The Year of the Exome

Next-generation sequencing technologies have dramatically altered the landscapes of genetics and genomics. There has been considerable interest in applying NGS platforms to selected regions of the human genome. Targeted sequencing of just the coding regions of the human genome — the exome — is of particular interest, because these regions presumably harbor the lion’s share of relevant genetic variation. In 2010, low-cost, high-throughput exome sequencing was made possible.

Two companies emerged as the titans of exome capture for sequencing:

  • Nimblegen, whose SeqCap EZ Exome kit claims to yield >10x coverage for 90% of the exons from 18,000 genes.
  • Agilent, whose SureSelect All Exon kits target 40-50 megabases of CCDS exons.

So which one is better? That’s a difficult question to answer, particularly because most groups with early access to these technologies are bound by non-disclosure agreements. Based on information in the public domain, such as the 20+ articles this year that employed exome sequencing, there is no clear winner. Some studies used Nimblegen, some used Agilent, and all of them achieved some kind of scientific success, or else we wouldn’t have read them. Clearly both of the companies are working hard to improve their products, and to incorporate the suggestions/requests of customers into their products. Both platforms saw a “version 2” release this year with a larger target space and other improvements. At Personal Genomes I saw at least two posters for studies where 1,000 or more exomes would be (or have been) sequenced. One thing is clear: Agilent and Roche/Nimblegen are selling exome kits like crazy.

Many fruits of exome sequencing have already come to market. A search for publications with ‘exome’ in the title turned up dozens of entries – two thirds of which were research articles on exome sequencing, and the other third, news briefs or reviews discussing its potential. A significant portion of these were low-hanging fruit: rare diseases of suspected genetic origin for which the causal gene(s) had not been identified. You can recognize these because they often have “syndrome” in the name: Fowler syndrome [13], Miller Syndrome [17], Kabuki syndrome [16], Sensenbrenner syndrome [7], Brown-Vialetto-van Laere syndrome [9] were all figured out (genetically) by exome sequencing this year. Mutations in a number of genes were linked to other rare inherited disorders:

  • WDR62 (severe brain malformations) [2]
  • GPSM2 (nonsyndromic hearing loss) [23]
  • STIM1 (fatal classic Kaposi sarcoma) [5]
  • ACAD9 (complex I deficiency) [8]
  • VCP (familial ALS) [10]
  • ADIPOQ (insulin resistance atherosclerosis) [4]
  • PIGV (hyperphosphatasia mental retardation) [12]
  • ANGPTL3 (familial combined hyperlipidemia) [15]
  • TGM6 (spinocerebellar ataxias) [24]
  • FADD (autoimmune lymphoproliferative syndrome) [3]

You might think that given how rare these diseases are, the impact of such findings is not very significant. But to an investigator who’s spent his or her life studying a rare disease (or the family that has it), the possibility of finding the disease-causing gene in a single experiment is simply irresistible. Though the sample numbers are small, the ramifications of these discoveries are not. They enable everyone in the world with a rare disease, even if this only totals a handful of patients, to be efficiently genotyped for causal mutations. They shed light on new and unanticipated mechanisms of disease pathogenesis. They’ve even justified having CXXorfXX genes in the set of human genes (C20orf54 was shown to cause Brown-Vialetto-van Laere syndrome [9]).

Larger studies of more common, more complex phenotypes are already beginning to pop up.  A collaboration between the University of Copenhagen (Denmark) and BGI (Shenzen) has sequenced the exomes of at least 250 individuals. A subset of these (n=50) were used to study adaptation to high altitude [26], while another 200 were the subject of a recent Nature Genetics paper [14] entitled “Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants,”  (whose inline title could have just been “Duh”).

Thus, exome sequencing has already enabled significant advances in the understanding of [rare] human diseases. In the coming year, I expect we’ll see a dramatic scale-up as exome sequencing is applied to thousands of patients with cancer, diabetes, autism, and other common diseases. Who knows? Maybe 2011 will be the year of exome sequencing as well.


  1. Bainbridge, M. N., M. Wang, et al. “Whole exome capture in solution with 3 Gbp of data.” Genome Biol 11(6): R62.
  2. Bilguvar, K., A. K. Ozturk, et al. “Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations.” Nature 467(7312): 207-10.
  3. Bolze, A., M. Byun, et al. “Whole-exome-sequencing-based discovery of human FADD deficiency.” Am J Hum Genet 87(6): 873-81.
  4. Bowden, D. W., S. S. An, et al. “Molecular basis of a linkage peak: exome sequencing and family-based analysis identify a rare genetic variant in the ADIPOQ gene in the IRAS Family Study.” Hum Mol Genet 19(20): 4112-20.
  5. Byun, M., A. Abhyankar, et al. “Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma.” J Exp Med 207(11): 2307-12.
  6. Cirulli, E. T., A. Singh, et al. “Screening the human exome: a comparison of whole genome and whole transcriptome sequencing.” Genome Biol 11(5): R57.
  7. Gilissen, C., H. H. Arts, et al. “Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome.” Am J Hum Genet 87(3): 418-23.
  8. Haack, T. B., K. Danhauser, et al. “Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency.” Nat Genet 42(12): 1131-4.
  9. Johnson, J. O., J. R. Gibbs, et al. “Exome sequencing in Brown-Vialetto-van Laere syndrome.” Am J Hum Genet 87(4): 567-9; author reply 569-70.
  10. Johnson, J. O., J. Mandrioli, et al. “Exome sequencing reveals VCP mutations as a cause of familial ALS.” Neuron 68(5): 857-64.
  11. Kozlowski, P., M. de Mezer, et al. “Trinucleotide repeats in human genome and exome.” Nucleic Acids Res 38(12): 4027-39.
  12. Krawitz, P. M., M. R. Schweiger, et al. “Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome.” Nat Genet 42(10): 827-9.
  13. Lalonde, E., S. Albrecht, et al. “Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing.” Hum Mutat 31(8): 918-23.
  14. Li, Y., N. Vinckenbosch, et al. “Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants.” Nat Genet 42(11): 969-72.
  15. Musunuru, K., J. P. Pirruccello, et al. “Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.” N Engl J Med 363(23): 2220-7.
  16. Ng, S. B., A. W. Bigham, et al. “Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome.” Nat Genet 42(9): 790-3.
  17. Ng, S. B., K. J. Buckingham, et al. “Exome sequencing identifies the cause of a mendelian disorder.” Nat Genet 42(1): 30-5.
  18. Otto, E. A., T. W. Hurd, et al. “Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy.” Nat Genet 42(10): 840-50.
  19. Rosenfeld, J. A., A. K. Malhotra, et al. “Novel multi-nucleotide polymorphisms in the human genome characterized by whole genome and exome sequencing.” Nucleic Acids Res 38(18): 6102-11.
  20. Summerer, D., N. Schracke, et al. “Targeted high throughput sequencing of a cancer-related exome subset by specific sequence capture with a fully automated microarray platform.” Genomics 95(4): 241-6.
  21. Teer, J. K. and J. C. Mullikin “Exome sequencing: the sweet spot before whole genomes.” Hum Mol Genet 19(R2): R145-51.
  22. Tennessen, J. A., J. Madeoy, et al. “Signatures of positive selection apparent in a small sample of human exomes.” Genome Res 20(10): 1327-34.
  23. Walsh, T., H. Shahin, 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(1): 90-4.
  24. Wang, J. L., X. Yang, et al. “TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing.” Brain 133(Pt 12): 3510-8.
  25. Worthey, E. A., A. N. Mayer, et al. “Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease.” Genet Med.
  26. Yi, X., Y. Liang, et al. “Sequencing of 50 human exomes reveals adaptation to high altitude.” Science 329(5987): 75-8.
  27. Zhao, Q., E. F. Kirkness, et al. “Systematic detection of putative tumor suppressor genes through the combined use of exome and transcriptome sequencing.” Genome Biol 11(11): R114.
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Dan Koboldt
Dan Koboldt


I couldn't agree more; we are learning a great deal about the genetics and pathology of diseases from these studies. I'd much rather definitively pinpoint the causal gene of a rare disorder than obtain a list of 20 "associations" for a common one.

Keith Robison
Keith Robison

It's also difficult to over-emphasize that studying exquisitely rare genetic disorders throws very useful light on general biological processes which are important to understanding common diseases. We know an awful lot about cancer from looking at very rare cancer syndromes and the genes underlying them (e.g. NF1, NF2, STK11(LKB1)).

This is one reason I have a high level for contempt for GWAS critics fixation on "missing heritability" -- I'm far less interested in what might be missing than in the nuggets which have been found.