Abstract
Next-generation sequencing (NGS) techniques have greatly accelerated the molecular elucidation of Mendelian disorders, and affordable NGS-based diagnostic tests are around the corner that promise to detect or rule out mutations in specific subsets of the known disease genes. Whole exome sequencing and shortly afterwards whole genome sequencing (WGS) will become an even more comprehensive alternative to such targeted tests. In view of the current enthusiasm to implement these methods, but also given their rapidly dropping costs, it is quite possible that WGS will soon be adopted as universal intake test in Clinical Genetics. Central databases and large-scale genotype–phenotype comparisons will be required to progressively identify the clinically relevant sequence variants and to distinguish them from neutral polymorphisms in the human genome, and these databases will become indispensable for the interpretation of individual genome sequences. In this scenario, there will be massively growing demand for genetic counselling, but the need for experienced syndromologists will not increase proportionally, as the success of the diagnostic process will become far less dependent on the ability of clinical geneticists to reliably recognize genetic syndromes.
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Bainbridge MN, Wiszniewski W, Murdock DR, Friedman J, Gonzaga-Jauregui C, Newsham I, Reid JG, Fink JK, Morgan MB, Gingras MC, Muzny DM, Hoang LD, Yousaf S, Lupski JR, Gibbs RA (2011) Whole-genome sequencing for optimized patient management. Sci Transl Med 3(87):87re83. doi:10.1126/scitranslmed.3002243
Bell CJ, Dinwiddie DL, Miller NA, Hateley SL, Ganusova EE, Mudge J, Langley RJ, Zhang L, Lee CC, Schilkey FD, Sheth V, Woodward JE, Peckham HE, Schroth GP, Kim RW, Kingsmore SF (2011) Carrier testing for severe childhood recessive diseases by next-generation sequencing. Sci Transl Med 3(65):65ra4. doi:10.1126/scitranslmed.3001756
Bentley DR, Balasubramanian S, Swerdlow HP, Smith GP, Milton J, Brown CG, Hall KP, Evers DJ, Barnes CL, Bignell HR, Boutell JM, Bryant J, Carter RJ, Keira Cheetham R, Cox AJ, Ellis DJ, Flatbush MR, Gormley NA, Humphray SJ, Irving LJ, Karbelashvili MS, Kirk SM, Li H, Liu X, Maisinger KS, Murray LJ, Obradovic B, Ost T, Parkinson ML, Pratt MR, Rasolonjatovo IM, Reed MT, Rigatti R, Rodighiero C, Ross MT, Sabot A, Sankar SV, Scally A, Schroth GP, Smith ME, Smith VP, Spiridou A, Torrance PE, Tzonev SS, Vermaas EH, Walter K, Wu X, Zhang L, Alam MD, Anastasi C, Aniebo IC, Bailey DM, Bancarz IR, Banerjee S, Barbour SG, Baybayan PA, Benoit VA, Benson KF, Bevis C, Black PJ, Boodhun A, Brennan JS, Bridgham JA, Brown RC, Brown AA, Buermann DH, Bundu AA, Burrows JC, Carter NP, Castillo N, Chiara ECM, Chang S, Neil Cooley R, Crake NR, Dada OO, Diakoumakos KD, Dominguez-Fernandez B, Earnshaw DJ, Egbujor UC, Elmore DW, Etchin SS, Ewan MR, Fedurco M, Fraser LJ, Fuentes Fajardo KV, Scott Furey W, George D, Gietzen KJ, Goddard CP, Golda GS, Granieri PA, Green DE, Gustafson DL, Hansen NF, Harnish K, Haudenschild CD, Heyer NI, Hims MM, Ho JT, Horgan AM, Hoschler K, Hurwitz S, Ivanov DV, Johnson MQ, James T, Huw Jones TA, Kang GD, Kerelska TH, Kersey AD, Khrebtukova I, Kindwall AP, Kingsbury Z, Kokko-Gonzales PI, Kumar A, Laurent MA, Lawley CT, Lee SE, Lee X, Liao AK, Loch JA, Lok M, Luo S, Mammen RM, Martin JW, McCauley PG, McNitt P, Mehta P, Moon KW, Mullens JW, Newington T, Ning Z, Ling Ng B, Novo SM, O'Neill MJ, Osborne MA, Osnowski A, Ostadan O, Paraschos LL, Pickering L, Pike AC, Chris Pinkard D, Pliskin DP, Podhasky J, Quijano VJ, Raczy C, Rae VH, Rawlings SR, Chiva Rodriguez A, Roe PM, Rogers J, Rogert Bacigalupo MC, Romanov N, Romieu A, Roth RK, Rourke NJ, Ruediger ST, Rusman E, Sanches-Kuiper RM, Schenker MR, Seoane JM, Shaw RJ, Shiver MK, Short SW, Sizto NL, Sluis JP, Smith MA, Ernest Sohna Sohna J, Spence EJ, Stevens K, Sutton N, Szajkowski L, Tregidgo CL, Turcatti G, Vandevondele S, Verhovsky Y, Virk SM, Wakelin S, Walcott GC, Wang J, Worsley GJ, Yan J, Yau L, Zuerlein M, Mullikin JC, Hurles ME, McCooke NJ, West JS, Oaks FL, Lundberg PL, Klenerman D, Durbin R, Smith AJ (2008) Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456(7218):53–59. doi:10.1038/nature07517
Check Hayden E (2009) Genomics shifts focus to rare diseases. Nature 461(7263):458. doi:10.1038/461458a
Chiu RW, Akolekar R, Zheng YW, Leung TY, Sun H, Chan KC, Lun FM, Go AT, Lau ET, To WW, Leung WC, Tang RY, Au-Yeung SK, Lam H, Kung YY, Zhang X, van Vugt JM, Minekawa R, Tang MH, Wang J, Oudejans CB, Lau TK, Nicolaides KH, Lo YM (2011) Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ 342:c7401
Cooper DN, Chen JM, Ball EV, Howells K, Mort M, Phillips AD, Chuzhanova N, Krawczak M, Kehrer-Sawatzki H, Stenson PD (2010) Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics. Hum Mutat 31(6):631–655. doi:10.1002/humu.21260
Eid J, Fehr A, Gray J, Luong K, Lyle J, Otto G, Peluso P, Rank D, Baybayan P, Bettman B, Bibillo A, Bjornson K, Chaudhuri B, Christians F, Cicero R, Clark S, Dalal R, Dewinter A, Dixon J, Foquet M, Gaertner A, Hardenbol P, Heiner C, Hester K, Holden D, Kearns G, Kong X, Kuse R, Lacroix Y, Lin S, Lundquist P, Ma C, Marks P, Maxham M, Murphy D, Park I, Pham T, Phillips M, Roy J, Sebra R, Shen G, Sorenson J, Tomaney A, Travers K, Trulson M, Vieceli J, Wegener J, Wu D, Yang A, Zaccarin D, Zhao P, Zhong F, Korlach J, Turner S (2009) Real-time DNA sequencing from single polymerase molecules. Science 323(5910):133–138. doi:10.1126/science.1162986
Gilissen C, Hoischen A, Brunner HG, Veltman JA (2011) Unlocking Mendelian disease using exome sequencing. Genome Biol 12(9):228. doi:10.1186/gb-2011-12-9-228
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 (2009) Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat Biotechnol 27(2):182–189. doi:10.1038/nbt.1523
Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S, Dobrzeniecka S, Cote M, Perreau-Linck E, Carmant L, D'Anjou G, Fombonne E, Addington AM, Rapoport JL, Delisi LE, Krebs MO, Mouaffak F, Joober R, Mottron L, Drapeau P, Marineau C, Lafreniere RG, Lacaille JC, Rouleau GA, Michaud JL (2009) Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med 360(6):599–605. doi:10.1056/NEJMoa0805392
Hodges E, Xuan Z, Balija V, Kramer M, Molla MN, Smith SW, Middle CM, Rodesch MJ, Albert TJ, Hannon GJ, McCombie WR (2007) Genome-wide in situ exon capture for selective resequencing. Nat Genet 39(12):1522–1527. doi:10.1038/ng.2007.42
Hu H, Wrogemann K, Kalscheuer V, Tzschach A, Richard H, Haas SA, Menzel C, Bienek M, Froyen G, Raynaud M, Van Bokhoven H, Chelly J, Ropers H, Chen W (2009a) Erratum to: mutation screening in 86 known X-linked mental retardation genes by droplet-based multiplex PCR and massive parallel sequencing. Hugo J 3(1–4):83. doi:10.1007/s11568-010-9142-1
Hu H, Wrogemann K, Kalscheuer V, Tzschach A, Richard H, Haas SA, Menzel C, Bienek M, Froyen G, Raynaud M, Van Bokhoven H, Chelly J, Ropers H, Chen W (2009b) Mutation screening in 86 known X-linked mental retardation genes by droplet-based multiplex PCR and massive parallel sequencing. Hugo J 3(1–4):41–49. doi:10.1007/s11568-010-9137-y 9137
Kingsmore SF, Saunders CJ (2011) Deep sequencing of patient genomes for disease diagnosis: when will it become routine? Sci Transl Med 3(87):87ps23. doi:10.1126/scitranslmed.3002695
Levy S, Sutton G, Ng PC, Feuk L, Halpern AL, Walenz BP, Axelrod N, Huang J, Kirkness EF, Denisov G, Lin Y, MacDonald JR, Pang AW, Shago M, Stockwell TB, Tsiamouri A, Bafna V, Bansal V, Kravitz SA, Busam DA, Beeson KY, McIntosh TC, Remington KA, Abril JF, Gill J, Borman J, Rogers YH, Frazier ME, Scherer SW, Strausberg RL, Venter JC (2007) The diploid genome sequence of an individual human. PLoS Biol 5(10):e254. doi:10.1371/journal.pbio.0050254
Li Y, Vinckenbosch N, Tian G, Huerta-Sanchez E, Jiang T, Jiang H, Albrechtsen A, Andersen G, Cao H, Korneliussen T, Grarup N, Guo Y, Hellman I, Jin X, Li Q, Liu J, Liu X, Sparso T, Tang M, Wu H, Wu R, Yu C, Zheng H, Astrup A, Bolund L, Holmkvist J, Jorgensen T, Kristiansen K, Schmitz O, Schwartz TW, Zhang X, Li R, Yang H, Wang J, Hansen T, Pedersen O, Nielsen R (2010) Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nat Genet 42(11):969–972. doi:10.1038/ng.680
Mamanova L, Coffey AJ, Scott CE, Kozarewa I, Turner EH, Kumar A, Howard E, Shendure J, Turner DJ (2010) Target-enrichment strategies for next-generation sequencing. Nat Methods 7(2):111–118. doi:10.1038/nmeth.1419
Mardis ER (2008) Next-generation DNA sequencing methods. Annu Rev Genomics Hum Genet 9:387–402. doi:10.1146/annurev.genom.9.081307.164359
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 (2005) Genome sequencing in microfabricated high-density picolitre reactors. Nature 437(7057):376–380. doi:10.1038/nature03959
Mondal K, Shetty AC, Patel V, Cutler DJ, Zwick ME (2011) Targeted sequencing of the human X chromosome exome. Genomics. doi:10.1016/j.ygeno.2011.04.004
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 (2011) Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. doi:10.1038/nature10423
Papageorgiou EA, Karagrigoriou A, Tsaliki E, Velissariou V, Carter NP, Patsalis PC (2011) Fetal-specific DNA methylation ratio permits noninvasive prenatal diagnosis of trisomy 21. Nat Med 17(4):510–513. doi:10.1038/nm.2312
Pelak K, Shianna KV, Ge D, Maia JM, Zhu M, Smith JP, Cirulli ET, Fellay J, Dickson SP, Gumbs CE, Heinzen EL, Need AC, Ruzzo EK, Singh A, Campbell CR, Hong LK, Lornsen KA, McKenzie AM, Sobreira NL, Hoover-Fong JE, Milner JD, Ottman R, Haynes BF, Goedert JJ, Goldstein DB (2010) The characterization of twenty sequenced human genomes. PLoS Genet 6(9). doi:10.1371/journal.pgen.1001111
Ropers HH (2007) New perspectives for the elucidation of genetic disorders. Am J Hum Genet 81(2):199–207. doi:10.1086/520679
Ropers HH (2010a) Genetics of early onset cognitive impairment. Annu Rev Genomics Hum Genet 11:161–187. doi:10.1146/annurev-genom-082509-141640
Ropers HH (2010b) Single gene disorders come into focus–again. Dialogues Clin Neurosci 12(1):95–102
Sboner A, Mu XJ, Greenbaum D, Auerbach RK, Gerstein MB (2011) The real cost of sequencing: higher than you think! Genome Biol 12(8):125. doi:10.1186/gb-2011-12-8-125
Shendure J (2011) Next-generation human genetics. Genome Biol 12(9):408. doi:10.1186/gb-2011-12-9-408
Tucker EJ, Hershman SG, Kohrer C, Belcher-Timme CA, Patel J, Goldberger OA, Christodoulou J, Silberstein JM, McKenzie M, Ryan MT, Compton AG, Jaffe JD, Carr SA, Calvo SE, Rajbhandary UL, Thorburn DR, Mootha VK (2011) Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation. Cell Metab 14(3):428–434. doi:10.1016/j.cmet.2011.07.010
Vissers LE, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, van Lier B, Arts P, Wieskamp N, del Rosario M, van Bon BW, Hoischen A, de Vries BB, Brunner HG, Veltman JA (2010) A de novo paradigm for mental retardation. Nat Genet 42(12):1109–1112. doi:10.1038/ng.712
Wheeler DA, Srinivasan M, Egholm M, Shen Y, Chen L, McGuire A, He W, Chen YJ, Makhijani V, Roth GT, Gomes X, Tartaro K, Niazi F, Turcotte CL, Irzyk GP, Lupski JR, Chinault C, Song XZ, Liu Y, Yuan Y, Nazareth L, Qin X, Muzny DM, Margulies M, Weinstock GM, Gibbs RA, Rothberg JM (2008) The complete genome of an individual by massively parallel DNA sequencing. Nature 452(7189):872–876. doi:10.1038/nature06884
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I thank Gabriele Eder for her secretarial assistance.
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A contribution to the special issue “Genetic Aspects of Preconception Consultation in Primary Care”.
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Ropers, HH. On the future of genetic risk assessment. J Community Genet 3, 229–236 (2012). https://doi.org/10.1007/s12687-012-0092-2
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DOI: https://doi.org/10.1007/s12687-012-0092-2