, American journal of human genetics.

[13]  Giardina Emiliano,et al.  Mitochondrial Serine Protease HTRA2 p.G399S in a Female with Di George Syndrome and Parkinson's Disease , 2018, Parkinson's disease.

[14]  The 100 000 Genomes Project: bringing whole genome sequencing to the NHS , 2018, British Medical Journal.

[15]  Hui Yang,et al.  Phenolyzer: phenotype-based prioritization of candidate genes for human diseases , 2015, Nature Methods.

[16]  Caroline F. Wright,et al.  De novo mutations in regulatory elements in neurodevelopmental disorders , 2018, Nature.

[17]  Noam Shomron,et al.  Differential analysis of mutations in the Jewish population and their implications for diseases , 2017, Genetics research.

[18]  Jan O. Korbel,et al.  Phenotypic impact of genomic structural variation: insights from and for human disease , 2013, Nature Reviews Genetics.

[19]  Doron Lancet,et al.  MalaCards: an amalgamated human disease compendium with diverse clinical and genetic annotation and structured search , 2016, Nucleic Acids Res..

[20]  Ira M. Hall,et al.  Genomic Analysis in the Age of Human Genome Sequencing , 2019, Cell.

[21]  Doron Lancet,et al.  PathCards: multi-source consolidation of human biological pathways , 2015, Database J. Biol. Databases Curation.

[22]  Charles Auffray,et al.  Ten years of Genome Medicine , 2019, Genome Medicine.

[23]  Clara Gaff,et al.  Patient safety in genomic medicine: an exploratory study , 2016, Genetics in Medicine.

[24]  Mauricio O. Carneiro,et al.  From FastQ Data to High‐Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline , 2013, Current protocols in bioinformatics.

[25]  Damian Smedley,et al.  Improved exome prioritization of disease genes through cross-species phenotype comparison , 2014, Genome research.

[26]  Na Cai,et al.  11,670 whole-genome sequences representative of the Han Chinese population from the CONVERGE project , 2017, Scientific Data.

[27]  G. Bejerano,et al.  Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers , 2016, Genetics in Medicine.

[28]  Menachem Motiei,et al.  Can molecular profiling enhance radiotherapy? Impact of personalized targeted gold nanoparticles on radiosensitivity and imaging of adenoid cystic carcinoma , 2017, Theranostics.

[29]  Doron Lancet,et al.  GeneHancer: genome-wide integration of enhancers and target genes in GeneCards , 2017, Database J. Biol. Databases Curation.

[30]  Catherine A Brownstein,et al.  Unique bioinformatic approach and comprehensive reanalysis improve diagnostic yield of clinical exomes , 2019, European Journal of Human Genetics.

[31]  Lei Zhang,et al.  Whole-exome sequencing identifies a somatic missense mutation of NBN in clear cell sarcoma of the salivary gland. , 2016, Oncology reports.

[32]  Steven J. M. Jones,et al.  CIViC is a community knowledgebase for expert crowdsourcing the clinical interpretation of variants in cancer , 2017, Nature Genetics.

[33]  Pablo Cingolani,et al.  © 2012 Landes Bioscience. Do not distribute. , 2022 .

[34]  Julie O. Culver,et al.  Genetics, genomics, and cancer risk assessment , 2011, CA: a cancer journal for clinicians.

[35]  Jana Marie Schwarz,et al.  MutationTaster evaluates disease-causing potential of sequence alterations , 2010, Nature Methods.

[36]  G. Ast,et al.  Expanding the MYBPC1 phenotypic spectrum: a novel homozygous mutation causes arthrogryposis multiplex congenita , 2016, Clinical genetics.

[37]  Bruna L. Freire,et al.  Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause , 2017, Hormone Research in Paediatrics.

[38]  Antonio Novelli,et al.  LTBP2‐related “Marfan‐like” phenotype in two Roma/Gypsy subjects with the LTBP2 homozygous p.R299X variant , 2019, American journal of medical genetics. Part A.

[39]  D. Lancet,et al.  A role for TENM1 mutations in congenital general anosmia , 2016, Clinical genetics.

[40]  B. Fernandez,et al.  Utility of whole‐exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care , 2015, Clinical genetics.

[41]  Evan Bolton,et al.  Database resources of the National Center for Biotechnology Information , 2017, Nucleic Acids Res..

[42]  Renan Valieris,et al.  Utility of trio-based exome sequencing in the elucidation of the genetic basis of isolated syndromic intellectual disability: illustrative cases , 2018, The application of clinical genetics.

[43]  Doron Lancet,et al.  TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability. , 2016, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[44]  Tsviya Olender,et al.  VarElect: the phenotype-based variation prioritizer of the GeneCards Suite , 2016, BMC Genomics.

[45]  Hilde van der Togt,et al.  Publisher's Note , 2003, J. Netw. Comput. Appl..

[46]  Heidi L Rehm,et al.  CORRIGENDUM: ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing , 2017, Genetics in Medicine.

[47]  K. Eilbeck,et al.  Settling the score: variant prioritization and Mendelian disease , 2017, Nature Reviews Genetics.

[48]  Aik Choon Tan,et al.  A Survey of Computational Tools to Analyze and Interpret Whole Exome Sequencing Data , 2016, International journal of genomics.

[49]  S. Gabriel,et al.  Analysis of 6,515 exomes reveals a recent origin of most human protein-coding variants , 2012, Nature.

[50]  Jean-Baptiste Cazier,et al.  Choice of transcripts and software has a large effect on variant annotation , 2014, Genome Medicine.

[51]  Justin C. Fay,et al.  Identification of deleterious mutations within three human genomes. , 2009, Genome research.

[52]  Bernat Gel,et al.  Benchmarking of Whole Exome Sequencing and Ad Hoc Designed Panels for Genetic Testing of Hereditary Cancer , 2017, Scientific Reports.

[53]  Eric Vilain,et al.  Clinical exome sequencing for genetic identification of rare Mendelian disorders. , 2014, JAMA.

[54]  Kengo Kinoshita,et al.  Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals , 2015, Nature Communications.

[55]  Doron Sagiv,et al.  Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin. , 2018, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[56]  Mingming Jia,et al.  COSMIC: somatic cancer genetics at high-resolution , 2016, Nucleic Acids Res..

[57]  Gregory D. Schuler,et al.  Database resources of the National Center for Biotechnology Information: update , 2004, Nucleic acids research.

[58]  Olivier Bodenreider,et al.  The Unified Medical Language System (UMLS): integrating biomedical terminology , 2004, Nucleic Acids Res..

[59]  Antonio Novelli,et al.  Helsmoortel-Van der Aa Syndrome as emerging clinical diagnosis in intellectually disabled children with autistic traits and ocular involvement. , 2018, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[60]  Mahdi Sarmady,et al.  mtDNA Variation and Analysis Using Mitomap and Mitomaster , 2013, Current protocols in bioinformatics.

[61]  Chunlei Liu,et al.  ClinVar: improving access to variant interpretations and supporting evidence , 2017, Nucleic Acids Res..

[62]  Mathew Varghese,et al.  Mutation burden profile in familial Alzheimer's disease cases from India , 2017, Neurobiology of Aging.

[63]  P. Bork,et al.  A method and server for predicting damaging missense mutations , 2010, Nature Methods.

[64]  W. Chung,et al.  Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics , 2016, Genetics in Medicine.

[65]  E. Boerwinkle,et al.  dbNSFP v3.0: A One‐Stop Database of Functional Predictions and Annotations for Human Nonsynonymous and Splice‐Site SNVs , 2016, Human mutation.

[66]  Davis J. McCarthy,et al.  Factors influencing success of clinical genome sequencing across a broad spectrum of disorders , 2015, Nature Genetics.

[67]  Christian Gilissen,et al.  A Post‐Hoc Comparison of the Utility of Sanger Sequencing and Exome Sequencing for the Diagnosis of Heterogeneous Diseases , 2013, Human mutation.

[68]  Heng Li,et al.  A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data , 2011, Bioinform..

[69]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[70]  Anna Lehman,et al.  The cost and diagnostic yield of exome sequencing for children with suspected genetic disorders: a benchmarking study , 2018, Genetics in Medicine.

[71]  Poh San Lai,et al.  Specific phenotype semantics facilitate gene prioritization in clinical exome sequencing , 2019, European journal of human genetics : EJHG.

[72]  C. Turnbull,et al.  Introducing whole-genome sequencing into routine cancer care: the Genomics England 100 000 Genomes Project. , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[73]  Matthew N. Bainbridge,et al.  A visual and curatorial approach to clinical variant prioritization and disease gene discovery in genome-wide diagnostics , 2016, Genome Medicine.

[74]  James Y. Zou.  Analysis of protein-coding genetic variation in 60,706 humans , 2015, Nature.

[75]  P. Ng,et al.  SIFT missense predictions for genomes , 2015, Nature Protocols.

[76]  Nathalie Boddaert,et al.  Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect , 2012, Journal of Inherited Metabolic Disease.

[77]  Matthew E Hurles,et al.  The functional impact of structural variation in humans. , 2008, Trends in genetics : TIG.

[78]  Rolf Schröder,et al.  Clinical exome sequencing: results from 2819 samples reflecting 1000 families , 2016, European Journal of Human Genetics.

[79]  D. Lancet,et al.  Exome sequencing as a differential diagnosis tool: resolving mild trichohepatoenteric syndrome , 2015, Clinical genetics.

[80]  R. Wilson,et al.  The Next-Generation Sequencing Revolution and Its Impact on Genomics , 2013, Cell.

[81]  Min Yu,et al.  Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis , 2017, Human molecular genetics.

[82]  Tsippi Iny Stein,et al.  The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses , 2016, Current protocols in bioinformatics.

[83]  Maurice H. T. Ling,et al.  Advancing Personalized Medicine Through the Application of Whole Exome Sequencing and Big Data Analytics , 2019, Front. Genet..

[84]  Chittibabu Guda,et al.  A Comparison of Variant Calling Pipelines Using Genome in a Bottle as a Reference , 2015, BioMed research international.

[85]  Magalie S Leduc,et al.  Clinical whole-exome sequencing for the diagnosis of mendelian disorders. , 2013, The New England journal of medicine.

[86]  Tsviya Olender,et al.  Next-generation sequencing of patients with congenital anosmia , 2017, European Journal of Human Genetics.

[87]  A global reference for human genetic variation , 2015, Nature.

[88]  T. Tuohy,et al.  Hereditary and familial colon cancer. , 2010, Gastroenterology.

[89]  Yang Liu,et al.  A novel SLC6A8 mutation associated with intellectual disabilities in a Chinese family exhibiting creatine transporter deficiency: case report , 2018, BMC Medical Genetics.

[90]  Felipe Fidalgo,et al.  Role of rare germline copy number variation in melanoma-prone patients. , 2016, Future oncology.

[91]  Tudor Groza,et al.  Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources , 2018, Nucleic Acids Res..

[92]  Kengo Kinoshita,et al.  A 12-kb structural variation in progressive myoclonic epilepsy was newly identified by long-read whole-genome sequencing , 2019, Journal of Human Genetics.

[93]  Hugo Y. K. Lam,et al.  Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes , 2012, Cell.

[94]  M. Kamran Azim,et al.  Exome sequencing identifies a novel frameshift variant causing hypomagnesemia with secondary hypocalcemia , 2018, CEN Case Reports.

[95]  S M Caspar,et al.  Clinical sequencing: From raw data to diagnosis with lifetime value , 2018, Clinical genetics.

[96]  François Schiettecatte,et al.  OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders , 2014, Nucleic Acids Res..

[97]  A. Jelin,et al.  Whole Exome Sequencing: Applications in Prenatal Genetics. , 2018, Obstetrics and gynecology clinics of North America.

[98]  Elizabeth M. Smigielski,et al.  dbSNP: the NCBI database of genetic variation , 2001, Nucleic Acids Res..

[99]  Marc S. Williams,et al.  ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing , 2013, Genetics in Medicine.

[100]  Gabor T. Marth,et al.  A global reference for human genetic variation , 2015, Nature.

[101]  Pablo Cingolani,et al.  Using Drosophila melanogaster as a Model for Genotoxic Chemical Mutational Studies with a New Program, SnpSift , 2012, Front. Gene..