Clinical Consequences of Chromothripsis and Other Catastrophic Cellular Events

  • Maki FukamiEmail author
  • Hiroki KurahashiEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1769)


Chromothripsis was initially described as a novel cause of chromosomal rearrangements in cancer cells and was subsequently implicated in the development of gross chromosomal rearrangements in the germline. Other catastrophic cellular events such as chromoanasynthesis and chromoplexy have also been observed in human cells. Such events have been associated with various phenotypes including mental retardation and congenital malformations. Here, we introduce representative cases of human disorders arising from somatic or germline chromothripsis or similar catastrophic events. In this chapter, we use the term “chromoanagenesis” to indicate all catastrophic events including chromothripsis.

Key words

Germline Rearrangement Gene Deletion Duplication Congenital anomaly Tumor 


  1. 1.
    Kurahashi H, Bolor H, Kato T et al (2009) Recent advance in our understanding of the molecular nature of chromosomal abnormalities. J Hum Genet 54(5):253–360. CrossRefPubMedGoogle Scholar
  2. 2.
    Richardson C, Jasin M (2000) Frequent chromosomal translocations induced by DNA double-strand breaks. Nature 405:697–700CrossRefPubMedGoogle Scholar
  3. 3.
    Hastings PJ, Lupski JR, Rosenberg SM et al (2009) Mechanisms of change in gene copy number. Nat Rev Genet 10(8):551–564. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Shaikh TH, Kurahashi H, Saitta SC et al (2000) Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet 9(4):489–501CrossRefPubMedGoogle Scholar
  5. 5.
    Edelmann L, Pandita RK, Spiteri E et al (1999) A common molecular basis for rearrangement disorders on chromosome 22q11. Hum Mol Genet 8(7):1157–1167CrossRefPubMedGoogle Scholar
  6. 6.
    Lupski JR (1998) Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet 14(10):417–422CrossRefPubMedGoogle Scholar
  7. 7.
    Kurahashi H, Inagaki H, Ohye T et al (2010) The constitutional t(11;22): implications for a novel mechanism responsible for gross chromosomal rearrangements. Clin Genet 78(4):299–309. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Lee JA, Carvalho CM, Lupski JR (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131(7):1235–1247CrossRefPubMedGoogle Scholar
  9. 9.
    Conrad DF, Bird C, Blackburne B et al (2010) Mutation spectrum revealed by breakpoint sequencing of human germline CNVs. Nat Genet 42(5):385–391. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Stephens PJ, Greenman CD, Fu B et al (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144(1):27–40. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Forment JV, Kaidi A, Jackson SP (2012) Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat Rev Cancer 12(10):663–670. CrossRefPubMedGoogle Scholar
  12. 12.
    Kloosterman WP, Guryev V, van Roosmalen M et al (2011) Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline. Hum Mol Genet 20(10):1916–1924. CrossRefPubMedGoogle Scholar
  13. 13.
    Liu P, Erez A, Nagamani SC et al (2011) Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146(6):889–903. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Chiang C, Jacobsen JC, Ernst C et al (2012) Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration. Nat Genet 44(4):390–397, S1. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kloosterman WP, Tavakoli-Yaraki M, van Roosmalen MJ et al (2012) Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms. Cell Rep 1(6):648–655. CrossRefPubMedGoogle Scholar
  16. 16.
    Holland AJ, Cleveland DW (2012) Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements. Nat Med 18(11):1630–1638. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kurahashi H, Ohye T, Inagaki H et al (2012) Mechanism of complex gross chromosomal rearrangements: a commentary on concomitant microduplications of MECP2 and ATRX in male patients with severe mental retardation. J Hum Genet 57(2):81–83. CrossRefPubMedGoogle Scholar
  18. 18.
    Weckselblatt B, Hermetz KE, Rudd MK (2015) Unbalanced translocations arise from diverse mutational mechanisms including chromothripsis. Genome Res 25(7):937–947. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kato T, Ouchi Y, Inagaki H et al (2017) Genomic characterization of chromosomal insertions: implication for mechanism leading to the chromothripsis. Cytogenet Genome Res.
  20. 20.
    Pellestor F, Gatinois V, Puechberty J et al (2014) Chromothripsis: potential origin in gametogenesis and preimplantation cell divisions. A review. Fertil Steril 102(6):1785–1796. CrossRefPubMedGoogle Scholar
  21. 21.
    Marchetti F, Essers J, Kanaar R et al (2007) Disruption of maternal DNA repair increases sperm-derived chromosomal aberrations. Proc Natl Acad Sci U S A 104(45):17725–17729CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Zhang CZ, Spektor A, Cornils H et al (2015) Chromothripsis from DNA damage in micronuclei. Nature 522(7555):179–184. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ly P, Teitz LS, Kim DH et al (2017) Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining. Nat Cell Biol 19(1):68–75. CrossRefPubMedGoogle Scholar
  24. 24.
    Fukami M, Shima H, Suzuki E et al (2017) Catastrophic cellular events leading to complex chromosomal rearrangements in the germline. Clin Genet 91(5):653–660. CrossRefPubMedGoogle Scholar
  25. 25.
    Poot M, Haaf T (2015) Mechanisms of origin, phenotypic effects and diagnostic implications of complex chromosome rearrangements. Mol Syndromol 6(3):110–134. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kloosterman WP, Cuppen E (2013) Chromothripsis in congenital disorders and cancer: similarities and differences. Curr Opin Cell Biol 25(3):341–348. CrossRefPubMedGoogle Scholar
  27. 27.
    de Pagter MS, van Roosmalen MJ, Baas AF et al (2015) Chromothripsis in healthy individuals affects multiple protein-coding genes and can result in severe congenital abnormalities in offspring. Am J Hum Genet 96:651–656CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Masset H, Hestand MS, Van Esch H et al (2016) A distinct class of chromoanagenesis events characterized by focal copy number gains. Hum Mutat 37:661–668CrossRefPubMedGoogle Scholar
  29. 29.
    Pellestor F, Anahory T, Lefort G et al (2011) Complex chromosomal rearrangements: origin and meiotic behavior. Hum Reprod Update 17(4):476–494. CrossRefPubMedGoogle Scholar
  30. 30.
    Suzuki E, Shima H, Toki M et al (2017) Complex X-chromosomal rearrangements in two women with ovarian dysfunction: implications for chromothripsis/chromoanasynthesis-dependent and independent origins of complex genomic alterations. Cytogenet Genome Res 150(2):86–92. CrossRefGoogle Scholar
  31. 31.
    Ochalski ME, Engle N, Wakim A et al (2011) Complex X chromosome rearrangement delineated by array comparative genome hybridization in a woman with premature ovarian insufficiency. Fertil Steril 95:2433.e9–2433.15Google Scholar
  32. 32.
    Auger J, Bonnet C, Valduga M et al (2013) De novo complex X chromosome rearrangement unmasking maternally inherited CSF2RA deletion in a girl with pulmonary alveolar proteinosis. Am J Med Genet A 161A:2594–2599PubMedGoogle Scholar
  33. 33.
    Zhong Q, Layman LC (2012) Genetic considerations in the patient with turner syndrome—45,X with or without mosaicism. Fertil Steril 98:775–779CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    McDermott DH, Gao JL, Liu Q et al (2015) Chromothriptic cure of WHIM syndrome. Cell 160:686–699CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Zanardo ÉA, Piazzon FB, Dutra RL et al (2014) Complex structural rearrangement features suggesting chromoanagenesis mechanism in a case of 1p36 deletion syndrome. Mol Gen Genomics 289:1037–1043CrossRefGoogle Scholar
  36. 36.
    Plaisancié J, Kleinfinger P, Cances C et al (2014) Constitutional chromoanasynthesis: description of a rare chromosomal event in a patient. Eur J Med Genet 57:567–570CrossRefPubMedGoogle Scholar
  37. 37.
    Kloosterman WP, Koster J, Molenaar JJ (2014) Prevalence and clinical implications of chromothripsis in cancer genomes. Curr Opin Oncol 26:64–67CrossRefPubMedGoogle Scholar
  38. 38.
    Mehine M, Kaasinen E, Mäkinen N et al (2013) Characterization of uterine leiomyomas by whole-genome sequencing. N Engl J Med 369:43–53CrossRefPubMedGoogle Scholar
  39. 39.
    Storchová Z, Kloosterman WP (2016) The genomic characteristics and cellular origin of chromothripsis. Curr Opin Cell Biol 40:106–113CrossRefPubMedGoogle Scholar
  40. 40.
    Rode A, Maass KK, Willmund KV et al (2016) Chromothripsis in cancer cells: an update. Int J Cancer 138(10):2322–2333. CrossRefPubMedGoogle Scholar
  41. 41.
    Hatch EM, Hetzer MW (2015) Linking micronuclei to chromosome fragmentation. Cell 161:1502–1504CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Molecular EndocrinologyNational Research Institute for Child Health and DevelopmentTokyoJapan
  2. 2.Division of Molecular Genetics, Institute for Comprehensive Medical ScienceFujita Health UniversityToyoakeJapan

Personalised recommendations