- McKusick, V. A. Mendelian Inheritance in Man and its online version, OMIM. Am. J. Hum. Genet. 80, 588–604 (2007).
Article CAS PubMed PubMed Central Google Scholar
- Kaiser, J. Human genetics. Affordable 'exomes' fill gaps in a catalogue of rare diseases. Science 330, 903 (2010).
CAS PubMed Google Scholar
- Antonarakis, S. E. & Beckmann, J. S. Mendelian disorders deserve more attention. Nature Rev. Genet. 7, 277–282 (2006).
CAS PubMed Google Scholar
- Schork, N. J., Murray, S. S., Frazer, K. A. & Topol, E. J. Common vs. rare allele hypotheses for complex diseases. Curr. Opin. Genet. Dev. 19, 212–219 (2009).
CAS PubMed PubMed Central Google Scholar
- Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).
CAS PubMed PubMed Central Google Scholar
- McClellan, J. & King, M. C. Genetic heterogeneity in human disease. Cell 141, 210–217 (2010).
Article CAS PubMed Google Scholar
- Metzker, M. L. Sequencing technologies — the next generation. Nature Rev. Genet. 11, 31–46 (2010).
CAS PubMed Google Scholar
- Mamanova, L. et al. Target-enrichment strategies for next-generation sequencing. Nature Methods 7, 111–118 (2010).
CAS PubMed Google Scholar
- Biesecker, L. G. Exome sequencing makes medical genomics a reality. Nature Genet. 42, 13–14 (2010).
CAS PubMed Google Scholar
- Ng, S. B. et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461, 272–276 (2009). This was the first study to show the feasibility of using exome sequencing to identify disease-causing variants.
CAS PubMed PubMed Central Google Scholar
- Ng, S. B. et al. Exome sequencing identifies the cause of a Mendelian disorder. Nature Genet. 42, 30–35 (2010). This was the first study to use exome sequencing to discover the genetic basis of a monogenic disorder.
CAS PubMed Google Scholar
- Bilguvar, K. et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467, 207–210 (2010). This is an outstanding paper demonstrating the narrowing to a single candidate gene that is made possible by exome sequencing a single case in the context of a consanguineous pedigree and a recessive phenotype.
CAS PubMed PubMed Central Google Scholar
- Stenson, P. D. et al. The Human Gene Mutation Database: providing a comprehensive central mutation database for molecular diagnostics and personalized genomics. Hum. Genomics 4, 69–72 (2009).
CAS PubMed PubMed Central Google Scholar
- Kryukov, G. V., Pennacchio, L. A. & Sunyaev, S. R. Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am. J. Hum. Genet. 80, 727–739 (2007).
CAS PubMed PubMed Central Google Scholar
- Simpson, M. A. et al. Mutations in NOTCH2 cause Hajdu–Cheney syndrome, a disorder of severe and progressive bone loss. Nature Genet. 43, 303–305 (2011).
CAS PubMed Google Scholar
- Krawitz, P. M. et al. Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome. Nature Genet. 42, 827–829 (2010).
CAS PubMed Google Scholar
- Tsurusaki, Y. et al. Rapid detection of a mutation causing X-linked leucoencephalopathy by exome sequencing. J. Med. Genet. 48, 606–609 (2011).
CAS PubMed Google Scholar
- Liu, Y. et al. Confirmation by exome sequencing of the pathogenic role of NCSTN mutations in acne inversa (hidradenitis suppurativa). J. Invest. Dermatol. 131, 1570–1572 (2011).
CAS PubMed Google Scholar
- Yamaguchi, T. et al. Exome resequencing combined with linkage analysis identifies novel PTH1R variants in primary failure of tooth eruption in Japanese. J. Bone Miner. Res. 26, 1655–1661 (2011).
CAS PubMed Google Scholar
- Zuchner, S. et al. Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa. Am. J. Hum. Genet. 88, 201–206 (2011).
PubMed PubMed Central Google Scholar
- Otto, E. A. et al. Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal–renal ciliopathy. Nature Genet. 42, 840–850 (2010).
CAS PubMed Google Scholar
- Haack, T. B. et al. Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nature Genet. 42, 1131–1134 (2010).
CAS PubMed Google Scholar
- Ng, S. B. et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nature Genet. 42, 790–793 (2010).
CAS PubMed Google Scholar
- Al Badr, W. et al. Exome capture and massively parallel sequencing identifies a novel HPSE2 mutation in a Saudi Arabian child with Ochoa (urofacial) syndrome. J. Pediatr. Urol. 28 Mar 2011 (doi:10.1016/j.jpurol.2011.02.034).
PubMed PubMed Central Google Scholar
- Bolze, A. et al. Whole-exome-sequencing-based discovery of human FADD deficiency. Am. J. Hum. Genet. 87, 873–881 (2010).
CAS PubMed PubMed Central Google Scholar
- Caliskan, M. et al. Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13. Hum. Mol. Genet. 20, 1285–1289 (2011).
CAS PubMed PubMed Central Google Scholar
- Glazov, E. A. et al. Whole-exome re-sequencing in a family quartet identifies POP1 mutations as the cause of a novel skeletal dysplasia. PLoS Genet. 7, e1002027 (2011).
CAS PubMed PubMed Central Google Scholar
- Walsh, T. et al. Whole exome sequencing and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of nonsyndromic hearing loss DFNB82. Am. J. Hum. Genet. 87, 90–94 (2010).
CAS PubMed PubMed Central Google Scholar
- Johnston, J. J. et al. Massively parallel sequencing of exons on the X chromosome identifies RBM10 as the gene that causes a syndromic form of cleft palate. Am. J. Hum. Genet. 86, 743–748 (2010).
CAS PubMed PubMed Central Google Scholar
- Norton, N. et al. Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. Am. J. Hum. Genet. 88, 273–282 (2011).
CAS PubMed PubMed Central Google Scholar
- Musunuru, K. et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N. Engl. J. Med. 363, 2220–2227 (2010).
CAS PubMed PubMed Central Google Scholar
- Johnson, J. O. et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68, 857–864 (2010).
CAS PubMed PubMed Central Google Scholar
- Wang, J. L. et al. TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain 133, 3510–3518 (2010).
PubMed Google Scholar
- Gilissen, C. et al. Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. Am. J. Hum. Genet. 87, 418–423 (2010).
CAS PubMed PubMed Central Google Scholar
- Lalonde, E. et al. Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing. Hum. Mutat. 31, 918–923 (2010).
CAS PubMed Google Scholar
- Sirmaci, A. et al. MASP1 mutations in patients with facial, umbilical, coccygeal, and auditory findings of Carnevale, Malpuech, OSA, and Michels syndromes. Am. J. Hum. Genet. 87, 679–686 (2010).
CAS PubMed PubMed Central Google Scholar
- Hoischen, A. et al. De novo mutations of SETBP1 cause Schinzel–Giedion syndrome. Nature Genet. 42, 483–485 (2010).
CAS PubMed Google Scholar
- Kalay, E. et al. CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nature Genet. 43, 23–26 (2011).
CAS PubMed Google Scholar
- Hubisz, M. J., Pollard, K. S. & Siepel, A. PHAST and RPHAST: phylogenetic analysis with space/time models. Brief. Bioinf. 12, 41–51 (2011).
CAS Google Scholar
- Cooper, G. M. et al. Single-nucleotide evolutionary constraint scores highlight disease-causing mutations. Nature Methods 7, 250–251 (2010).
CAS PubMed PubMed Central Google Scholar
- Kumar, P. H. & S. Ng, P. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nature Protoc. 4, 1073–1081 (2009).
CAS Google Scholar
- Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nature Methods 7, 248–249 (2010).
CAS PubMed PubMed Central Google Scholar
- Stone, E. A. & Sidow, A. Physicochemical constraint violation by missense substitutions mediates impairment of protein function and disease severity. Genome Res. 15, 978–986 (2005).
CAS PubMed PubMed Central Google Scholar
- Nachman, M. W. & Crowell, S. L. Estimate of the mutation rate per nucleotide in humans. Genetics 156, 297–304 (2000).
CAS PubMed PubMed Central Google Scholar
- Vissers, L. E. et al. A de novo paradigm for mental retardation. Nature Genet. 42, 1109–1112 (2010). This was the first study to use exome sequencing of parent–child trios of affected offspring and their unaffected parents to identify de novo variants and thus candidate genes for a complex trait characterized by substantial locus heterogeneity.
CAS PubMed Google Scholar
- Girard, S. L. et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nature Genet. 43, 860–863 (2011).
CAS PubMed Google Scholar
- O'Roak, B. J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature Genet. 43, 585–589 (2011).
CAS PubMed Google Scholar
- Blakemore, A. I. & Froguel, P. Investigation of Mendelian forms of obesity holds out the prospect of personalized medicine. Ann. N.Y. Acad. Sci. 1214, 180–189 (2010).
CAS PubMed Google Scholar
- Dietz, H. C. New therapeutic approaches to Mendelian disorders. N. Engl. J. Med. 363, 852–863 (2010).
CAS PubMed Google Scholar
- St. Hilaire, C. et al. NT5E mutations and arterial calcifications. N. Engl. J. Med. 364, 432–42 (2011).
Google Scholar
- Choi, M. et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc. Natl Acad. Sci. USA 106, 19096–19101 (2009). This paper provides the first example of applying exome sequencing to make an unanticipated diagnosis in a clinical setting.
CAS PubMed PubMed Central Google Scholar
- Worthey, E. A. et al. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet. Med. 13, 255–262 (2011). This is an outstanding example of the clinical diagnosis of a rare disorder by exome sequencing leading to a subsequent, life-saving change in treatment.
PubMed Google Scholar
- Bonnefond, A. et al. Molecular diagnosis of neonatal diabetes mellitus using next-generation sequencing of the whole exome. PLoS ONE 5, e13630 (2010).
PubMed PubMed Central Google Scholar
- Montenegro, G. et al. Exome sequencing allows for rapid gene identification in a Charcot–Marie–Tooth family. Ann. Neurol. 69, 464–470 (2011).
CAS PubMed PubMed Central Google Scholar
- Chiu, R. W. et al. Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proc. Natl Acad. Sci. USA 105, 20458–20463 (2008).
CAS PubMed PubMed Central Google Scholar
- Chiu, R. W. & Lo, Y. M. Non-invasive prenatal diagnosis by fetal nucleic acid analysis in maternal plasma: the coming of age. Semin. Fetal Neonatal Med. 16, 88–93 (2011).
PubMed Google Scholar
- Bell, C. J. et al. Carrier testing for severe childhood recessive diseases by next-generation sequencing. Sci. Transl. Med. 3, 65ra4 (2011). This work reports on efforts to implement pre-conception carrier screening for over 400 recessive disorders by hybrid capture and next-generation sequencing.
CAS PubMed PubMed Central Google Scholar
- Ashley, E. A. et al. Clinical assessment incorporating a personal genome. Lancet 375, 1525–1535 (2010). This paper illustrates both the promise and challenges we face in the clinical interpretation of exome or genome sequences of individual patients.
CAS PubMed PubMed Central Google Scholar
- Kingsmore, S. F. & Saunders, C. J. Deep sequencing of patient genomes for disease diagnosis: when will it become routine? Sci. Transl. Med. 3, 87ps23 (2011).
PubMed PubMed Central Google Scholar
- Scriver, C. R. The PAH gene, phenylketonuria, and a paradigm shift. Hum. Mutat. 28, 831–845 (2007).
CAS PubMed Google Scholar
- Ormond, K. E. et al. Challenges in the clinical application of whole-genome sequencing. Lancet 375, 1749–1751 (2010).
PubMed Google Scholar
- Tong, M. Y., Cassa, C. A. & Kohane, I. S. Automated validation of genetic variants from large databases: ensuring that variant references refer to the same genomic locations. Bioinformatics 27, 891–893 (2011).
CAS PubMed PubMed Central Google Scholar
- Kohonen-Corish, M. R. et al. How to catch all those mutations—the report of the third Human Variome Project Meeting, UNESCO Paris, May 2010. Hum. Mutat. 31, 1374–1381 (2010).
PubMed PubMed Central Google Scholar
- Roach, J. C. et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328, 636–639 (2010). This was the first study to report the sequencing of the entire genome for each member of a family with a Mendelian disorder.
CAS PubMed PubMed Central Google Scholar
- Beskow, L. M. & Burke, W. Offering individual genetic research results: context matters. Sci. Transl. Med. 2, 38cm20 (2010).
PubMed PubMed Central Google Scholar
- Richards, C. S. et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007. Genet. Med. 10, 294–300 (2008).
CAS PubMed Google Scholar
- 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 (2011).
Google Scholar
- Caulfield, T. et al. Research ethics recommendations for whole-genome research: consensus statement. PLoS Biol. 6, e73 (2008).
PubMed PubMed Central Google Scholar
- Wolf, S. M. et al. Managing incidental findings in human subjects research: analysis and recommendations. J. Law Med. Ethics 36, 219–248 (2008).
PubMed PubMed Central Google Scholar
- Ravitsky, V. & Wilfond, B. S. Disclosing individual genetic results to research participants. Am. J. Bioeth. 6, 8–17 (2006).
PubMed Google Scholar
- Green, E. D. & Guyer, M. S. Charting a course for genomic medicine from base pairs to bedside. Nature 470, 204–213 (2011).
CAS PubMed Google Scholar
- Dahl, F. et al. Multigene amplification and massively parallel sequencing for cancer mutation discovery. Proc. Natl Acad. Sci. USA 104, 9387–9392 (2007).
CAS PubMed PubMed Central Google Scholar
- Fredriksson, S. et al. Multiplex amplification of all coding sequences within 10 cancer genes by Gene-Collector. Nucleic Acids Res. 35, e47 (2007).
PubMed PubMed Central Google Scholar
- Gnirke, A. et al. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nature Biotech. 27, 182–189 (2009).
CAS Google Scholar
- Okou, D. T. et al. Microarray-based genomic selection for high-throughput resequencing. Nature Methods 4, 907–909 (2007).
CAS PubMed Google Scholar
- Porreca, G. J. et al. Multiplex amplification of large sets of human exons. Nature Methods 4, 931–936 (2007).
CAS PubMed Google Scholar
- Albert, T. J. et al. Direct selection of human genomic loci by microarray hybridization. Nature Methods 4, 903–905 (2007).
CAS PubMed Google Scholar
- Turner, E. H., Lee, C., Ng, S. B., Nickerson, D. A. & Shendure, J. Massively parallel exon capture and library-free resequencing across 16 genomes. Nature Methods 6, 315–316 (2009).
CAS PubMed PubMed Central Google Scholar
- Turner, E. H., Ng, S. B., Nickerson, D. A. & Shendure, J. Methods for genomic partitioning. Annu. Rev. Genomics Hum. Genet. 10, 263–284 (2009).
CAS PubMed Google Scholar
- Nielsen, R., Paul, J. S., Albrechtsen, A. & Song, Y. S. Genotype and SNP calling from next-generation sequencing data. Nature Rev. Genet. 12, 443–451 (2011).
CAS PubMed Google Scholar
- Alkan, C., Coe, B. P. & Eichler, E. E. Genome structural variation discovery and genotyping. Nature Rev. Genet. 12, 363–376 (2011).
CAS PubMed Google Scholar
- Adey, A. et al. Rapid, low-input, low-bias construction of shotgun fragment libraries by high-density in vitro transposition. Genome Biol. 11, R119 (2010).
CAS PubMed PubMed Central Google Scholar
- Cirulli, E. T. & Goldstein, D. B. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nature Rev. Genet. 11, 415–425 (2010).
CAS PubMed Google Scholar
- Lanktree, M. B., Hegele, R. A., Schork, N. J. & Spence, J. D. Extremes of unexplained variation as a phenotype: an efficient approach for genome-wide association studies of cardiovascular disease. Circ. Cardiovasc. Genet. 3, 215–221 (2010).
CAS PubMed PubMed Central Google Scholar
- Cohen, J. C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004). This was an important study that demonstrated the effectiveness of sequencing candidate genes at the extremes of a phenotype to find rare alleles influencing risk for a complex trait.
CAS PubMed Google Scholar
- Li, B. & Leal, S. M. Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am. J. Hum. Genet. 83, 311–321 (2008).
CAS PubMed PubMed Central Google Scholar
- Morris, A. P. & Zeggini, E. An evaluation of statistical approaches to rare variant analysis in genetic association studies. Genet. Epidemiol. 34, 188–193 (2010).
PubMed Google Scholar
- Price, A. L. et al. Pooled association tests for rare variants in exon-resequencing studies. Am. J. Hum. Genet. 86, 832–838 (2010).
PubMed PubMed Central Google Scholar
- Madsen, B. E. & Browning, S. R. A groupwise association test for rare mutations using a weighted sum statistic. PLoS Genet. 5, e1000384 (2009).
PubMed PubMed Central Google Scholar
- Bansal, V., Libiger, O., Torkamani, A. & Schork, N. J. Statistical analysis strategies for association studies involving rare variants. Nature Rev. Genet. 11, 773–785 (2010).
CAS PubMed Google Scholar
- DePristo, M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nature Genet. 43, 491–498 (2011).
CAS PubMed Google Scholar