Personalized Medicine. Medical opportunities and challenges in the massive sequencing era

Leandro Sastre, Elena G. Árias-Salgado, Leandro Sastre


DNA sequencing capacity has increased tremendously in the last ten years due to the development of massive sequencing techniques, also known as Next Generation Sequencing. A large amount of information on the sequence of the human genome, its organization, transcription and regulation of gene expression has been generated form healthy individuals and also from patients suffering a broad group of diseases. The technical capacity to determine the sequence of patients’ DNAs at decreasing cost and the knowledge already generated is making possible a precise molecular diagnosis for many diseases in clinical settings. Determining the molecular basis of the disease for each particular patient has important implications in diagnosis, prognosis, genetic counselling and for the determination of an optimal treatment, moving towards a personalized medicine. In this review the available sequencing platforms will be briefly analyzed. DNA sequencing for clinical practice can be extended to different levels and the advantages and disadvantages of Whole Genome Sequencing (WGS), Whole Exome Sequencing (WES), RNA sequencing, Targeted Panel Sequencing and Mehylated DNA Sequencing will be discussed. The application of these technologies to Monogenic, Multigenic diseases and Cancer will be reviewed. Finally, the clinical implementation of massive parallel sequencing technologies and the present challenges will be discussed.


massive sequencing; molecular genetics; exome; genome; personalized medicine

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Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463-7.

Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature. 2001 Feb 15;409(6822):860-921.

Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, et al. A map of human genome variation from population-scale sequencing. Nature. 2010 Oct 28;467(7319):1061-73.

Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, et al. A global reference for human genetic variation. Nature. 2015 Oct 01;526(7571):68-74.

Walter K, Min JL, Huang J, Crooks L, Memari Y, McCarthy S, et al. The UK10K project identifies rare variants in health and disease. Nature. 2015 Oct 01;526(7571):82-90.

Park ST, Kim J. Trends in Next-Generation Sequencing and a New Era for Whole Genome Sequencing. Int Neurourol J. 2016 Nov;20(Suppl 2):S76-83.

Fu W, O'Connor TD, Jun G, Kang HM, Abecasis G, Leal SM, et al. Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature. 2012 Jan 10;493(7431):216-20.

Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016 Aug 18;536(7616):285-91.

Marian AJ. Challenges in medical applications of whole exome/genome sequencing discoveries. Trends Cardiovasc Med. 2012 Nov;22(8):219-23.

Singleton AB. Exome sequencing: a transformative technology. Lancet Neurol. 2011 Oct;10(10):942-6.

MacArthur DG, Balasubramanian S, Frankish A, Huang N, Morris J, Walter K, et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science. 2012 Feb 17;335(6070):823-8.

Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012 Sep 6;489(7414):57-74.

Sastre L. Clinical implications of the ENCODE project. Clin Transl Oncol. 2012 Nov;14(11):801-2.

Forrest AR, Kawaji H, Rehli M, Baillie JK, de Hoon MJ, Haberle V, et al. A promoter-level mammalian expression atlas. Nature. 2014 Mar 27;507(7493):462-70.

Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, et al. An atlas of active enhancers across human cell types and tissues. Nature. 2014 Mar 27;507(7493):455-61.

Ding Z, Mangino M, Aviv A, Spector T, Durbin R. Estimating telomere length from whole genome sequence data. Nucleic Acids Res. 2014 May;42(9):e75.

Perona R, Iarriccio L, Pintado-Berninches L, Rodriguez-Centeno J, Manguan-Garcia C, Garcia E, et al. Molecular diagnosis and precission therapeutic approaches for telomere biology disorders. In: Larramendy M, Soloneski S, editors. Telomeres: INTECH; 2016. p. 77-117.

Petersen BS, Fredrich B, Hoeppner MP, Ellinghaus D, Franke A. Opportunities and challenges of whole-genome and -exome sequencing. BMC Genet. 2017 Feb 14;18(1):14.

Sheikine Y, Kuo FC, Lindeman NI. Clinical and Technical Aspects of Genomic Diagnostics for Precision Oncology. J Clin Oncol. 2017 Mar 20;35(9):929-33.

Horak P, Frohling S, Glimm H. Integrating next-generation sequencing into clinical oncology: strategies, promises and pitfalls. ESMO Open. 2016;1(5):e000094.

Surrey LF, Luo M, Chang F, Li MM. The Genomic Era of Clinical Oncology: Integrated Genomic Analysis for Precision Cancer Care. Cytogenet Genome Res. 2016;150(3-4):162-75.

Fuller CW, Kumar S, Porel M, Chien M, Bibillo A, Stranges PB, et al. Real-time single-molecule electronic DNA sequencing by synthesis using polymer-tagged nucleotides on a nanopore array. Proc Natl Acad Sci U S A. 2016 May 10;113(19):5233-8.

Sastre L. New DNA sequencing technologies open a promising era for cancer research and treatment. Clin Transl Oncol. 2011 May;13(5):301-6.

Alioto TS, Buchhalter I, Derdak S, Hutter B, Eldridge MD, Hovig E, et al. A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing. Nat Commun. 2015 Dec 09;6:10001.

Kluk MJ, Lindsley RC, Aster JC, Lindeman NI, Szeto D, Hall D, et al. Validation and Implementation of a Custom Next-Generation Sequencing Clinical Assay for Hematologic Malignancies. J Mol Diagn. 2016 Jul;18(4):507-15.

Wagle N, Berger MF, Davis MJ, Blumenstiel B, Defelice M, Pochanard P, et al. High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing. Cancer Discov. 2012 Jan;2(1):82-93.

Beadling C, Wald AI, Warrick A, Neff TL, Zhong S, Nikiforov YE, et al. A Multiplexed Amplicon Approach for Detecting Gene Fusions by Next-Generation Sequencing. J Mol Diagn. 2016 Mar;18(2):165-75.

Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet. 2009 Jan;10(1):57-63.

Lee TI, Young RA. Transcriptional regulation and its misregulation in disease. Cell. 2013 Mar 14;152(6):1237-51.

Mele M, Ferreira PG, Reverter F, DeLuca DS, Monlong J, Sammeth M, et al. Human genomics. The human transcriptome across tissues and individuals. Science. 2015 May 08;348(6235):660-5.

Consoritium TG. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015 May 08;348(6235):648-60.

Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000 Aug 17;406(6797):747-52.

Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. 2015 Nov 19;373(21):2005-14.

Cardoso F, van't Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med. 2016 Aug 25;375(8):717-29.

Gallego-Paez LM, Bordone MC, Leote AC, Saraiva-Agostinho N, Ascensao-Ferreira M, Barbosa-Morais NL. Alternative splicing: the pledge, the turn, and the prestige : The key role of alternative splicing in human biological systems. Hum Genet. 2017 Apr 03.

Byron SA, Van Keuren-Jensen KR, Engelthaler DM, Carpten JD, Craig DW. Translating RNA sequencing into clinical diagnostics: opportunities and challenges. Nat Rev Genet. 2016 May;17(5):257-71.

Robertson KD. DNA methylation and human disease. Nat Rev Genet. 2005 Aug;6(8):597-610.

Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003 Nov 20;349(21):2042-54.

Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015 Feb 19;518(7539):317-30.

Smith M. DNA Sequence Analysis in Clinical Medicine, Proceeding Cautiously. Front Mol Biosci. 2017;4:24.

Stuart BD, Choi J, Zaidi S, Xing C, Holohan B, Chen R, et al. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nat Genet. 2015 May;47(5):512-7.

Kuhlenbaumer G, Hullmann J, Appenzeller S. Novel genomic techniques open new avenues in the analysis of monogenic disorders. Hum Mutat. 2011 Feb;32(2):144-51.

Sastre L. Exome sequencing: what clinicians need to know. Advances in Genomics and Genetics. 2014;4:15-27.

Chakravorty S, Hegde M. Gene and Variant Annotation for Mendelian Disorders in the Era of Advanced Sequencing Technologies. Annu Rev Genomics Hum Genet. 2017 Apr 17.

Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012 Nov 1;491(7422):56-65.

Glusman G, Caballero J, Mauldin DE, Hood L, Roach JC. 2011Kaviar: an accessible system for testing SNV novelty. Bioinformatics. Nov 15;27(22):3216-7.

Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014 Jan;133(1):1-9.

Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009 Apr;84(4):524-33.

Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016 Jan 04;44(D1):D862-8.

Pinero J, Bravo A, Queralt-Rosinach N, Gutierrez-Sacristan A, Deu-Pons J, Centeno E, et al. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res. 2016 Jan 04;45(D1):D833-D9.

Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4(7):1073-81.

Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010 Apr;7(4):248-9.

Quang D, Chen Y, Xie X. DANN: a deep learning approach for annotating the pathogenicity of genetic variants. Bioinformatics. 2015 Mar 01;31(5):761-3.

Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014 Mar;46(3):310-5.

Shihab HA, Rogers MF, Gough J, Mort M, Cooper DN, Day IN, et al. An integrative approach to predicting the functional effects of non-coding and coding sequence variation. Bioinformatics. 2015 May 15;31(10):1536-43.

Jian X, Boerwinkle E, Liu X. In silico prediction of splice-altering single nucleotide variants in the human genome. Nucleic Acids Res. 2014 Dec 16;42(22):13534-44.

Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK, et al. RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. Science. 2014 Jan 09;347(6218):1254806.

Katsanos KH, Papadakis KA. Pharmacogenetics of inflammatory bowel disease. Pharmacogenomics. 2014 Dec;15(16):2049-62.

Morris DL, Sheng Y, Zhang Y, Wang YF, Zhu Z, Tombleson P, et al. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus. Nat Genet. 2016 Aug;48(8):940-6.

Baumgart DC, Sandborn WJ. Crohn's disease. Lancet. 2012 Nov 03;380(9853):1590-605.

Ellinghaus D, Bethune J, Petersen BS, Franke A. The genetics of Crohn's disease and ulcerative colitis--status quo and beyond. Scand J Gastroenterol. 2015 Jan;50(1):13-23.

Akbarian S, Liu C, Knowles JA, Vaccarino FM, Farnham PJ, Crawford GE, et al. The PsychENCODE project. Nat Neurosci. 2015 Dec;18(12):1707-12.

Harripaul R, Noor A, Ayub M, Vincent JB. The Use of Next-Generation Sequencing for Research and Diagnostics for Intellectual Disability. Cold Spring Harb Perspect Med. 2017 Mar 01;7(3).

Essers JB, Lee JJ, Kugathasan S, Stevens CR, Grand RJ, Daly MJ. Established genetic risk factors do not distinguish early and later onset Crohn's disease. Inflamm Bowel Dis. 2009 Oct;15(10):1508-14.

MacArthur J, Bowler E, Cerezo M, Gil L, Hall P, Hastings E, et al. The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog). Nucleic Acids Res. 2016 Jan 04;45(D1):D896-D901.

Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015 Sep;47(9):979-86.

Musante L, Ropers HH. Genetics of recessive cognitive disorders. Trends Genet. 2014 Jan;30(1):32-9.

Wright CF, Fitzgerald TW, Jones WD, Clayton S, McRae JF, van Kogelenberg M, et al. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet. 2015 Apr 04;385(9975):1305-14.

Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med. 2013 Oct 17;369(16):1502-11.

Tan CA, Topper S, Del Gaudio D, Nelakuditi V, Shchelochkov O, Nowaczyk MJ, et al. Characterization of patients referred for non-specific intellectual disability testing: the importance of autosomal genes for diagnosis. Clin Genet. 2015 Feb 19;89(4):478-83.

Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 2012 Sep 14;150(6):1107-20.

Pleasance ED, Stephens PJ, O'Meara S, McBride DJ, Meynert A, Jones D, et al. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. 2010 Jan 14;463(7278):184-90.

Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2010 Jan 14;463(7278):191-6.

Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011 Jan 7;144(1):27-40.

Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, et al. Punctuated evolution of prostate cancer genomes. Cell. 2013 Apr 25;153(3):666-77.

Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013 Oct 17;502(7471):333-9.

Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014 Jan 23;505(7484):495-501.

Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet. 2013 Oct;45(10):1113-20.

Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R, et al. A census of human cancer genes. Nat Rev Cancer. 2004 Mar;4(3):177-83.

Forbes SA, Beare D, Gunasekaran P, Leung K, Bindal N, Boutselakis H, et al. COSMIC: exploring the world's knowledge of somatic mutations in human cancer. Nucleic Acids Res. 2015 Jan;43(Database issue):D805-11.

Yang Y, Dong X, Xie B, Ding N, Chen J, Li Y, et al. Databases and web tools for cancer genomics study. Genomics Proteomics Bioinformatics. 2015 Feb;13(1):46-50.

Genome CLC. A genomics-based classification of human lung tumors. Sci Transl Med. 2013 Oct 30;5(209):209ra153.

Ellis MJ, Perou CM. The genomic landscape of breast cancer as a therapeutic roadmap. Cancer Discov. 2013 Jan;3(1):27-34.

Li MM, Datto M, Duncavage EJ, Kulkarni S, Lindeman NI, Roy S, et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017 Jan;19(1):4-23.

Sabari JK, Santini F, Bergagnini I, Lai WV, Arbour KC, Drilon A. Changing the Therapeutic Landscape in Non-small Cell Lung Cancers: the Evolution of Comprehensive Molecular Profiling Improves Access to Therapy. Curr Oncol Rep. 2017 Apr;19(4):24.

Katona BW, Rustgi AK. Gastric Cancer Genomics: Advances and Future Directions. Cell Mol Gastroenterol Hepatol. 2017 Mar;3(2):211-7.

Soto J, Rodriguez-Antolin C, Vallespin E, de Castro Carpeno J, Ibanez de Caceres I. The impact of next-generation sequencing on the DNA methylation-based translational cancer research. Transl Res. 2016 Mar;169:1-18 e1.

Ibanez de Caceres I, Battagli C, Esteller M, Herman JG, Dulaimi E, Edelson MI, et al. Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients. Cancer Res. 2004 Sep 15;64(18):6476-81.

Ibanez de Caceres I, Cortes-Sempere M, Moratilla C, Machado-Pinilla R, Rodriguez-Fanjul V, Manguan-Garcia C, et al. IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer. Oncogene. 2010 Mar 18;29(11):1681-90.

Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009 Oct 8;461(7265):809-13.

Roukos DH. Spatiotemporal diversification of intrapatient genomic clones and early drug development concepts realize the roadmap of precision cancer medicine. Drug Discov Today. 2017 Apr 08.

Lebofsky R, Decraene C, Bernard V, Kamal M, Blin A, Leroy Q, et al. Circulating tumor DNA as a non-invasive substitute to metastasis biopsy for tumor genotyping and personalized medicine in a prospective trial across all tumor types. Mol Oncol. 2015 Apr;9(4):783-90.

Kalluri R. The biology and function of exosomes in cancer. J Clin Invest. 2016 Apr 01;126(4):1208-15.

Rothe F, Laes JF, Lambrechts D, Smeets D, Vincent D, Maetens M, et al. Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer. Ann Oncol. 2014 Oct;25(10):1959-65.

Lohr JG, Adalsteinsson VA, Cibulskis K, Choudhury AD, Rosenberg M, Cruz-Gordillo P, et al. Whole-exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer. Nat Biotechnol. 2014 May;32(5):479-84.

Gawad C, Koh W, Quake SR. Single-cell genome sequencing: current state of the science. Nat Rev Genet. 2016 Mar;17(3):175-88.

Sequist LV, Heist RS, Shaw AT, Fidias P, Rosovsky R, Temel JS, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol. 2011 Dec;22(12):2616-24.

Chia PL, Do H, Morey A, Mitchell P, Dobrovic A, John T. Temporal changes of EGFR mutations and T790M levels in tumour and plasma DNA following AZD9291 treatment. Lung Cancer. 2016 Aug;98:29-32.

Chan KC, Jiang P, Zheng YW, Liao GJ, Sun H, Wong J, et al. Cancer genome scanning in plasma: detection of tumor-associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing. Clin Chem. 2013 Jan;59(1):211-24.

Legendre C, Gooden GC, Johnson K, Martinez RA, Liang WS, Salhia B. Whole-genome bisulfite sequencing of cell-free DNA identifies signature associated with metastatic breast cancer. Clin Epigenetics. 2015;7:100.

Melchor L, Benitez J. The complex genetic landscape of familial breast cancer. Hum Genet. 2013 Aug;132(8):845-63.

Phelan CM, Kuchenbaecker KB, Tyrer JP, Kar SP, Lawrenson K, Winham SJ, et al. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer. Nat Genet. 2017 May;49(5):680-91.

Mason CE, Afshinnekoo E, Tighe S, Wu S, Levy S. International Standards for Genomes, Transcriptomes, and Metagenomes. J Biomol Tech. 2017 Apr;28(1):8-18.

Munro SA, Lund SP, Pine PS, Binder H, Clevert DA, Conesa A, et al. Assessing technical performance in differential gene expression experiments with external spike-in RNA control ratio mixtures. Nat Commun. 2014 Sep 25;5:5125.

Zook JM, Catoe D, McDaniel J, Vang L, Spies N, Sidow A, et al. Extensive sequencing of seven human genomes to characterize benchmark reference materials. Sci Data. 2016 Jun 07;3:160025.

Consortium SM-I. A comprehensive assessment of RNA-seq accuracy, reproducibility and information content by the Sequencing Quality Control Consortium. Nat Biotechnol. 2014 Sep;32(9):903-14.

t Hoen PA, Friedlander MR, Almlof J, Sammeth M, Pulyakhina I, Anvar SY, et al. Reproducibility of high-throughput mRNA and small RNA sequencing across laboratories. Nat Biotechnol. 2013 Nov;31(11):1015-22.

Li S, Tighe SW, Nicolet CM, Grove D, Levy S, Farmerie W, et al. Multi-platform assessment of transcriptome profiling using RNA-seq in the ABRF next-generation sequencing study. Nat Biotechnol. 2014 Sep;32(9):915-25.

Gargis AS, Kalman L, Bick DP, da Silva C, Dimmock DP, Funke BH, et al. Good laboratory practice for clinical next-generation sequencing informatics pipelines. Nat Biotechnol. 2015 Jul;33(7):689-93.

Philippakis AA, Azzariti DR, Beltran S, Brookes AJ, Brownstein CA, Brudno M, et al. The Matchmaker Exchange: a platform for rare disease gene discovery. Hum Mutat. 2015 Oct;36(10):915-21.

Bodenreider O. The Unified Medical Language System (UMLS): integrating biomedical terminology. Nucleic Acids Res. 2004 Jan 01;32(Database issue):D267-70.

Kohler S, Vasilevsky NA, Engelstad M, Foster E, McMurry J, Ayme S, et al. The Human Phenotype Ontology in 2017. Nucleic Acids Res. 2017 Jan 04;45(D1):D865-D76.

Dienstmann R, Dong F, Borger D, Dias-Santagata D, Ellisen LW, Le LP, et al. Standardized decision support in next generation sequencing reports of somatic cancer variants. Mol Oncol. 2014 Jul;8(5):859-73.

Hynes SO, Pang B, James JA, Maxwell P, Salto-Tellez M. Tissue-based next generation sequencing: application in a universal healthcare system. Br J Cancer. 2017 Feb 28;116(5):553-60.

Shahmirzadi L, Chao EC, Palmaer E, Parra MC, Tang S, Gonzalez KD. Patient decisions for disclosure of secondary findings among the first 200 individuals undergoing clinical diagnostic exome sequencing. Genet Med. 2014 Oct 10;16(5):395-9.

Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013 Jul;15(7):565-74.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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. Genet Med. 2015 May;17(5):405-24.



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