Genetic risk factors that underlie many rare and common neurological disorders remain poorly understood because of the multifactorial and heterogeneous nature of these complex traits. With the decreasing cost of massively parallel sequencing technologies, whole-genome and whole-exome sequencing will soon allow the characterization of the full spectrum of sequence and structural variants present in each individual. Methods are being developed to parse the huge amount of genomic data and to sift out which variants are associated with diseases. Numerous challenges are inherent in the identification of rare and common variants that have a role in complex neurological diseases, and tools are being developed to overcome these challenges. Given that genomic data will soon be the main driver towards the goal of personalized medicine, future developments in the production and interpretation of data, as well as in ethics and counselling, will be needed for whole-genome and whole-exome sequencing to be used as informative tools in a clinical setting.
Whole-genome and whole-exome sequencing is becoming increasingly affordable for use in a clinical setting
Recent studies demonstrate successes in applying whole-genome or whole-exome sequencing to disease gene discovery and clinical diagnosis of complex neurological diseases, but they also highlight major challenges in data interpretation
The various tools and methods that have been developed to process next-generation sequencing data and to parse the list of genomic variants must be carefully evaluated for clinical use
The majority of genomic variants do not have known or confirmed clinical effects, and caution is needed in the interpretation and reporting of genetic results
Basic guidelines have been drawn up for the implementation of genetic testing in a clinical setting; these guidelines are likely to be reviewed and changed over time
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Mardis, E. R. A decade's perspective on DNA sequencing technology. Nature 470, 198–203 (2011).
Erdmann, J. Next generation technology edges genome sequencing toward the clinic. Chem. Biol. 18, 1513–1514 (2011).
Pierce, B. L. & Ahsan, H. Clinical assessment incorporating a personal genome. Lancet 376, 869 (2010).
Hong, K. W. & Oh, B. Overview of personalized medicine in the disease genomic era. BMB Rep. 43, 643–648 (2010).
Ng, S. B. et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461, 272–276 (2009).
Mamanova, L. et al. Target-enrichment strategies for next-generation sequencing. Nat. Methods 7, 111–118 (2010).
DNA sequencing costs. National Human Genome Research Institute [online], (2012).
Pareek, C. S., Smoczynski, R. & Tretyn, A. Sequencing technologies and genome sequencing. J. Appl. Genet. 52, 413–435 (2011).
Metzker, M. L. Sequencing technologies—the next generation. Nat. Rev. Genet. 11, 31–46 (2010).
Lupski, J. R. et al. Whole-genome sequencing in a patient with Charcot–Marie–Tooth neuropathy. N. Engl. J. Med. 362, 1181–1191 (2010).
Bilguvar, K. et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467, 207–210 (2010).
Wang, J. L. et al. TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain 133, 3510–3518 (2011).
Wang, J. L. et al. Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias. Brain 134, 3493–3501 (2011).
Lee, H. et al. Exome sequencing identifies PDE4D mutations in acrodysostosis. Am. J. Hum. Genet. 90, 746–751 (2012).
Wan, J. et al. Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. Nat. Genet. 44, 704–708 (2012).
Walker, R. H. et al. Genetic diagnosis of neuroacanthocytosis disorders using exome sequencing. Mov. Disord. 27, 539–543 (2011).
Weedon, M. N. et al. Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot–Marie–Tooth disease. Am. J. Hum. Genet. 89, 308–312 (2011).
Montenegro, G. et al. Exome sequencing allows for rapid gene identification in a Charcot–Marie–Tooth family. Ann. Neurol. 69, 464–470 (2011).
Zimprich, A. et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 89, 168–175 (2011).
Vilariño-Güell, C. et al. VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89, 162–167 (2011).
Chartier-Harlin, M. C. et al. Translation initiator EIF4G1 mutations in familial Parkinson disease. Am. J. Hum. Genet. 89, 398–406 (2011).
Guerreiro, R. J. et al. Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease. Neurobiol. Aging 33, 1008.e17–1008.e23 (2011).
Ramagopalan, S. V. et al. Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann. Neurol. 70, 881–886 (2011).
Hayden, E. C. Sequencing set to alter clinical landscape. Nature 482, 288 (2012).
Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).
Choi, M. et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc. Natl Acad. Sci. USA 106, 19096–19101 (2009).
Johansson, A. C. & Feuk, L. Characterizing and interpreting genetic variation from personal genome sequencing. Methods Mol. Biol. 838, 343–367 (2012).
Clark, M. J. et al. Performance comparison of exome DNA sequencing technologies. Nat. Biotechnol. 29, 908–914 (2012).
DePristo, M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491–498 (2011).
Wheeler, D. A. et al. The complete genome of an individual by massively parallel DNA sequencing. Nature 452, 872–876 (2008).
Levy, S. et al. The diploid genome sequence of an individual human. PLoS Biol. 5, e254 (2007).
Bentley, D. R. et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53–59 (2008).
Ng, P. C. et al. Genetic variation in an individual human exome. PLoS Genet. 4, e1000160 (2008).
Genomes [online], (2012).
Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).
SIFT, J. Craig Venter Institute [online], (2011).
Ng, P. C. & Henikoff, S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 31, 3812–3814 (2003).
PolyPhen-2 Wiki [online], (2012).
Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).
MutationTaster [online], (2010).
Schwarz, J. M., Rodelsperger, C., Schuelke, M. & Seelow, D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat. Methods 7, 575–576 (2010).
Condel [online], (2012).
Gonzalez-Perez, A. & Lopez-Bigas, N. Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel. Am. J. Hum. Genet. 88, 440–449 (2011).
Tchernitchko, D., Goossens, M. & Wajcman, H. In silico prediction of the deleterious effect of a mutation: proceed with caution in clinical genetics. Clin. Chem. 50, 1974–1978 (2004).
Variant Annotation, Analysis and Search Tool. Yandell Lab [online], (2011).
Yandell, M. et al. A probabilistic disease-gene finder for personal genomes. Genome Res. 21, 1529–1542 (2011).
Endeavour. BIOInformatics [online], (2010).
Schuierer, S., Tranchevent, L. C., Dengler, U. & Moreau, Y. Large-scale benchmark of Endeavour using MetaCore maps. Bioinformatics 26, 1922–1923 (2010).
Johnson, J. O. et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68, 857–864 (2011).
Bras, J., Verloes, A., Schneider, S. A., Mole, S. E. & Guerreiro, R. J. Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis. Hum. Mol. Genet. 21, 2646–2650 (2012).
The Human Gene Mutation Database [online], (2008).
MacArthur, D. G. et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335, 823–828 (2012).
Tennessen, J. A. et al. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science http://dx.doi.org/10.1126/science.1219240.
Nelson, M. R. et al. An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people. Science http://dx.doi.org/10.1126/science.1217876.
Visscher, P. M., Brown, M. A., McCarthy, M. I. & Yang, J. Five years of GWAS discovery. Am. J. Hum. Genet. 90, 7–24 (2012).
ENCODE Project Consortium. The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 306, 636–640 (2004).
Park, P. J. ChIP–seq: advantages and challenges of a maturing technology. Nat. Rev. Genet. 10, 669–680 (2009).
Kasowski, M. et al. Variation in transcription factor binding among humans. Science 328, 232–235 (2010).
Regulatory Sequence Analysis Tools [online], (2011).
Thomas-Chollier, M. et al. RSAT 2011: regulatory sequence analysis tools. Nucleic Acids Res. 39, W86–W91 (2011).
mRNA by SNP Browser v1.0.1. Center for Statistical Genetics [online], (2007).
Dixon, A. L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).
Montgomery, S. B., Lappalainen, T., Gutierrez-Arcelus, M. & Dermitzakis, E. T. Rare and common regulatory variation in population-scale sequenced human genomes. PLoS Genet. 7, e1002144 (2011).
Satake, W. et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat. Genet. 41, 1303–1307 (2009).
Simon-Sanchez, J. et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat. Genet. 41, 1308–1312 (2009).
Do, C. B. et al. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease. PLoS Genet. 7, e1002141 (2011).
Nalls, M. A. et al. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet 377, 641–649 (2011).
Klassen, T. et al. Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Cell 145, 1036–1048 (2011).
Calvo, S. E. et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci. Transl. Med. 4, 118ra10 (2012).
Lupski, J. R., Belmont, J. W., Boerwinkle, E. & Gibbs, R. A. Clan genomics and the complex architecture of human disease. Cell 147, 32–43 (2011).
Tucci, A. et al. Study of the genetic variability in a Parkinson's disease gene: EIF4G1. Neurosci. Lett. 518, 19–22 (2012).
Bansal, V., Libiger, O., Torkamani, A. & Schork, N. J. Statistical analysis strategies for association studies involving rare variants. Nat. Rev. Genet. 11, 773–785 (2010).
Kiezun, A., Garimella, K., Do, R., Stitziel, N. O. & Neale, B. M. Exome sequencing and the genetic basis of complex traits. Nat. Genet. 44, 623–630 (2012).
Mathieson, I. & McVean, G. Differential confounding of rare and common variants in spatially structured populations. Nat. Genet. 44, 243–246 (2012).
Roach, J. C. et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328, 636–639 (2010).
O'Roak, B. J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet. 43, 585–589 (2011).
Girard, S. L. et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat. Genet. 43, 860–863 (2011).
Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012).
O'Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012).
Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012).
Kumari, U. & Tan, E. K. LRRK2 in Parkinson's disease: genetic and clinical studies from patients. FEBS J. 276, 6455–6463 (2009).
Phimister, E. G., Feero, W. G. & Guttmacher, A. E. Realizing genomic medicine. N. Engl. J. Med. 366, 757–759 (2012).
Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).
Fabsitz, R. R. et al. Ethical and practical guidelines for reporting genetic research results to study participants: updated guidelines from a National Heart, Lung, and Blood Institute working group. Circ. Cardiovasc. Genet. 3, 574–580 (2010).
Cassa, C. A. et al. Disclosing pathogenic genetic variants to research participants: quantifying an emerging ethical responsibility. Genome Res. 22, 421–428 (2011).
Personal Genome Project [online], (2012).
Lyon, G. J. Personalized medicine: Bring clinical standards to human-genetics research. Nature 482, 300–301 (2012).
The authors declare no competing financial interests.
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Foo, JN., Liu, JJ. & Tan, EK. Whole-genome and whole-exome sequencing in neurological diseases. Nat Rev Neurol 8, 508–517 (2012). https://doi.org/10.1038/nrneurol.2012.148
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