Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Somatic mosaicism and neurodevelopmental disease

Nature Neuroscience volume 21, pages 1504–1514 (2018)Cite this article

Subjects

Abstract

Traditionally, we have considered genetic mutations that cause neurodevelopmental diseases to be inherited or de novo germline mutations. Recently, we have come to appreciate the importance of de novo somatic mutations, which occur postzygotically and are thus present in only a subset of the cells of an affected individual. The advent of next-generation sequencing and single-cell sequencing technologies has shown that somatic mutations contribute to normal and abnormal human brain development. Somatic mutations are one important cause of neuronal migration and brain overgrowth disorders, as suggested by visible focal lesions. In addition, somatic mutations contribute to neurodevelopmental diseases without visible lesions, including epileptic encephalopathies, intellectual disability, and autism spectrum disorder, and may contribute to a broad range of neuropsychiatric diseases. Studying somatic mutations provides insight into the mechanisms underlying human brain development and neurodevelopmental diseases and has important implications for diagnosis and treatment.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Types of mutations and their detection using NGS.
Fig. 2: Somatic mutations in neuronal migration disorders.
Fig. 3: FCD and HME represent a continuum, with lesion differences reflecting the time and place of origin of the mutation.

References

  1. Jónsson, H. et al. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature 549, 519–522 (2017).

    Article  PubMed  CAS  Google Scholar 

  2. Kong, A. et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature 488, 471–475 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. O’Roak, B. J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet. 43, 585–589 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Veltman, J. A. & Brunner, H. G. De novo mutations in human genetic disease. Nat. Rev. Genet. 13, 565–575 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Larsen, F. W. & Mouridsen, S. E. The outcome in children with childhood autism and Asperger syndrome originally diagnosed as psychotic. A 30-year follow-up study of subjects hospitalized as children. Eur. Child Adolesc. Psychiatry 6, 181–190 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Power, R. A. et al. Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings. JAMA Psychiatry 70, 22–30 (2013).

    Article  PubMed  Google Scholar 

  7. Philp, A. J. et al. The phosphatidylinositol 3′-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res. 61, 7426–7429 (2001).

    CAS  PubMed  Google Scholar 

  8. Biesecker, L. G. & Spinner, N. B. A genomic view of mosaicism and human disease. Nat. Rev. Genet. 14, 307–320 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Azevedo, F. A. et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J. Comp. Neurol. 513, 532–541 (2009).

    Article  PubMed  Google Scholar 

  10. Workman, A. D., Charvet, C. J., Clancy, B., Darlington, R. B. & Finlay, B. L. Modeling transformations of neurodevelopmental sequences across mammalian species. J. Neurosci. 33, 7368–7383 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bae, T. et al. Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis. Science 359, 550–555 (2018). This study used clonal cell expansion of fetal human neuronal progenitor cells to estimate the somatic mutation rate during neurogenesis.

    Article  CAS  PubMed  Google Scholar 

  12. Lodato, M. A. et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359, 555–559 (2018). This study used whole-genome sequencing of single human neurons to demonstrate that somatic SNVs in human neurons accumulate linearly with age.

    Article  CAS  PubMed  Google Scholar 

  13. Poduri, A., Evrony, G. D., Cai, X. & Walsh, C. A. Somatic mutation, genomic variation, and neurological disease. Science 341, 1237758 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. D’Gama, A. M. et al. Somatic mutations activating the mTOR pathway in dorsal telencephalic progenitors cause a continuum of cortical dysplasias. Cell Rep. 21, 3754–3766 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Dou, Y. et al. Postzygotic single-nucleotide mosaicisms contribute to the etiology of autism spectrum disorder and autistic traits and the origin of mutations. Hum. Mutat. 38, 1002–1013 (2017). This study, along with refs 16–18, analyzed WES of people with ASD to estimate the contribution of somatic mutationsto ASD risk.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Freed, D. & Pevsner, J. The contribution of mosaic variants to autism spectrum disorder. PLoS Genet. 12, e1006245 (2016). This study, along with refs. 15,17,18, analyzed WES of people with ASD to estimate the contribution of somatic mutations to ASD risk.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Krupp, D. R. et al. Exonic mosaic mutations contribute risk for autism spectrum disorder. Am. J. Hum.Genet. 101, 369–390 (2017). This study, along with refs. 15,16,18, analyzed WES of people with ASD to estimate the contribution of somatic mutations to ASD risk.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lim, E. T. et al. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Nat. Neurosci. 20, 1217–1224 (2017). This study, along with refs 15–17, analyzed WES of people with ASD to estimate the contribution of somatic mutations to ASD risk.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lodato, M. A. et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350, 94–98 (2015). This study used whole-genome sequencing of single human neurons to estimate the number of somatic mutations in each postmitotic neuron.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gennaro, E. et al. Somatic and germline mosaicisms in severe myoclonic epilepsy of infancy. Biochem. Biophys. Res. Commun. 341, 489–493 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Nakamura, K. et al. Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 81, 992–998 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Vadlamudi, L. et al. Timing of de novo mutagenesis--a twin study of sodium-channel mutations. N. Engl. J. Med. 363, 1335–1340 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Xu, X. et al. Amplicon resequencing identified parental mosaicism for approximately 10% of “de novo” SCN1A mutations in children with Dravet syndrome. Hum. Mutat. 36, 861–872 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Zerem, A. et al. Paternal germline mosaicism of a SCN2A mutation results in Ohtahara syndrome in half siblings. Eur. J. Paediatr. Neurol. 18, 567–571 (2014).

    Article  PubMed  Google Scholar 

  25. D’Gama, A. M. et al. Targeted DNA sequencing from autism spectrum disorder brains implicates multiple genetic mechanisms. Neuron 88, 910–917 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Cai, X. et al. Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep. 8, 1280–1289 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. McConnell, M. J. et al. Mosaic copy number variation in human neurons. Science 342, 632–637 (2013). This study demonstrated that mosaic CNVs are common in human neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Crowe, C. A., Schwartz, S., Black, C. J. & Jaswaney, V. Mosaic trisomy 22: a case presentation and literature review of trisomy 22 phenotypes. Am. J. Med. Genet. 71, 406–413 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Daber, R. et al. Mosaic trisomy 17: variable clinical and cytogenetic presentation. Am. J. Med. Genet. A. 155A, 2489–2495 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Gérard-Blanluet, M. et al. Mosaic trisomy 9 and lobar holoprosencephaly. Am. J. Med. Genet. 111, 295–300 (2002).

    Article  PubMed  Google Scholar 

  31. Laus, A. C. et al. Karyotype/phenotype correlation in partial trisomies of the long arm of chromosome 16: case report and review of literature. Am. J. Med. Genet. A. 158A, 821–827 (2012).

    Article  PubMed  CAS  Google Scholar 

  32. Pangalos, C. et al. Understanding the mechanism(s) of mosaic trisomy 21 by using DNA polymorphism analysis. Am. J. Hum. Genet. 54, 473–481 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Patel, C. et al. Mosaic trisomy 1q: The longest surviving case. Am. J. Med. Genet. A. 149A, 1795–1800 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Schrander-Stumpel, C. T. et al. Mosaic tetrasomy 8p in two patients: clinical data and review of the literature. Am. J. Med. Genet. 50, 377–380 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Muotri, A. R. et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature 468, 443–446 (2010). This study showed the first association between a neurodevelopmental disease, Rett syndrome, and increased somatic L1 insertions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lindhurst, M. J. et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N. Engl. J. Med. 365, 611–619 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kurek, K. C. et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am. J. Hum. Genet. 90, 1108–1115 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shirley, M. D. et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N. Engl. J. Med. 368, 1971–1979 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kingsmore, S. et al. Exome sequencing reveals de novo germline mutation of the mammalian target of rapamycin (MTOR) in a patient with megalencephaly and intractable seizures. Journal of Genomes and Exomes 2, 63–72 (2013).

    Article  Google Scholar 

  40. Knudson, A. G. Jr. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl. Acad. Sci. USA 68, 820–823 (1971).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Maertens, O. et al. Comprehensive NF1 screening on cultured Schwann cells from neurofibromas. Hum. Mutat. 27, 1030–1040 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Garcia-Linares, C. et al. Dissecting loss of heterozygosity (LOH) in neurofibromatosis type 1-associated neurofibromas: Importance of copy neutral LOH. Hum. Mutat. 32, 78–90 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Crino, P. B., Aronica, E., Baltuch, G. & Nathanson, K. L. Biallelic TSC gene inactivation in tuberous sclerosis complex. Neurology 74, 1716–1723 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Qin, W. et al. Analysis of TSC cortical tubers by deep sequencing of TSC1, TSC2 and KRAS demonstrates that small second-hit mutations in these genes are rare events. Brain Pathol. 20, 1096–1105 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tyburczy, M. E. et al. A shower of second hit events as the cause of multifocal renal cell carcinoma in tuberous sclerosis complex. Hum. Mol. Genet. 24, 1836–1842 (2015).

    Article  CAS  PubMed  Google Scholar 

  46. Sheen, V. L. et al. Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. Hum. Mol. Genet. 10, 1775–1783 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Guerrini, R. et al. Germline and mosaic mutations of FLN1 in men with periventricular heterotopia. Neurology 63, 51–56 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Parrini, E., Mei, D., Wright, M., Dorn, T. & Guerrini, R. Mosaic mutations of the FLN1 gene cause a mild phenotype in patients with periventricular heterotopia. Neurogenetics 5, 191–196 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Sicca, F. et al. Mosaic mutations of the LIS1 gene cause subcortical band heterotopia. Neurology 61, 1042–1046 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Gleeson, J. G. et al. Somatic and germline mosaic mutations in the doublecortin gene are associated with variable phenotypes. Am. J. Hum. Genet. 67, 574–581 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jamuar, S. S. et al. Somatic mutations in cerebral cortical malformations. N. Engl. J. Med. 371, 733–743 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Rohlin, A. et al. Parallel sequencing used in detection of mosaic mutations: comparison with four diagnostic DNA screening techniques. Hum. Mutat. 30, 1012–1020 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Blümcke, I. et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 52, 158–174 (2011).

    Article  PubMed  Google Scholar 

  54. Poduri, A. et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74, 41–48 (2012). This study, along with refs 59,61, used direct study of human brain tissue to identify a genetic cause for HME.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hua, Y. & Crino, P. B. Single cell lineage analysis in human focal cortical dysplasia. Cereb. Cortex 13, 693–699 (2003).

    Article  PubMed  Google Scholar 

  56. Blumcke, I. et al. Histopathological findings in brain tissue obtained during epilepsy surgery. N. Engl. J. Med. 377, 1648–1656 (2017).

    Article  PubMed  Google Scholar 

  57. Harvey, A. S., Cross, J. H., Shinnar, S., Mathern, G. W. & Taskforce, I. P. E. S. S. Defining the spectrum of international practice in pediatric epilepsy surgery patients. Epilepsia 49, 146–155 (2008).

    Article  PubMed  Google Scholar 

  58. Jansen, L. A. et al. PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain 138, 1613–1628 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Lee, J. H. et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.Nat. Genet. 44, 941–945 (2012). This study, along with refs 54,61, used direct study of human brain tissue to identify a genetic cause for HME.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lim, J. S. et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat. Med. 21, 395–400 (2015).

    Article  CAS  PubMed  Google Scholar 

  61. Rivière, J. B. et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. 44, 934–940 (2012). This study, along with refs 54,59, used direct study of human brain tissue to identify a genetic cause for HME.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. D’Gama, A. M. et al. mTOR pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann. Neurol. 77, 720–725 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Lim, J. S. et al. Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia. Am. J. Hum. Genet. 100, 454–472 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Baulac, S. et al. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann. Neurol. 77, 675–683 (2015).

    Article  CAS  PubMed  Google Scholar 

  65. Sim, J. C. et al. Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3. Ann. Neurol. 79, 132–137 (2016).

    Article  CAS  PubMed  Google Scholar 

  66. Scheffer, I. E. et al. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann. Neurol. 75, 782–787 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Weckhuysen, S. et al. Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia 57, 994–1003 (2016).

    Article  CAS  PubMed  Google Scholar 

  68. Evrony, G. D. et al. Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151, 483–496 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Baek, S. T. et al. An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development. Nat. Med. 21, 1445–1454 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Roy, A. et al. Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy. eLife 4, e12703 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Yuskaitis, C. J. et al. A mouse model of DEPDC5-related epilepsy: neuronal loss of Depdc5 causes dysplastic and ectopic neurons, increased mTOR signaling, and seizure susceptibility. Neurobiol. Dis. 111, 91–101 (2018).

    Article  CAS  PubMed  Google Scholar 

  72. Allen, A. S. et al. De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Carvill, G. L. et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat. Genet. 45, 825–830 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Depienne, C. et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet. 5, e1000381 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Veeramah, K. R. et al. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia 54, 1270–1281 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Weckhuysen, S. et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann. Neurol. 71, 15–25 (2012).

    Article  CAS  PubMed  Google Scholar 

  77. Stosser, M. B. et al. High frequency of mosaic pathogenic variants in genes causing epilepsy-related neurodevelopmental disorders. Genet. Med. 20, 403–410 (2018).

    Article  CAS  PubMed  Google Scholar 

  78. Perez, D., Hsieh, D. T. & Rohena, L. Somatic mosaicism of PCDH19 in a male with early infantile epileptic encephalopathy and review of the literature. Am. J. Med. Genet. A. 173, 1625–1630 (2017).

    Article  CAS  PubMed  Google Scholar 

  79. Pederick, D. T. et al. Abnormal cell sorting underlies the unique X–linked inheritance of PCDH19 epilepsy. Neuron 97, 59–66 (2018).

    Article  CAS  PubMed  Google Scholar 

  80. Fu, C. et al. GABAergic interneuron development and function is modulated by the Tsc1 gene. Cereb. Cortex 22, 2111–2119 (2012).

    Article  PubMed  Google Scholar 

  81. American Psychiatric Association & DSM-5 Task Force. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. (American Psychiatric Association, Washington, D.C., 2013).

  82. Autism and Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators. Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill. Summ. 63, 1–21 (2014).

    Google Scholar 

  83. Kanner, L. Autistic disturbances of affective contact. Acta Paedopsychiatr. 35, 100–136 (1968).

    CAS  PubMed  Google Scholar 

  84. Bailey, A. et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol. Med. 25, 63–77 (1995).

    Article  CAS  PubMed  Google Scholar 

  85. Steffenburg, S. et al. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J. Child Psychol. Psychiatry 30, 405–416 (1989).

    Article  CAS  PubMed  Google Scholar 

  86. De Rubeis, S. et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209–215 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Levy, D. et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70, 886–897 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Lim, E. T. et al. Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. Neuron 77, 235–242 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. O’Roak, B. J. et al. Recurrent de novo mutations implicate novel genes underlying simplex autism risk. Nat. Commun. 5, 5595 (2014).

    Article  PubMed  CAS  Google Scholar 

  93. O’Roak, B. J. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. O’Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Pinto, D. et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368–372 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sanders, S. J. et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70, 863–885 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yu, T. W. et al. Using whole-exome sequencing to identify inherited causes of autism. Neuron 77, 259–273 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Bourdon, V. et al. Evidence of somatic mosaicism for a MECP2 mutation in females with Rett syndrome: diagnostic implications. J. Med. Genet. 38, 867–871 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Clayton-Smith, J., Watson, P., Ramsden, S. & Black, G. C. Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males. Lancet 356, 830–832 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. Helderman-van den Enden, A. T. et al. Monozygotic twin brothers with the fragile X syndrome: different CGG repeats and different mental capacities. J. Med. Genet. 36, 253–257 (1999).

    CAS  PubMed  Google Scholar 

  103. Tinschert, S. et al. Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene. Eur. J. Hum. Genet. 8, 455–459 (2000).

    Article  CAS  PubMed  Google Scholar 

  104. Verhoef, S. et al. High rate of mosaicism in tuberous sclerosis complex. Am. J. Hum. Genet. 64, 1632–1637 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Vogt, J. et al. Monozygotic twins discordant for neurofibromatosis type 1 due to a postzygotic NF1 gene mutation. Hum. Mutat. 32, E2134–E2147 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Castermans, D. et al. Position effect leading to haploinsufficiency in a mosaic ring chromosome 14 in a boy with autism. Eur. J. Hum. Genet. 16, 1187–1192 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Havlovicova, M. et al. A girl with neurofibromatosis type 1, atypical autism and mosaic ring chromosome 17. Am. J. Med. Genet. A. 143A, 76–81 (2007).

    Article  PubMed  Google Scholar 

  108. Kakinuma, H., Ozaki, M., Sato, H. & Takahashi, H. Variation in GABA-A subunit gene copy number in an autistic patient with mosaic 4 p duplication (p12p16). Am. J. Med. Genet. B. Neuropsychiatr. Genet. 147B, 973–975 (2008).

    Article  PubMed  Google Scholar 

  109. Meyer, K. J., Axelsen, M. S., Sheffield, V. C., Patil, S. R. & Wassink, T. H. Germline mosaic transmission of a novel duplication of PXDN and MYT1L to two male half-siblings with autism. Psychiatr. Genet. 22, 137–140 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Oliveira, G. et al. Partial tetrasomy of chromosome 3q and mosaicism in a child with autism. J. Autism Dev. Disord. 33, 177–185 (2003).

    Article  PubMed  Google Scholar 

  111. Papanikolaou, K. et al. A case of partial trisomy of chromosome 8p associated with autism. J. Autism Dev. Disord. 36, 705–709 (2006).

    Article  PubMed  Google Scholar 

  112. Sauter, S. et al. Autistic disorder and chromosomal mosaicism 46,XY[123]/46,XY,del(20)(pter --> p12.2)[10]. Am. J. Med. Genet. A. 120A, 533–536 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Yurov, Y. B. et al. Unexplained autism is frequently associated with low-level mosaic aneuploidy. J. Med. Genet. 44, 521–525 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hoischen, A., Krumm, N. & Eichler, E. E. Prioritization of neurodevelopmental disease genes by discovery of new mutations. Nat. Neurosci. 17, 764–772 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wintle, R. F. et al. A genotype resource for postmortem brain samples from the Autism Tissue Program. Autism Res. 4, 89–97 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Casanova, M. F. et al. Focal cortical dysplasias in autism spectrum disorders. Acta Neuropathol. Commun. 1, 67 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Stoner, R. et al. Patches of disorganization in the neocortex of children with autism. N. Engl. J. Med. 370, 1209–1219 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Willsey, A. J. et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 155, 997–1007 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Castronovo, P. et al. Somatic mosaicism in Cornelia de Lange syndrome: a further contributor to the wide clinical expressivity? Clin. Genet. 78, 560–564 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Gervasini, C. et al. Molecular characterization of a mosaic NIPBL deletion in a Cornelia de Lange patient with severe phenotype. Eur. J. Med. Genet. 56, 138–143 (2013).

    Article  PubMed  Google Scholar 

  121. Vissers, L. E., Gilissen, C. & Veltman, J. A. Genetic studies in intellectual disability and related disorders. Nat. Rev. Genet. 17, 9–18 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. Gilissen, C. et al. Genome sequencing identifies major causes of severe intellectual disability. Nature 511, 344–347 (2014).

    Article  CAS  PubMed  Google Scholar 

  123. Acuna-Hidalgo, R. et al. Post-zygotic point mutations are an underrecognized source of de novo genomic variation. Am. J. Hum. Genet. 97, 67–74 (2015). This study reanalyzed whole-genome sequencing from an ID cohort to demonstrate that somatic mutations are under-recognized and miscategorized as germline de novo mutations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. King, D. A. et al. Mosaic structural variation in children with developmental disorders. Hum. Mol. Genet. 24, 2733–2745 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Cannon, T. D., Kaprio, J., Lönnqvist, J., Huttunen, M. & Koskenvuo, M. The genetic epidemiology of schizophrenia in a Finnish twin cohort. A population-based modeling study. Arch. Gen. Psychiatry 55, 67–74 (1998).

    Article  CAS  PubMed  Google Scholar 

  126. Yurov, Y. B. et al. The schizophrenia brain exhibits low-level aneuploidy involving chromosome 1. Schizophr. Res. 98, 139–147 (2008).

    Article  PubMed  Google Scholar 

  127. Yurov, Y. B., Vostrikov, V. M., Vorsanova, S. G., Monakhov, V. V. & Iourov, I. Y. Multicolor fluorescent in situ hybridization on post-mortem brain in schizophrenia as an approach for identification of low-level chromosomal aneuploidy in neuropsychiatric diseases. Brain Dev. 23(Suppl 1), S186–S190 (2001).

    Article  PubMed  Google Scholar 

  128. Sakai, M. et al. Assessment of copy number variations in the brain genome of schizophrenia patients. Mol. Cytogenet. 8, 46 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Ruderfer, D. M. et al. Mosaic copy number variation in schizophrenia. Eur. J. Hum. Genet. 21, 1007–1011 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Bundo, M. et al. Increased L1 retrotransposition in the neuronal genome in schizophrenia. Neuron 81, 306–313 (2014). This study used L1 copy number quantification to demonstrate increased L1 insertions in neurons from schizophrenia patients.

    Article  CAS  PubMed  Google Scholar 

  131. Doyle, G. A. et al. Analysis of LINE-1 elements in DNA from postmortem brains of individuals with schizophrenia. Neuropsychopharmacology 42, 2602–2611 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. McConnell, M. J. et al. Intersection of diverse neuronal genomes and neuropsychiatric disease: the Brain Somatic Mosaicism Network. Science 356, eaal1641 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Yang, Y. et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N. Engl. J. Med. 369, 1502–1511 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Campbell, I. M. et al. Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders. Am. J. Hum. Genet. 95, 173–182 (2014). This study screened children with genomic disorders and their parents to demonstrate that parental somatic mosaicism is under-recognized and that mutations initially categorized as germline de novo mutations are sometimes detectable in DNA from parental blood.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Dey, S. S., Kester, L., Spanjaard, B., Bienko, M. & van Oudenaarden, A. Integrated genome and transcriptome sequencing of the same cell. Nat. Biotechnol. 33, 285–289 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Janiszewska, M. et al. In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer. Nat. Genet. 47, 1212–1219 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Mariani, J. et al. FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell 162, 375–390 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Abyzov, A. et al. Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 492, 438–442 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Hollingsworth, E. W. et al. iPhemap: an atlas of phenotype to genotype relationships of human iPSC models of neurological diseases. EMBO Mol. Med. 9, 1742–1762 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Lehner, T., Miller, B. L. & State, M. W. Genomics, Circuits, and Pathways in Clinical Neuropsychiatry. (Academic Press, Boston, MA, USA, 2016).

    Google Scholar 

  141. Bijlsma, E. K., Wallace, A. J. & Evans, D. G. Misleading linkage results in an NF2 presymptomatic test owing to mosaicism. J. Med. Genet. 34, 934–936 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Halliday, D. et al. Genetic severity score predicts clinical phenotype in NF2. J. Med. Genet. 54, 657–664 (2017).

    Article  PubMed  CAS  Google Scholar 

  143. Heyries, K. A. et al. Megapixel digital PCR. Nat. Methods 8, 649–651 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Dean, F. B., Nelson, J. R., Giesler, T. L. & Lasken, R. S. Rapid amplification of plasmid and phage DNA using Phi 29 DNA polymerase and multiply-primed rolling circle amplification. Genome Res. 11, 1095–1099 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Zong, C., Lu, S., Chapman, A. R. & Xie, X. S. Genome-wide detection of single-nucleotide and copy-number variations of a single human cell. Science 338, 1622–1626 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Hiatt, J. B., Pritchard, C. C., Salipante, S. J., O’Roak, B. J. & Shendure, J. Single molecule molecular inversion probes for targeted, high-accuracy detection of low-frequency variation. Genome Res. 23, 843–854 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Erwin, J. A. et al. L1-associated genomic regions are deleted in somatic cells of the healthy human brain. Nat. Neurosci. 19, 1583–1591 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Evrony, G. D., Lee, E., Park, P. J. & Walsh, C. A. Resolving rates of mutation in the brain using single-neuron genomics. eLife 5, e12966 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Upton, K. R. et al. Ubiquitous L1 mosaicism in hippocampal neurons. Cell 161, 228–239 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Gole, J. et al. Massively parallel polymerase cloning and genome sequencing of single cells using nanoliter microwells. Nat. Biotechnol. 31, 1126–1132 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank members of the Walsh laboratory for helpful discussions. A.M.D. was supported by the NIGMS (T32GM007753). C.A.W. was supported by the NINDS (R01NS079277), the NIMH (U01MH106883) through the Brain Somatic Mosaicism Network, the Allen Discovery Center program through The Paul G. Allen Frontiers Group, and the Manton Center for Orphan Disease Research. C.A.W. is an Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA, USA

    Alissa M. D’Gama & Christopher A. Walsh

  2. Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA, USA

    Alissa M. D’Gama & Christopher A. Walsh

  3. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Alissa M. D’Gama & Christopher A. Walsh

Authors
  1. Alissa M. D’Gama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher A. Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher A. Walsh.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

D’Gama, A.M., Walsh, C.A. Somatic mosaicism and neurodevelopmental disease. Nat Neurosci 21, 1504–1514 (2018). https://doi.org/10.1038/s41593-018-0257-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41593-018-0257-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing