25th Medical Genetics: De novo mutations and NGS diagnostics

Author: J. A. Veltman
Submitted: Friday 6th of July 2012 09:05:38 AM
Submitted by: egf
Language: English
Content type: Learning resource
Educational levels: qc2, qc3

Abstract

Recent studies have indicated that humans have an exceptionally high per-generation mutation rate of 7.6 x 10-9 to 2.2 x 10-8. These spontaneous germline mutations can have serious phenotypic consequences when affecting functionally relevant bases in the genome. In fact, their occurrence may explain why neuropsychiatric diseases with a severely reduced fecundity remain frequent in the human population, especially when the mutational target is large and comprised of many genes. This would explain a major paradox in the evolutionary genetic theory of these disorders. In 2010 we used a family-based exome sequencing approach to test this de novo mutation hypothesis in 10 patients with unexplained mental retardation. Unique non-synonymous de novo mutations were identified and validated in nine genes. Six of these, identified in different patients, are likely pathogenic based on gene function, evolutionary conservation and mutation impact. Our findings provide strong experimental support for a de novo paradigm for mental retardation. Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population.1 In my presentation I will explain this work as well as ongoing work on this topic as we are replicating this work currently in 100 sporadic patients. In addition I will discuss related recent work in autism2-5. References: 1. Vissers LELM, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, van Lier B, Arts P, Wieskamp N, del Rosario M, van Bon BWM, Hoischen A, de Vries BBA, Brunner HG, Veltman JA. A de novo paradigm for mental retardation. Nat Genet 42: 1109-12 (2010). 2. O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485: 246-50 (2012). 3. Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH Jr, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485: 242-5 (2012). 4. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, G√ľnel M, Roeder K, Geschwind DH, Devlin B, State MW. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485: 237-41 (2012). 5. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB, Mardis ER, Wilson RK, Schatz MC, McCombie WR, Wigler M. De novo gene disruptions in children on the autistic spectrum. Neuron 74: 285

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abstract Veltman_De_novo_mutations_and_NGS_diagnostics_2012_5213.pdf

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J. A. Veltman. 25th Medical Genetics: De novo mutations and NGS diagnostics. EUROGENE portal. July 2012. online: http://eurogene.open.ac.uk/content/25th-medical-genetics-de-novo-mutations-and-ngs-diagnostics

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