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Implementation of Exome Sequencing Assay

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Genomic Applications in Pathology

Abstract

Next-generation sequencing (NGS) is driving our current approaches to molecular diagnosis and characterization of inherited genetic disorders and is also enabling the discovery of genetic variants that induce susceptibility to non-inherited disorders. Advancements in NGS platforms and bioinformatics pipelines have allowed high-throughput, cost-effective, and efficient coverage of all coding regions of the genome, making whole-exome sequencing (WES) highly feasible in a clinical setting. Consequentially, the specificity and sensitivity for detecting all coding changes have tremendously improved, and the efforts and duration required to narrow down to the precise disease-associated variant(s) have significantly reduced. Rightly so, WES and whole-genome sequencing (WGS) are fast becoming the one-for-all clinical genetic tests, leading our way to precision medicine. In this chapter, we summarize the evolving roles of WES, which range from its use as a disease diagnostic tool for rare single-gene Mendelian disorders to a routine screening tool for monitoring disease progression and treatment response in cancer patients, as well as a tool for novel gene discovery in a research setting. This chapter highlights the achievements and limitations of the technology and emphasizes the challenges involved in the implementation of WES assays for clinical care.

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References

  1. Margulies M, Egholm M, Altman WE, Attiya S, Bader JS, Bemben LA, Berka J, Braverman MS, Chen YJ, Chen Z, Dewell SB, Du L, Fierro JM, Gomes XV, Godwin BC, He W, Helgesen S, Ho CH, Irzyk GP, Jando SC, Alenquer ML, Jarvie TP, Jirage KB, Kim JB, Knight JR, Lanza JR, Leamon JH, Lefkowitz SM, Lei M, Li J, Lohman KL, Lu H, Makhijani VB, McDade KE, McKenna MP, Myers EW, Nickerson E, Nobile JR, Plant R, Puc BP, Ronan MT, Roth GT, Sarkis GJ, Simons JF, Simpson JW, Srinivasan M, Tartaro KR, Tomasz A, Vogt KA, Volkmer GA, Wang SH, Wang Y, Weiner MP, Yu P, Begley RF, Rothberg JM. Genome sequencing in microfabricated high-density picolitre reactors. Nature. 2005;437(7057):376–80. https://doi.org/10.1038/nature03959.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Albert TJ, Molla MN, Muzny DM, Nazareth L, Wheeler D, Song X, Richmond TA, Middle CM, Rodesch MJ, Packard CJ, Weinstock GM, Gibbs RA. Direct selection of human genomic loci by microarray hybridization. Nat Methods. 2007;4(11):903–5. https://doi.org/10.1038/nmeth1111.

    Article  CAS  PubMed  Google Scholar 

  3. Bashiardes S, Veile R, Helms C, Mardis ER, Bowcock AM, Lovett M. Direct genomic selection. Nat Methods. 2005;2(1):63–9. https://doi.org/10.1038/nmeth0105-63.

    Article  CAS  PubMed  Google Scholar 

  4. Gnirke A, Melnikov A, Maguire J, Rogov P, LeProust EM, Brockman W, Fennell T, Giannoukos G, Fisher S, Russ C, Gabriel S, Jaffe DB, Lander ES, Nusbaum C. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat Biotechnol. 2009;27(2):182–9. https://doi.org/10.1038/nbt.1523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hodges E, Xuan Z, Balija V, Kramer M, Molla MN, Smith SW, Middle CM, Rodesch MJ, Albert TJ, Hannon GJ, McCombie WR. Genome-wide in situ exon capture for selective resequencing. Nat Genet. 2007;39(12):1522–7. https://doi.org/10.1038/ng.2007.42.

    Article  CAS  PubMed  Google Scholar 

  6. Mamanova L, Coffey AJ, Scott CE, Kozarewa I, Turner EH, Kumar A, Howard E, Shendure J, Turner DJ. Target-enrichment strategies for next-generation sequencing. Nat Methods. 2010;7(2):111–8. https://doi.org/10.1038/nmeth.1419.

    Article  CAS  PubMed  Google Scholar 

  7. Mardis ER. Next-generation DNA sequencing methods. Annu Rev Genomics Hum Genet. 2008;9:387–402. https://doi.org/10.1146/annurev.genom.9.081307.164359.

    Article  CAS  PubMed  Google Scholar 

  8. Ansorge WJ. Next-generation DNA sequencing techniques. New Biotechnol. 2009;25(4):195–203. https://doi.org/10.1016/j.nbt.2008.12.009.

    Article  CAS  Google Scholar 

  9. Metzker ML. Sequencing technologies – the next generation. Nat Rev Genet. 2010;11(1):31–46. https://doi.org/10.1038/nrg2626.

    Article  CAS  PubMed  Google Scholar 

  10. Shendure J, Ji H. Next-generation DNA sequencing. Nat Biotechnol. 2008;26(10):1135–45. https://doi.org/10.1038/nbt1486.

    Article  CAS  PubMed  Google Scholar 

  11. Gowrisankar S, Lerner-Ellis JP, Cox S, White ET, Manion M, LeVan K, Liu J, Farwell LM, Iartchouk O, Rehm HL, Funke BH. Evaluation of second-generation sequencing of 19 dilated cardiomyopathy genes for clinical applications. J Mol Diagn. 2010;12(6):818–27. https://doi.org/10.2353/jmoldx.2010.100014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jones MA, Bhide S, Chin E, Ng BG, Rhodenizer D, Zhang VW, Sun JJ, Tanner A, Freeze HH, Hegde MR. Targeted polymerase chain reaction-based enrichment and next generation sequencing for diagnostic testing of congenital disorders of glycosylation. Genet Med. 2011;13(11):921–32. https://doi.org/10.1097/GIM.0b013e318226fbf2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lemke JR, Riesch E, Scheurenbrand T, Schubach M, Wilhelm C, Steiner I, Hansen J, Courage C, Gallati S, Burki S, Strozzi S, Simonetti BG, Grunt S, Steinlin M, Alber M, Wolff M, Klopstock T, Prott EC, Lorenz R, Spaich C, Rona S, Lakshminarasimhan M, Kroll J, Dorn T, Kramer G, Synofzik M, Becker F, Weber YG, Lerche H, Bohm D, Biskup S. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia. 2012;53(8):1387–98. https://doi.org/10.1111/j.1528-1167.2012.03516.x.

    Article  CAS  PubMed  Google Scholar 

  14. Lin X, Tang W, Ahmad S, Lu J, Colby CC, Zhu J, Yu Q. Applications of targeted gene capture and next-generation sequencing technologies in studies of human deafness and other genetic disabilities. Hear Res. 2012;288(1–2):67–76. https://doi.org/10.1016/j.heares.2012.01.004.

    Article  CAS  PubMed  Google Scholar 

  15. Neveling K, Collin RW, Gilissen C, van Huet RA, Visser L, Kwint MP, Gijsen SJ, Zonneveld MN, Wieskamp N, de Ligt J, Siemiatkowska AM, Hoefsloot LH, Buckley MF, Kellner U, Branham KE, den Hollander AI, Hoischen A, Hoyng C, Klevering BJ, van den Born LI, Veltman JA, Cremers FP, Scheffer H. Next-generation genetic testing for retinitis pigmentosa. Hum Mutat. 2012;33(6):963–72. https://doi.org/10.1002/humu.22045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Valencia CA, Ankala A, Rhodenizer D, Bhide S, Littlejohn MR, Keong LM, Rutkowski A, Sparks S, Bonnemann C, Hegde M. Comprehensive mutation analysis for congenital muscular dystrophy: a clinical PCR-based enrichment and next-generation sequencing panel. PLoS One. 2013;8(1):e53083. https://doi.org/10.1371/journal.pone.0053083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Valencia CA, Rhodenizer D, Bhide S, Chin E, Littlejohn MR, Keong LM, Rutkowski A, Bonnemann C, Hegde M. Assessment of target enrichment platforms using massively parallel sequencing for the mutation detection for congenital muscular dystrophy. J Mol Diagn. 2012;14(3):233–46. https://doi.org/10.1016/j.jmoldx.2012.01.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Vasta V, Ng SB, Turner EH, Shendure J, Hahn SH. Next generation sequence analysis for mitochondrial disorders. Genome Med. 2009;1(10):100. https://doi.org/10.1186/gm100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ankala A, Kohn JN, Dastur R, Gaitonde P, Khadilkar SV, Hegde MR. Ancestral founder mutations in calpain-3 in the Indian Agarwal community: historical, clinical, and molecular perspective. Muscle Nerve. 2013;47(6):931–7. https://doi.org/10.1002/mus.23763.

    Article  CAS  PubMed  Google Scholar 

  20. Mitra AP, Pagliarulo V, Yang D, Waldman FM, Datar RH, Skinner DG, Groshen S, Cote RJ. Generation of a concise gene panel for outcome prediction in urinary bladder cancer. J Clin Oncol. 2009;27(24):3929–37. https://doi.org/10.1200/JCO.2008.18.5744.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Holcomb CL, Hoglund B, Anderson MW, Blake LA, Bohme I, Egholm M, Ferriola D, Gabriel C, Gelber SE, Goodridge D, Hawbecker S, Klein R, Ladner M, Lind C, Monos D, Pando MJ, Proll J, Sayer DC, Schmitz-Agheguian G, Simen BB, Thiele B, Trachtenberg EA, Tyan DB, Wassmuth R, White S, Erlich HA. A multi-site study using high-resolution HLA genotyping by next generation sequencing. Tissue Antigens. 2011;77(3):206–17. https://doi.org/10.1111/j.1399-0039.2010.01606.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Proll J, Danzer M, Stabentheiner S, Niklas N, Hackl C, Hofer K, Atzmuller S, Hufnagl P, Gully C, Hauser H, Krieger O, Gabriel C. Sequence capture and next generation resequencing of the MHC region highlights potential transplantation determinants in HLA identical haematopoietic stem cell transplantation. DNA Res. 2011;18(4):201–10. https://doi.org/10.1093/dnares/dsr008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Serizawa M, Sekizuka T, Okutani A, Banno S, Sata T, Inoue S, Kuroda M. Genomewide screening for novel genetic variations associated with ciprofloxacin resistance in Bacillus anthracis. Antimicrob Agents Chemother. 2010;54(7):2787–92. https://doi.org/10.1128/AAC.01405-09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Coonrod EM, Durtschi JD, Margraf RL, Voelkerding KV. Developing genome and exome sequencing for candidate gene identification in inherited disorders: an integrated technical and bioinformatics approach. Arch Pathol Lab Med. 2013;137(3):415–33. https://doi.org/10.5858/arpa.2012-0107-RA.

    Article  CAS  PubMed  Google Scholar 

  25. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754–60. https://doi.org/10.1093/bioinformatics/btp324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M, McKenna A, Fennell TJ, Kernytsky AM, Sivachenko AY, Cibulskis K, Gabriel SB, Altshuler D, Daly MJ. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491–8. https://doi.org/10.1038/ng.806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, Genome Project Data Processing Subgroup. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25(16):2078–9. https://doi.org/10.1093/bioinformatics/btp352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164. https://doi.org/10.1093/nar/gkq603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. 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;17(5):405–24. https://doi.org/10.1038/gim.2015.30.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Dorschner MO, Amendola LM, Turner EH, Robertson PD, Shirts BH, Gallego CJ, Bennett RL, Jones KL, Tokita MJ, Bennett JT, Kim JH, Rosenthal EA, Kim DS, National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project, Tabor HK, Bamshad MJ, Motulsky AG, Scott CR, Pritchard CC, Walsh T, Burke W, Raskind WH, Byers P, Hisama FM, Nickerson DA, Jarvik GP. Actionable, pathogenic incidental findings in 1,000 participants’ exomes. Am J Hum Genet. 2013;93(4):631–40. https://doi.org/10.1016/j.ajhg.2013.08.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hegde M, Bale S, Bayrak-Toydemir P, Gibson J, Jeng LJ, Joseph L, Laser J, Lubin IM, Miller CE, Ross LF, Rothberg PG, Tanner AK, Vitazka P, Mao R. Reporting incidental findings in genomic scale clinical sequencing--a clinical laboratory perspective: a report of the Association for Molecular Pathology. J Mol Diagn. 2015;17(2):107–17. https://doi.org/10.1016/j.jmoldx.2014.10.004.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Whiffin N, Minikel E, Walsh R, O’Donnell-Luria AH, Karczewski K, Ing AY, Barton PJR, Funke B, Cook SA, MacArthur D, Ware JS. Using high-resolution variant frequencies to empower clinical genome interpretation. Genet Med. 2017;19(10):1151–8. https://doi.org/10.1038/gim.2017.26.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Robinson PN, Kohler S, Oellrich A, Sanger Mouse Genetics Project, Wang K, Mungall CJ, Lewis SE, Washington N, Bauer S, Seelow D, Krawitz P, Gilissen C, Haendel M, Smedley D. Improved exome prioritization of disease genes through cross-species phenotype comparison. Genome Res. 2014;24(2):340–8. https://doi.org/10.1101/gr.160325.113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Frankish A, Harrow J. GENCODE pseudogenes. Methods Mol Biol. 2014;1167:129–55. https://doi.org/10.1007/978-1-4939-0835-6_10.

    Article  PubMed  Google Scholar 

  35. Pei B, Sisu C, Frankish A, Howald C, Habegger L, Mu XJ, Harte R, Balasubramanian S, Tanzer A, Diekhans M, Reymond A, Hubbard TJ, Harrow J, Gerstein MB. The GENCODE pseudogene resource. Genome Biol. 2012;13(9):R51. https://doi.org/10.1186/gb-2012-13-9-r51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gymrek M, Golan D, Rosset S, Erlich Y. lobSTR: a short tandem repeat profiler for personal genomes. Genome Res. 2012;22(6):1154–62. https://doi.org/10.1101/gr.135780.111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cao MD, Balasubramanian S, Boden M. Sequencing technologies and tools for short tandem repeat variation detection. Brief Bioinform. 2015;16(2):193–204. https://doi.org/10.1093/bib/bbu001.

    Article  CAS  PubMed  Google Scholar 

  38. Gelfand Y, Hernandez Y, Loving J, Benson G. VNTRseek-a computational tool to detect tandem repeat variants in high-throughput sequencing data. Nucleic Acids Res. 2014;42(14):8884–94. https://doi.org/10.1093/nar/gku642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bean LJ, Hegde MR. Gene variant databases and sharing: creating a global genomic variant database for personalized medicine. Hum Mutat. 2016;37(6):559–63. https://doi.org/10.1002/humu.22982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bean LJ, Hegde MR. Gene variant databases and sharing: creating a global genomic variant database for personalized medicine. Hum Mutat. 2017;38(1):122. https://doi.org/10.1002/humu.23064.

    Article  PubMed  Google Scholar 

  41. Garber KB, Vincent LM, Alexander JJ, Bean LJH, Bale S, Hegde M. Reassessment of genomic sequence variation to harmonize interpretation for personalized medicine. Am J Hum Genet. 2016;99(5):1140–9. https://doi.org/10.1016/j.ajhg.2016.09.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li Q, Wang K. InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines. Am J Hum Genet. 2017;100(2):267–80. https://doi.org/10.1016/j.ajhg.2017.01.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bean LJH, Hegde MR. Clinical implications and considerations for evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines. Genome Med. 2017;9(1):111. https://doi.org/10.1186/s13073-017-0508-z.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Ghosh R, Oak N, Plon SE. Evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines. Genome Biol. 2017;18(1):225. https://doi.org/10.1186/s13059-017-1353-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, Musolf A, Li Q, Holzinger E, Karyadi D, Cannon-Albright LA, Teerlink CC, Stanford JL, Isaacs WB, Xu J, Cooney KA, Lange EM, Schleutker J, Carpten JD, Powell IJ, Cussenot O, Cancel-Tassin G, Giles GG, MacInnis RJ, Maier C, Hsieh CL, Wiklund F, Catalona WJ, Foulkes WD, Mandal D, Eeles RA, Kote-Jarai Z, Bustamante CD, Schaid DJ, Hastie T, Ostrander EA, Bailey-Wilson JE, Radivojac P, Thibodeau SN, Whittemore AS, Sieh W. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99(4):877–85. https://doi.org/10.1016/j.ajhg.2016.08.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Carter H, Douville C, Stenson PD, Cooper DN, Karchin R. Identifying Mendelian disease genes with the variant effect scoring tool. BMC Genomics. 2013;14(Suppl 3):S3. https://doi.org/10.1186/1471-2164-14-S3-S3.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Dong L, Shi B, Tian G, Li Y, Wang B, Zhou M. An accurate de novo algorithm for glycan topology determination from mass spectra. IEEE/ACM Trans Comput Biol Bioinform. 2015;12(3):568–78. https://doi.org/10.1109/TCBB.2014.2368981.

    Article  CAS  PubMed  Google Scholar 

  48. Katsonis P, Koire A, Wilson SJ, Hsu TK, Lua RC, Wilkins AD, Lichtarge O. Single nucleotide variations: biological impact and theoretical interpretation. Protein Sci. 2014;23(12):1650–66. https://doi.org/10.1002/pro.2552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nakken S, Fournous G, Vodak D, Aasheim LB, Myklebost O, Hovig E. Personal cancer genome reporter: variant interpretation report for precision oncology. Bioinformatics. 2017;34(10):1778–80. https://doi.org/10.1093/bioinformatics/btx817.

    Article  CAS  PubMed Central  Google Scholar 

  50. Chakravorty S, Hegde M. Gene and variant annotation for Mendelian disorders in the era of advanced sequencing technologies. Annu Rev Genomics Hum Genet. 2017;18:229–56. https://doi.org/10.1146/annurev-genom-083115-022545.

    Article  CAS  PubMed  Google Scholar 

  51. Choi M, Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P, Nayir A, Bakkaloglu A, Ozen S, Sanjad S, Nelson-Williams C, Farhi A, Mane S, Lifton RP. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A. 2009;106(45):19096–101. https://doi.org/10.1073/pnas.0910672106.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hebert SC. Bartter syndrome. Curr Opin Nephrol Hypertens. 2003;12(5):527–32. https://doi.org/10.1097/01.mnh.0000088732.87142.43.

    Article  PubMed  Google Scholar 

  53. Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989;245(4922):1073–80.

    Article  CAS  PubMed  Google Scholar 

  54. Kurotaki N, Imaizumi K, Harada N, Masuno M, Kondoh T, Nagai T, Ohashi H, Naritomi K, Tsukahara M, Makita Y, Sugimoto T, Sonoda T, Hasegawa T, Chinen Y, Tomita Ha HA, Kinoshita A, Mizuguchi T, Yoshiura Ki K, Ohta T, Kishino T, Fukushima Y, Niikawa N, Matsumoto N. Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Genet. 2002;30(4):365–6. https://doi.org/10.1038/ng863.

    Article  CAS  PubMed  Google Scholar 

  55. Lander ES, Botstein D. Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science. 1987;236(4808):1567–70.

    Article  CAS  PubMed  Google Scholar 

  56. Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, van der Vliet WA, Huys EH, de Jong PJ, Hamel BC, Schoenmakers EF, Brunner HG, Veltman JA, van Kessel AG. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet. 2004;36(9):955–7. https://doi.org/10.1038/ng1407.

    Article  CAS  PubMed  Google Scholar 

  57. Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010;42(1):30–5. https://doi.org/10.1038/ng.499.

    Article  CAS  PubMed  Google Scholar 

  58. Miller M, Fineman R, Smith DW. Postaxial acrofacial dysostosis syndrome. J Pediatr. 1979;95(6):970–5.

    Article  CAS  PubMed  Google Scholar 

  59. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;42(9):790–3. https://doi.org/10.1038/ng.646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Maxmen A. Exome sequencing deciphers rare diseases. Cell. 2011;144(5):635–7. https://doi.org/10.1016/j.cell.2011.02.033.

    Article  CAS  PubMed  Google Scholar 

  61. St Hilaire C, Ziegler SG, Markello TC, Brusco A, Groden C, Gill F, Carlson-Donohoe H, Lederman RJ, Chen MY, Yang D, Siegenthaler MP, Arduino C, Mancini C, Freudenthal B, Stanescu HC, Zdebik AA, Chaganti RK, Nussbaum RL, Kleta R, Gahl WA, Boehm M. NT5E mutations and arterial calcifications. N Engl J Med. 2011;364(5):432–42. https://doi.org/10.1056/NEJMoa0912923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gahl WA, Markello TC, Toro C, Fajardo KF, Sincan M, Gill F, Carlson-Donohoe H, Gropman A, Pierson TM, Golas G, Wolfe L, Groden C, Godfrey R, Nehrebecky M, Wahl C, Landis DM, Yang S, Madeo A, Mullikin JC, Boerkoel CF, Tifft CJ, Adams D. The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases. Genet Med. 2012;14(1):51–9. https://doi.org/10.1038/gim.0b013e318232a005.

    Article  CAS  PubMed  Google Scholar 

  63. Majewski J, Rosenblatt DS. Exome and whole-genome sequencing for gene discovery: the future is now! Hum Mutat. 2012;33(4):591–2. https://doi.org/10.1002/humu.22055.

    Article  PubMed  Google Scholar 

  64. Mefford HC. Diagnostic exome sequencing--are we there yet? N Engl J Med. 2012;367(20):1951–3. https://doi.org/10.1056/NEJMe1211659.

    Article  CAS  PubMed  Google Scholar 

  65. Botstein D, Risch N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet. 2003;33(Suppl):228–37. https://doi.org/10.1038/ng1090.

    Article  CAS  PubMed  Google Scholar 

  66. Bloch-Zupan A, Jamet X, Etard C, Laugel V, Muller J, Geoffroy V, Strauss JP, Pelletier V, Marion V, Poch O, Strahle U, Stoetzel C, Dollfus H. Homozygosity mapping and candidate prioritization identify mutations, missed by whole-exome sequencing, in SMOC2, causing major dental developmental defects. Am J Hum Genet. 2011;89(6):773–81. https://doi.org/10.1016/j.ajhg.2011.11.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, McDonald MT, Meisler MH, Goldstein DB. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012;49(6):353–61. https://doi.org/10.1136/jmedgenet-2012-100819.

    Article  CAS  PubMed  Google Scholar 

  68. Cabral RM, Kurban M, Wajid M, Shimomura Y, Petukhova L, Christiano AM. Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome. Genomics. 2012;99(4):202–8. https://doi.org/10.1016/j.ygeno.2012.01.005.

    Article  CAS  PubMed  Google Scholar 

  69. Campeau PM, Lu JT, Sule G, Jiang MM, Bae Y, Madan S, Hogler W, Shaw NJ, Mumm S, Gibbs RA, Whyte MP, Lee BH. Whole-exome sequencing identifies mutations in the nucleoside transporter gene SLC29A3 in dysosteosclerosis, a form of osteopetrosis. Hum Mol Genet. 2012;21(22):4904–9. https://doi.org/10.1093/hmg/dds326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Dundar H, Ozgul RK, Yalnizoglu D, Erdem S, Oguz KK, Tuncel D, Temucin CM, Dursun A. Identification of a novel Twinkle mutation in a family with infantile onset spinocerebellar ataxia by whole exome sequencing. Pediatr Neurol. 2012;46(3):172–7. https://doi.org/10.1016/j.pediatrneurol.2011.12.006.

    Article  PubMed  Google Scholar 

  71. Martinez FJ, Lee JH, Lee JE, Blanco S, Nickerson E, Gabriel S, Frye M, Al-Gazali L, Gleeson JG. Whole exome sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome. J Med Genet. 2012;49(6):380–5. https://doi.org/10.1136/jmedgenet-2011-100686.

    Article  CAS  PubMed  Google Scholar 

  72. Leidenroth A, Sorte HS, Gilfillan G, Ehrlich M, Lyle R, Hewitt JE. Diagnosis by sequencing: correction of misdiagnosis from FSHD2 to LGMD2A by whole-exome analysis. Eur J Hum Genet. 2012;20(9):999–1003. https://doi.org/10.1038/ejhg.2012.42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Antonarakis SE, Beckmann JS. Mendelian disorders deserve more attention. Nat Rev Genet. 2006;7(4):277–82. https://doi.org/10.1038/nrg1826.

    Article  CAS  PubMed  Google Scholar 

  74. Oti M, Brunner HG. The modular nature of genetic diseases. Clin Genet. 2007;71(1):1–11. https://doi.org/10.1111/j.1399-0004.2006.00708.x.

    Article  CAS  PubMed  Google Scholar 

  75. Peltonen L, Perola M, Naukkarinen J, Palotie A. Lessons from studying monogenic disease for common disease. Hum Mol Genet. 2006;15(1):R67–74. https://doi.org/10.1093/hmg/ddl060.

    Article  CAS  PubMed  Google Scholar 

  76. Betancur C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 2011;1380:42–77. https://doi.org/10.1016/j.brainres.2010.11.078.

    Article  CAS  PubMed  Google Scholar 

  77. Najmabadi H, Hu H, Garshasbi M, Zemojtel T, Abedini SS, Chen W, Hosseini M, Behjati F, Haas S, Jamali P, Zecha A, Mohseni M, Puttmann L, Vahid LN, Jensen C, Moheb LA, Bienek M, Larti F, Mueller I, Weissmann R, Darvish H, Wrogemann K, Hadavi V, Lipkowitz B, Esmaeeli-Nieh S, Wieczorek D, Kariminejad R, Firouzabadi SG, Cohen M, Fattahi Z, Rost I, Mojahedi F, Hertzberg C, Dehghan A, Rajab A, Banavandi MJ, Hoffer J, Falah M, Musante L, Kalscheuer V, Ullmann R, Kuss AW, Tzschach A, Kahrizi K, Ropers HH. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011;478(7367):57–63. https://doi.org/10.1038/nature10423.

    Article  CAS  PubMed  Google Scholar 

  78. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921–3.

    Article  CAS  PubMed  Google Scholar 

  79. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308(5720):385–9. https://doi.org/10.1126/science.1109557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Tan EK. Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in Parkinson’s disease. Ann Acad Med Singap. 2006;35(11):840–2.

    PubMed  Google Scholar 

  81. Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet. 2010;11(6):415–25. https://doi.org/10.1038/nrg2779.

    Article  CAS  PubMed  Google Scholar 

  82. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM. Finding the missing heritability of complex diseases. Nature. 2009;461(7265):747–53. https://doi.org/10.1038/nature08494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. McClellan J, King MC. Genetic heterogeneity in human disease. Cell. 2010;141(2):210–7. https://doi.org/10.1016/j.cell.2010.03.032.

    Article  CAS  PubMed  Google Scholar 

  84. Schork NJ, Murray SS, Frazer KA, Topol EJ. Common vs. rare allele hypotheses for complex diseases. Curr Opin Genet Dev. 2009;19(3):212–9. https://doi.org/10.1016/j.gde.2009.04.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Prasad A, Merico D, Thiruvahindrapuram B, Wei J, Lionel AC, Sato D, Rickaby J, Lu C, Szatmari P, Roberts W, Fernandez BA, Marshall CR, Hatchwell E, Eis PS, Scherer SW. A discovery resource of rare copy number variations in individuals with autism spectrum disorder. G3 (Bethesda). 2012;2(12):1665–85. https://doi.org/10.1534/g3.112.004689.

    Article  CAS  Google Scholar 

  86. Vaags AK, Lionel AC, Sato D, Goodenberger M, Stein QP, Curran S, Ogilvie C, Ahn JW, Drmic I, Senman L, Chrysler C, Thompson A, Russell C, Prasad A, Walker S, Pinto D, Marshall CR, Stavropoulos DJ, Zwaigenbaum L, Fernandez BA, Fombonne E, Bolton PF, Collier DA, Hodge JC, Roberts W, Szatmari P, Scherer SW. Rare deletions at the neurexin 3 locus in autism spectrum disorder. Am J Hum Genet. 2012;90(1):133–41. https://doi.org/10.1016/j.ajhg.2011.11.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bogardus C. Missing heritability and GWAS utility. Obesity (Silver Spring). 2009;17(2):209–10. https://doi.org/10.1038/oby.2008.613.

    Article  Google Scholar 

  88. Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB. Rare variants create synthetic genome-wide associations. PLoS Biol. 2010;8(1):e1000294. https://doi.org/10.1371/journal.pbio.1000294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH, Nadeau JH. Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet. 2010;11(6):446–50. https://doi.org/10.1038/nrg2809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Nielsen R. Genomics: in search of rare human variants. Nature. 2010;467(7319):1050–1. https://doi.org/10.1038/4671050a.

    Article  CAS  PubMed  Google Scholar 

  91. Pritchard JK. Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet. 2001;69(1):124–37. https://doi.org/10.1086/321272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Do R, Kathiresan S, Abecasis GR. Exome sequencing and complex disease: practical aspects of rare variant association studies. Hum Mol Genet. 2012;21(R1):R1–9. https://doi.org/10.1093/hmg/dds387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kiezun A, Garimella K, Do R, Stitziel NO, Neale BM, McLaren PJ, Gupta N, Sklar P, Sullivan PF, Moran JL, Hultman CM, Lichtenstein P, Magnusson P, Lehner T, Shugart YY, Price AL, de Bakker PI, Purcell SM, Sunyaev SR. Exome sequencing and the genetic basis of complex traits. Nat Genet. 2012;44(6):623–30. https://doi.org/10.1038/ng.2303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Berman JJ. Tumor taxonomy for the developmental lineage classification of neoplasms. BMC Cancer. 2004;4:88. https://doi.org/10.1186/1471-2407-4-88.

    Article  PubMed  PubMed Central  Google Scholar 

  95. de Coronado S, Haber MW, Sioutos N, Tuttle MS, Wright LW. NCI thesaurus: using science-based terminology to integrate cancer research results. Stud Health Technol Inform. 2004;107. (Pt 1:33–7.

    PubMed  Google Scholar 

  96. Berman J. Modern classification of neoplasms: reconciling differences between morphologic and molecular approaches. BMC Cancer. 2005;5:100. https://doi.org/10.1186/1471-2407-5-100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lonigro RJ, Grasso CS, Robinson DR, Jing X, Wu YM, Cao X, Quist MJ, Tomlins SA, Pienta KJ, Chinnaiyan AM. Detection of somatic copy number alterations in cancer using targeted exome capture sequencing. Neoplasia. 2011;13(11):1019–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sathirapongsasuti JF, Lee H, Horst BA, Brunner G, Cochran AJ, Binder S, Quackenbush J, Nelson SF. Exome sequencing-based copy-number variation and loss of heterozygosity detection: ExomeCNV. Bioinformatics. 2011;27(19):2648–54. https://doi.org/10.1093/bioinformatics/btr462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Chang H, Jackson DG, Kayne PS, Ross-Macdonald PB, Ryseck RP, Siemers NO. Exome sequencing reveals comprehensive genomic alterations across eight cancer cell lines. PLoS One. 2011;6(6):e21097. https://doi.org/10.1371/journal.pone.0021097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Pinkel D, Segraves R, Sudar D, Clark S, Poole I, Kowbel D, Collins C, Kuo WL, Chen C, Zhai Y, Dairkee SH, Ljung BM, Gray JW, Albertson DG. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet. 1998;20(2):207–11. https://doi.org/10.1038/2524.

    Article  CAS  PubMed  Google Scholar 

  101. McCarroll SA, Kuruvilla FG, Korn JM, Cawley S, Nemesh J, Wysoker A, Shapero MH, de Bakker PI, Maller JB, Kirby A, Elliott AL, Parkin M, Hubbell E, Webster T, Mei R, Veitch J, Collins PJ, Handsaker R, Lincoln S, Nizzari M, Blume J, Jones KW, Rava R, Daly MJ, Gabriel SB, Altshuler D. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet. 2008;40(10):1166–74. https://doi.org/10.1038/ng.238.

    Article  CAS  PubMed  Google Scholar 

  102. Yan XJ, Xu J, Gu ZH, Pan CM, Lu G, Shen Y, Shi JY, Zhu YM, Tang L, Zhang XW, Liang WX, Mi JQ, Song HD, Li KQ, Chen Z, Chen SJ. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet. 2011;43(4):309–15. https://doi.org/10.1038/ng.788.

    Article  CAS  PubMed  Google Scholar 

  103. Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Largaespada DA, Wessels LF, Richard S, Kahnoski RJ, Anema J, Tuveson DA, Perez-Mancera PA, Mustonen V, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT, Stratton MR, Futreal PA. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. 2011;469(7331):539–42. https://doi.org/10.1038/nature09639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, Antipin Y, Mitsiades N, Landers T, Dolgalev I, Major JE, Wilson M, Socci ND, Lash AE, Heguy A, Eastham JA, Scher HI, Reuter VE, Scardino PT, Sander C, Sawyers CL, Gerald WL. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11–22. https://doi.org/10.1016/j.ccr.2010.05.026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–15. https://doi.org/10.1038/nature10166.

    Article  CAS  Google Scholar 

  106. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031–7. https://doi.org/10.1056/NEJM200104053441401.

    Article  CAS  PubMed  Google Scholar 

  107. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39. https://doi.org/10.1056/NEJMoa040938.

    Article  CAS  PubMed  Google Scholar 

  108. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–500. https://doi.org/10.1126/science.1099314.

    Article  CAS  PubMed  Google Scholar 

  109. Barton NH. Genetic hitchhiking. Philos Trans R Soc Lond Ser B Biol Sci. 2000;355(1403):1553–62. https://doi.org/10.1098/rstb.2000.0716.

    Article  CAS  Google Scholar 

  110. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    Article  CAS  PubMed  Google Scholar 

  111. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, Paul JE, Boyle M, Woolcock BW, Kuchenbauer F, Yap D, Humphries RK, Griffith OL, Shah S, Zhu H, Kimbara M, Shashkin P, Charlot JF, Tcherpakov M, Corbett R, Tam A, Varhol R, Smailus D, Moksa M, Zhao Y, Delaney A, Qian H, Birol I, Schein J, Moore R, Holt R, Horsman DE, Connors JM, Jones S, Aparicio S, Hirst M, Gascoyne RD, Marra MA. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42(2):181–5. https://doi.org/10.1038/ng.518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, Delaney A, Gelmon K, Guliany R, Senz J, Steidl C, Holt RA, Jones S, Sun M, Leung G, Moore R, Severson T, Taylor GA, Teschendorff AE, Tse K, Turashvili G, Varhol R, Warren RL, Watson P, Zhao Y, Caldas C, Huntsman D, Hirst M, Marra MA, Aparicio S. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009;461(7265):809–13. https://doi.org/10.1038/nature08489.

    Article  CAS  PubMed  Google Scholar 

  113. Taylor BS, Ladanyi M. Clinical cancer genomics: how soon is now? J Pathol. 2011;223(2):318–26. https://doi.org/10.1002/path.2794.

    Article  PubMed  Google Scholar 

  114. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54. https://doi.org/10.1038/nature00766.

    Article  CAS  PubMed  Google Scholar 

  115. Millington GW. Mutations of the BRAF gene in human cancer, by Davies et al. (Nature 2002; 417: 949-54). Clin Exp Dermatol. 2013;38(2):222–3. https://doi.org/10.1111/ced.12015.

    Article  CAS  PubMed  Google Scholar 

  116. Lee JT, Li L, Brafford PA, van den Eijnden M, Halloran MB, Sproesser K, Haass NK, Smalley KS, Tsai J, Bollag G, Herlyn M. PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibits V600E-positive melanomas. Pigment Cell Melanoma Res. 2010;23(6):820–7. https://doi.org/10.1111/j.1755-148X.2010.00763.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Yang H, Higgins B, Kolinsky K, Packman K, Go Z, Iyer R, Kolis S, Zhao S, Lee R, Grippo JF, Schostack K, Simcox ME, Heimbrook D, Bollag G, Su F. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res. 2010;70(13):5518–27. https://doi.org/10.1158/0008-5472.CAN-10-0646.

    Article  CAS  PubMed  Google Scholar 

  118. Shi H, Moriceau G, Kong X, Lee MK, Lee H, Koya RC, Ng C, Chodon T, Scolyer RA, Dahlman KB, Sosman JA, Kefford RF, Long GV, Nelson SF, Ribas A, Lo RS. Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun. 2012;3:724. https://doi.org/10.1038/ncomms1727.

    Article  CAS  PubMed  Google Scholar 

  119. Solomon BD, Pineda-Alvarez DE, Hadley DW, Program NCS, Teer JK, Cherukuri PF, Hansen NF, Cruz P, Young AC, Blakesley RW, Lanpher B, Mayfield Gibson S, Sincan M, Chandrasekharappa SC, Mullikin JC. Personalized genomic medicine: lessons from the exome. Mol Genet Metab. 2011;104(1–2):189–91. https://doi.org/10.1016/j.ymgme.2011.06.022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hoischen A, Gilissen C, Arts P, Wieskamp N, van der Vliet W, Vermeer S, Steehouwer M, de Vries P, Meijer R, Seiqueros J, Knoers NV, Buckley MF, Scheffer H, Veltman JA. Massively parallel sequencing of ataxia genes after array-based enrichment. Hum Mutat. 2010;31(4):494–9. https://doi.org/10.1002/humu.21221.

    Article  CAS  PubMed  Google Scholar 

  121. Treangen TJ, Salzberg SL. Repetitive DNA and next-generation sequencing: computational challenges and solutions. Nat Rev Genet. 2011;13(1):36–46. https://doi.org/10.1038/nrg3117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Gargis AS, Kalman L, Berry MW, Bick DP, Dimmock DP, Hambuch T, Lu F, Lyon E, Voelkerding KV, Zehnbauer BA, Agarwala R, Bennett SF, Chen B, Chin EL, Compton JG, Das S, Farkas DH, Ferber MJ, Funke BH, Furtado MR, Ganova-Raeva LM, Geigenmuller U, Gunselman SJ, Hegde MR, Johnson PL, Kasarskis A, Kulkarni S, Lenk T, Liu CS, Manion M, Manolio TA, Mardis ER, Merker JD, Rajeevan MS, Reese MG, Rehm HL, Simen BB, Yeakley JM, Zook JM, Lubin IM. Assuring the quality of next-generation sequencing in clinical laboratory practice. Nat Biotechnol. 2012;30(11):1033–6. https://doi.org/10.1038/nbt.2403.

    Article  CAS  PubMed  Google Scholar 

  123. Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, Weaver MS, Ding L, Mardis ER, Wilson RK, Gajjar A, Ellison DW, Pappo AS, Pui CH, Nichols KE, Downing JR. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015;373(24):2336–46. https://doi.org/10.1056/NEJMoa1508054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Helleday T. Cancer phenotypic lethality, exemplified by the non-essential MTH1 enzyme being required for cancer survival. Ann Oncol. 2014;25(7):1253–5. https://doi.org/10.1093/annonc/mdu158.

    Article  CAS  PubMed  Google Scholar 

  125. Offit K. Decade in review--genomics: a decade of discovery in cancer genomics. Nat Rev Clin Oncol. 2014;11(11):632–4. https://doi.org/10.1038/nrclinonc.2014.170.

    Article  CAS  PubMed  Google Scholar 

  126. Lelieveld SH, Spielmann M, Mundlos S, Veltman JA, Gilissen C. Comparison of exome and genome sequencing technologies for the complete capture of protein-coding regions. Hum Mutat. 2015;36(8):815–22. https://doi.org/10.1002/humu.22813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Dragojlovic N, Elliott AM, Adam S, van Karnebeek C, Lehman A, Mwenifumbo JC, Nelson TN, du Souich C, Friedman JM, Lynd LD. The cost and diagnostic yield of exome sequencing for children with suspected genetic disorders: a benchmarking study. Genet Med. 2018; https://doi.org/10.1038/gim.2017.226.

  128. Long PA, Evans JM, Olson TM. Diagnostic yield of whole exome sequencing in pediatric dilated cardiomyopathy. J Cardiovasc Dev Dis. 2017;4(3):11. https://doi.org/10.3390/jcdd4030011.

    Article  CAS  PubMed Central  Google Scholar 

  129. Parsons DW, Roy A, Yang Y, Wang T, Scollon S, Bergstrom K, Kerstein RA, Gutierrez S, Petersen AK, Bavle A, Lin FY, Lopez-Terrada DH, Monzon FA, Hicks MJ, Eldin KW, Quintanilla NM, Adesina AM, Mohila CA, Whitehead W, Jea A, Vasudevan SA, Nuchtern JG, Ramamurthy U, McGuire AL, Hilsenbeck SG, Reid JG, Muzny DM, Wheeler DA, Berg SL, Chintagumpala MM, Eng CM, Gibbs RA, Plon SE. Diagnostic yield of clinical tumor and germline whole-exome sequencing for children with solid tumors. JAMA Oncol. 2016; https://doi.org/10.1001/jamaoncol.2015.5699.

  130. Rossi M, El-Khechen D, Black MH, Farwell Hagman KD, Tang S, Powis Z. Outcomes of diagnostic exome sequencing in patients with diagnosed or suspected autism spectrum disorders. Pediatr Neurol. 2017;70(34–43):e32. https://doi.org/10.1016/j.pediatrneurol.2017.01.033.

    Article  Google Scholar 

  131. Samocha KE, Robinson EB, Sanders SJ, Stevens C, Sabo A, McGrath LM, Kosmicki JA, Rehnstrom K, Mallick S, Kirby A, Wall DP, MacArthur DG, Gabriel SB, DePristo M, Purcell SM, Palotie A, Boerwinkle E, Buxbaum JD, Cook EH Jr, Gibbs RA, Schellenberg GD, Sutcliffe JS, Devlin B, Roeder K, Neale BM, Daly MJ. A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014;46(9):944–50. https://doi.org/10.1038/ng.3050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Trujillano D, Bertoli-Avella AM, Kumar Kandaswamy K, Weiss ME, Koster J, Marais A, Paknia O, Schroder R, Garcia-Aznar JM, Werber M, Brandau O, Calvo Del Castillo M, Baldi C, Wessel K, Kishore S, Nahavandi N, Eyaid W, Al Rifai MT, Al-Rumayyan A, Al-Twaijri W, Alothaim A, Alhashem A, Al-Sannaa N, Al-Balwi M, Alfadhel M, Rolfs A, Abou Jamra R. Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Eur J Hum Genet. 2017;25(2):176–82. https://doi.org/10.1038/ejhg.2016.146.

    Article  CAS  PubMed  Google Scholar 

  133. Vissers L, van Nimwegen KJM, Schieving JH, Kamsteeg EJ, Kleefstra T, Yntema HG, Pfundt R, van der Wilt GJ, Krabbenborg L, Brunner HG, van der Burg S, Grutters J, Veltman JA, Willemsen M. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017;19(9):1055–63. https://doi.org/10.1038/gim.2017.1.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Yavarna T, Al-Dewik N, Al-Mureikhi M, Ali R, Al-Mesaifri F, Mahmoud L, Shahbeck N, Lakhani S, AlMulla M, Nawaz Z, Vitazka P, Alkuraya FS, Ben-Omran T. High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders. Hum Genet. 2015;134(9):967–80. https://doi.org/10.1007/s00439-015-1575-0.

    Article  CAS  PubMed  Google Scholar 

  135. Xue Y, Ankala A, Wilcox WR, Hegde MR. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med. 2015;17(6):444–51. https://doi.org/10.1038/gim.2014.122.

    Article  CAS  PubMed  Google Scholar 

  136. Leslie EJ, O’Sullivan J, Cunningham ML, Singh A, Goudy SL, Ababneh F, Alsubaie L, Ch’ng GS, van der Laar IM, Hoogeboom AJ, Dunnwald M, Kapoor S, Jiramongkolchai P, Standley J, Manak JR, Murray JC, Dixon MJ. Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders. Am J Med Genet A. 2015;167A(3):545–52. https://doi.org/10.1002/ajmg.a.36896.

    Article  CAS  PubMed  Google Scholar��

  137. Harris E, Topf A, Barresi R, Hudson J, Powell H, Tellez J, Hicks D, Porter A, Bertoli M, Evangelista T, Marini-Betollo C, Magnusson O, Lek M, MacArthur D, Bushby K, Lochmuller H, Straub V. Exome sequences versus sequential gene testing in the UK highly specialised Service for Limb Girdle Muscular Dystrophy. Orphanet J Rare Dis. 2017;12(1):151. https://doi.org/10.1186/s13023-017-0699-9.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Schofield D, Alam K, Douglas L, Shrestha R, MacArthur DG, Davis M, Laing NG, Clarke NF, Burns J, Cooper ST, North KN, Sandaradura SA, O’Grady GL. Cost-effectiveness of massively parallel sequencing for diagnosis of paediatric muscle diseases. NPJ Genom Med. 2017;2:4. https://doi.org/10.1038/s41525-017-0006-7.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Johnson K, Topf A, Bertoli M, Phillips L, Claeys KG, Stojanovic VR, Peric S, Hahn A, Maddison P, Akay E, Bastian AE, Lusakowska A, Kostera-Pruszczyk A, Lek M, Xu L, MacArthur DG, Straub V. Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness. Orphanet J Rare Dis. 2017;12(1):173. https://doi.org/10.1186/s13023-017-0722-1.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Gullapalli RR, Desai KV, Santana-Santos L, Kant JA, Becich MJ. Next generation sequencing in clinical medicine: challenges and lessons for pathology and biomedical informatics. J Pathol Inform. 2012;3:40. https://doi.org/10.4103/2153-3539.103013.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Stower H. The exome factor. Genome Biol. 2011;12(9):407. https://doi.org/10.1186/gb-2011-12-9-407.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Haspel RL, Arnaout R, Briere L, Kantarci S, Marchand K, Tonellato P, Connolly J, Boguski MS, Saffitz JE. A call to action: training pathology residents in genomics and personalized medicine. Am J Clin Pathol. 2010;133(6):832–4. https://doi.org/10.1309/AJCPN6Q1QKCLYKXM.

    Article  PubMed  Google Scholar 

  143. Schrijver I, Natkunam Y, Galli S, Boyd SD. Integration of genomic medicine into pathology residency training: the stanford open curriculum. J Mol Diagn. 2013;15(2):141–8. https://doi.org/10.1016/j.jmoldx.2012.11.003.

    Article  PubMed  Google Scholar 

  144. Wall DP, Tonellato PJ. The future of genomics in pathology. F1000 Med Rep. 2012;4:14. https://doi.org/10.3410/M4-14.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA

    Samya Chakravorty, Arunkanth Ankala & Madhuri R. Hegde

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  1. Samya Chakravorty
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  2. Arunkanth Ankala
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  3. Madhuri R. Hegde
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Correspondence to Madhuri R. Hegde .

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  1. Professor and Chair of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    George Jabboure Netto

  2. Department of Pathology and Laboratory Medicine, NorthShore University HealthSystem, Clinical Professor of Pathology, University of Chicago Pritzker School of Medicine, Evanston, IL, USA

    Karen L. Kaul

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Chakravorty, S., Ankala, A., Hegde, M.R. (2019). Implementation of Exome Sequencing Assay. In: Netto, G., Kaul, K. (eds) Genomic Applications in Pathology. Springer, Cham. https://doi.org/10.1007/978-3-319-96830-8_17

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