1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Medicine
  4. Volume 66, 2015
  5. Article

Annual Review of Medicine

Volume 66, 2015

From De Novo Mutations to Personalized Therapeutic Interventions in Autism

Abstract

The high heritability, early age at onset, and reproductive disadvantages of autism spectrum disorders (ASDs) are consistent with an etiology composed of dominant-acting de novo (spontaneous) mutations. Mutation detection by microarray analysis and DNA sequencing has confirmed that de novo copy-number variants or point mutations in protein-coding regions of genes contribute to risk, and some of the underlying causal variants and genes have been identified. As our understanding of autism genes develops, the spectrum of autism is breaking up into quanta of many different genetic disorders. Given the diversity of etiologies and underlying biochemical pathways, personalized therapy for ASDs is logical, and clinical genetic testing is a prerequisite.

Keyword(s): autism spectrum disorder, clinical trials, copy-number variation, fragile X syndrome, genomics, metabolic disorders, mouse models, Rett syndrome, whole-genome sequencing
Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-091113-024550
2015-01-14
2024-04-18
Loading full text...

Full text loading...

/deliver/fulltext/med/66/1/annurev-med-091113-024550.html?itemId=/content/journals/10.1146/annurev-med-091113-024550&mimeType=html&fmt=ahah

Literature Cited

  1. Geschwind DH.1.  2009. Advances in autism. Annu. Rev. Med. 60:367–80 [Google Scholar]
  2. Power RA, Kyaga S, Uher R. 2.  et al. 2013. Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse versus their unaffected siblings. JAMA Psychiatry 70:22–30 [Google Scholar]
  3. 3. Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators 2012. Prevalence of autism spectrum disorders—Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill. Summ. 61:1–19 [Google Scholar]
  4. Ganz ML.4.  2007. The lifetime distribution of the incremental societal costs of autism. Arch. Pediatr. Adolesc. Med. 161:343–49 [Google Scholar]
  5. Bailey A, Lecouteur A, Gottesman I. 5.  et al. 1995. Autism as a strongly genetic disorder—evidence from a British twin study. Psychol. Med. 25:63–77 [Google Scholar]
  6. Ronald A, Hoekstra RA. 6.  2011. Autism spectrum disorders and autistic traits: a decade of new twin studies. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B:255–74 [Google Scholar]
  7. Hallmayer J, Cleveland S, Torres A. 7.  et al. 2011. Genetic heritability and shared environmental factors among twin pairs with autism. Arch. Gen. Psychiatry 68:1095–102 [Google Scholar]
  8. Ronemus M, Iossifov I, Levy D, Wigler M. 8.  2014. The role of de novo mutations in the genetics of autism spectrum disorders. Nat. Rev. Genet. 15:133–41 [Google Scholar]
  9. Freitag CM.9.  2007. The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol. Psychiatry 12:2–22 [Google Scholar]
  10. Anney R, Klei L, Pinto D. 10.  et al. 2012. Individual common variants exert weak effects on the risk for autism spectrum disorders. Hum. Mol. Genet. 21:4781–92 [Google Scholar]
  11. Anney R, Klei L, Pinto D. 11.  et al. 2010. A genome-wide scan for common alleles affecting risk for autism. Hum. Mol. Genet. 19:4072–82 [Google Scholar]
  12. Wang K, Zhang H, Ma D. 12.  et al. 2009. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459:528–33 [Google Scholar]
  13. Weiss LA, Arking DE, Daly MJ. 13.  et al. 2009. A genome-wide linkage and association scan reveals novel loci for autism. Nature 461:802–8 [Google Scholar]
  14. Gaugler T, Klei L, Sanders SJ. 14.  et al. 2014. Most genetic risk for autism resides with common variation. Nat. Genet. 46:881–85 [Google Scholar]
  15. Lee SH, Ripke S. 15. Cross-Disorder Group of the Psychiatric Genomics Consortium et al. 2013. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45:984–94 [Google Scholar]
  16. 16. Schizophrenia Working Group of the Psychiatric Genomics Consortium 2014. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–27 [Google Scholar]
  17. Sebat J, Lakshmi B, Malhotra D. 17.  et al. 2007. Strong association of de novo copy number mutations with autism. Science 316:445–49 [Google Scholar]
  18. Reichenberg A, Gross R, Weiser M. 18.  et al. 2006. Advancing paternal age and autism. Arch. Gen. Psychiatry 63:1026–32 [Google Scholar]
  19. Crow JF.19.  2000. The origins, patterns and implications of human spontaneous mutation. Nat. Rev. Genet. 1:40–47 [Google Scholar]
  20. Sebat J, Lakshmi B, Troge J. 20.  et al. 2004. Large-scale copy number polymorphism in the human genome. Science 305:525–28 [Google Scholar]
  21. Iafrate AJ, Feuk L, Rivera MN. 21.  et al. 2004. Detection of large-scale variation in the human genome. Nat. Genet. 36:949–51 [Google Scholar]
  22. Sanders SJ, Ercan-Sencicek AG, Hus V. 22.  et al. 2011. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70:863–85 [Google Scholar]
  23. Pinto D, Delaby E, Merico D. 23.  et al. 2014. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am. J. Hum. Genet. 94:677–94 [Google Scholar]
  24. Levy D, Ronemus M, Yamrom B. 24.  et al. 2011. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70:886–97 [Google Scholar]
  25. Kumar RA, KaraMohamed S, Sudi J. 25.  et al. 2008. Recurrent 16p11.2 microdeletions in autism. Hum. Mol. Genet. 17:628–38 [Google Scholar]
  26. Christian SL, Brune CW, Sudi J. 26.  et al. 2008. Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biol. Psychiatry 63:1111–17 [Google Scholar]
  27. Itsara A, Wu H, Smith JD. 27.  et al. 2010. De novo rates and selection of large copy number variation. Genome Res. 20:1469–81 [Google Scholar]
  28. Gilman SR, Iossifov I, Levy D. 28.  et al. 2011. Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70:898–907 [Google Scholar]
  29. Sanders SJ, Ercan-Sencicek AG, Hus V. 29.  et al. 2011. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70:863–85 [Google Scholar]
  30. O'Roak BJ, Deriziotis P, Lee C. 30.  et al. 2011. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet. 43:585–89 [Google Scholar]
  31. Nord AS, Roeb W, Dickel DE. 31.  et al. 2011. Reduced transcript expression of genes affected by inherited and de novo CNVs in autism. Eur. J. Hum. Genet. 19:727–31 [Google Scholar]
  32. Neale BM, Kou Y, Liu L. 32.  et al. 2012. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485:242–45 [Google Scholar]
  33. Sanders SJ, Murtha MT, Gupta AR. 33.  et al. 2012. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:237–41 [Google Scholar]
  34. Iossifov I, Ronemus M, Levy D. 34.  et al. 2012. De novo gene disruptions in children on the autistic spectrum. Neuron 74:285–99 [Google Scholar]
  35. Malhotra D, Sebat J. 35.  2012. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148:1223–41 [Google Scholar]
  36. O'Roak BJ, Vives L, Girirajan S. 36.  et al. 2012. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485:246–50 [Google Scholar]
  37. Bernstein BE, Birney E, Dunham I. 37.  et al. 2012. An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74 [Google Scholar]
  38. Michaelson JJ, Shi Y, Gujral M. 38.  et al. 2012. Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151:1431–42 [Google Scholar]
  39. Jiang YH, Yuen RK, Jin X. 39.  et al. 2013. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am. J. Hum. Genet. 93:249–63 [Google Scholar]
  40. Kong A, Frigge ML, Masson G. 40.  et al. 2012. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488:471–75 [Google Scholar]
  41. Goldstein DB, Allen A, Keebler J. 41.  et al. 2013. Sequencing studies in human genetics: design and interpretation. Nat. Rev. Genet. 14:460–70 [Google Scholar]
  42. MacArthur DG, Balasubramanian S, Frankish A. 42.  et al. 2012. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335:823–28 [Google Scholar]
  43. Tabor HK, Cho MK. 43.  2007. Ethical implications of array comparative genomic hybridization in complex phenotypes: points to consider in research. Genet. Med. 9:626–31 [Google Scholar]
  44. Kearney HM, Thorland EC, Brown KK. 44.  et al. 2011. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet. Med. 13:680–85 [Google Scholar]
  45. Bernier R, Golzio C, Xiong B. 45.  et al. 2014. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158:263–76 [Google Scholar]
  46. Mefford HC, Sharp AJ, Baker C. 46.  et al. 2008. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N. Engl. J. Med. 359:1685–99 [Google Scholar]
  47. Cook EH Jr, Lindgren V, Leventhal BL. 47.  et al. 1997. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am. J. Hum. Genet. 60:928–34 [Google Scholar]
  48. Burnside RD, Pasion R, Mikhail FM. 48.  et al. 2011. Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay. Hum. Genet. 130:517–28 [Google Scholar]
  49. Weiss LA, Shen YP, Korn JM. 49.  et al. 2008. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358:667–75 [Google Scholar]
  50. Sebat J, Levy DL, McCarthy SE. 50.  2009. Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet. 25:528–35 [Google Scholar]
  51. McCarthy SE, Makarov V, Kirov G. 51.  et al. 2009. Microduplications of 16p11.2 are associated with schizophrenia. Nat. Genet. 41:1223–27 [Google Scholar]
  52. Kirov G, Pocklington AJ, Holmans P. 52.  et al. 2012. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol. Psychiatry 17:142–53 [Google Scholar]
  53. Stefansson H, Meyer-Lindenberg A, Steinberg S. 53.  et al. 2014. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 505:361–66 [Google Scholar]
  54. Shinawi M, Liu P, Kang SH. 54.  et al. 2010. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J. Med. Genet. 47:332–41 [Google Scholar]
  55. Moreno-De-Luca A, Myers SM, Challman TD. 55.  et al. 2013. Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence. Lancet Neurol. 12:406–14 [Google Scholar]
  56. 56. Deleted in proof
  57. Stefansson H, Rujescu D, Cichon S. 57.  et al. 2008. Large recurrent microdeletions associated with schizophrenia. Nature 455:232–36 [Google Scholar]
  58. Fombonne E.58.  2009. Epidemiology of pervasive developmental disorders. Pediatr. Res. 65:591–98 [Google Scholar]
  59. Werling DM, Geschwind DH. 59.  2013. Understanding sex bias in autism spectrum disorder. Proc. Natl. Acad. Sci. USA 110:4868–69 [Google Scholar]
  60. Zhao X, Leotta A, Kustanovich V. 60.  et al. 2007. A unified genetic theory for sporadic and inherited autism. Proc. Natl. Acad. Sci. USA 104:12831–36 [Google Scholar]
  61. Ozonoff S, Young GS, Carter A. 61.  et al. 2011. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics 128:e488–95 [Google Scholar]
  62. Jacquemont S, Coe BP, Hersch M. 62.  et al. 2014. A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders. Am. J. Hum. Genet. 94:415–25 [Google Scholar]
  63. Purcell SM, Wray NR. 63. International Schizophrenia Consortium et al. 2009. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460:748–52 [Google Scholar]
  64. Girirajan S, Rosenfeld JA, Coe BP. 64.  et al. 2012. Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N. Engl. J. Med. 367:1321–31 [Google Scholar]
  65. Sung M, Fung DS, Cai Y, Ooi YP. 65.  2010. Pharmacological management in children and adolescents with pervasive developmental disorder. Aust. N.Z. J. Psychiatry 44:410–28 [Google Scholar]
  66. Sung M, Chin CH, Lim CG. 66.  et al. 2014. What's in the pipeline? Drugs in development for autism spectrum disorder. Neuropsychiatr. Dis. Treat. 10:371–81 [Google Scholar]
  67. Bickel H, Gerrard J, Hickmans EM. 67.  1953. Influence of phenylalanine intake on phenylketonuria. Lancet 265:812–13 [Google Scholar]
  68. Novarino G, El-Fishawy P, Kayserili H. 68.  et al. 2012. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science 338:394–97 [Google Scholar]
  69. Harris RA, Joshi M, Jeoung NH, Obayashi M. 69.  2005. Overview of the molecular and biochemical basis of branched-chain amino acid catabolism. J. Nutr. 135:1527S–30S [Google Scholar]
  70. Celestino-Soper PB, Shaw CA, Sanders SJ. 70.  et al. 2011. Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE. Hum. Mol. Genet. 20:4360–70 [Google Scholar]
  71. Celestino-Soper PB, Violante S, Crawford EL. 71.  et al. 2012. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proc. Natl. Acad. Sci. USA 109:7974–81 [Google Scholar]
  72. Geier DA, Kern JK, Davis G. 72.  et al. 2011. A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders. Med. Sci. Monit. Int. Med. J. Exp. Clin. Res. 17PI15–23
  73. Tierney E, Nwokoro NA, Porter FD. 73.  et al. 2001. Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 98:191–200 [Google Scholar]
  74. Sikora DM, Pettit-Kekel K, Penfield J. 74.  et al. 2006. The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. A 140:1511–18 [Google Scholar]
  75. Sikora DM, Ruggiero M, Petit-Kekel K. 75.  et al. 2004. Cholesterol supplementation does not improve developmental progress in Smith-Lemli-Opitz syndrome. J. Pediatr. 144:783–91 [Google Scholar]
  76. Aneja A, Tierney E. 76.  2008. Autism: the role of cholesterol in treatment. Int. Rev. Psychiatr. 20:165–70 [Google Scholar]
  77. Amir RE, Van den Veyver IB, Wan M. 77.  et al. 1999. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23:185–88 [Google Scholar]
  78. Guy J, Gan J, Selfridge J. 78.  et al. 2007. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315:1143–47 [Google Scholar]
  79. Buchovecky CM, Turley SD, Brown HM. 79.  et al. 2013. A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome. Nat. Genet. 45:1013–20 [Google Scholar]
  80. Ghosh A, Michalon A, Lindemann L. 80.  et al. 2013. Drug discovery for autism spectrum disorder: challenges and opportunities. Nat. Rev. Drug Discov. 12:777–90 [Google Scholar]
  81. Huber KM, Gallagher SM, Warren ST, Bear MF. 81.  2002. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl. Acad. Sci. USA 99:7746–50 [Google Scholar]
  82. Dolen G, Osterweil E, Rao BS. 82.  et al. 2007. Correction of fragile X syndrome in mice. Neuron 56:955–62 [Google Scholar]
  83. Auerbach BD, Osterweil EK, Bear MF. 83.  2011. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480:63–68 [Google Scholar]
  84. Henderson C, Wijetunge L, Kinoshita MN. 84.  et al. 2012. Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Sci. Transl. Med. 4:152ra28 [Google Scholar]
  85. Berry-Kravis EM, Hessl D, Rathmell B. 85.  et al. 2012. Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Sci. Transl. Med. 4:152ra27 [Google Scholar]
  86. Delahunty C, Walton-Bowen K, Kuriyams N. 86.  et al. 2013. Randomized, controlled, phase 2 trial of STX209 (arbaclofen) for social function in ASD. https://aap.confex.com/aap/2013/webprogrampress/Paper22373.html [Google Scholar]
  87. Jacquemont S, Curie A, des Portes V. 87.  et al. 2011. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci. Transl. Med. 3:64ra1 [Google Scholar]
  88. Braat S, Kooy RF. 88.  2014. Fragile X syndrome neurobiology translates into rational therapy. Drug Discov. Today 19:510–19 [Google Scholar]
  89. Kremer EJ, Pritchard M, Lynch M. 89.  et al. 1991. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252:1711–14 [Google Scholar]
  90. Constantino JN, Todd RD. 90.  2003. Autistic traits in the general population: a twin study. Arch. Gen. Psychiatry 60:524–30 [Google Scholar]
  91. Fischbach GD, Lord C. 91.  2010. The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron 68:192–95 [Google Scholar]
  92. O'Roak BJ, Vives L, Fu W. 92.  et al. 2012. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338:1619–22 [Google Scholar]
  93. 93. Deleted in proof
  94. de Ligt J, Willemsen MH, van Bon BW. 94.  et al. 2012. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367:1921–29 [Google Scholar]
  95. Rauch A, Wieczorek D, Graf E. 95.  et al. 2012. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380:1674–82 [Google Scholar]
  96. Gilissen C, Hehir-Kwa JY, Thung DT. 96.  et al. 2014. Genome sequencing identifies major causes of severe intellectual disability. Nature 511:344–47 [Google Scholar]
  97. Tabuchi K, Blundell J, Etherton MR. 97.  et al. 2007. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318:71–76 [Google Scholar]
  98. Hamdan FF, Piton A, Gauthier J. 98.  et al. 2009. De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy. Ann. Neurol. 65:748–53 [Google Scholar]
  99. Milh M, Villeneuve N, Chouchane M. 99.  et al. 2011. Epileptic and nonepileptic features in patients with early onset epileptic encephalopathy and STXBP1 mutations. Epilepsia 52:1828–34 [Google Scholar]
  100. Coe BP, Witherspoon K, Rosenfeld JA. 100.  et al. 2014. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat. Genet. 461063–71
  101. Hamdan FF, Daoud H, Piton A. 101.  et al. 2011. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol. Psychiatry 69:898–901 [Google Scholar]
  102. Golzio C, Willer J, Talkowski ME. 102.  et al. 2012. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 485:363–67 [Google Scholar]
  103. Docker D, Schubach M, Menzel M. 103.  et al. 2014. Further delineation of the SATB2 phenotype. Eur. J. Hum. Genet. 22:1034–39 [Google Scholar]
  104. Halgren C, Kjaergaard S, Bak M. 104.  et al. 2012. Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Clin. Genet. 82:248–55 [Google Scholar]
  105. Hoyer J, Ekici AB, Endele S. 105.  et al. 2012. Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability. Am. J. Hum. Genet. 90:565–72 [Google Scholar]
  106. 106. Deleted in proof
  107. Tatton-Brown K, Seal S, Ruark E. 107.  et al. 2014. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat. Genet. 46:385–88 [Google Scholar]
  108. Kuechler A, Zink AM, Wieland T. 108.  et al. 2014. Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome. Eur. J. Hum. Genet. In press
  109. Grozeva D, Carss K, Spasic-Boskovic O. 109.  et al. 2014. De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability. Am. J. Hum. Genet. 94:618–24 [Google Scholar]
  110. Le Fevre AK, Taylor S, Malek NH. 110.  et al. 2013. FOXP1 mutations cause intellectual disability and a recognizable phenotype. Am. J. Med. Genet. A 161A:3166–75 [Google Scholar]
/content/journals/10.1146/annurev-med-091113-024550
Loading
From De Novo Mutations to Personalized Therapeutic Interventions in Autism
Annual Review of Medicine 66, 487 (2015); https://doi.org/10.1146/annurev-med-091113-024550
/content/journals/10.1146/annurev-med-091113-024550
/content/journals/10.1146/annurev-med-091113-024550
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error