Skip to main content

Advertisement

SpringerLink
Log in

Mosaicism in Traditional Mendelian Diseases

  • Clinical Genetics (JM Stoler, Section Editor)
  • Published:
Current Genetic Medicine Reports Aims and scope Submit manuscript

Abstract

Somatic mutations are post-zygotic mutational event that leads to generation of two or more genotypes within an individual. With the recent advances in genomic technologies, there is an increasing recognition of the role of somatic mosaicism in Mendelian disease. Somatic mutation can occur at the chromosomal or the DNA sequence level and the distribution of somatic mosaicism among tissues depends on the timing of the mutation during fetal development. Certain types of somatic mutations are lethal when present in the germline and hence, are only seen in the somatic state, while there are other somatic mutations that have a milder phenotype than when present in the germline. Presence of somatic mutations can also modulate the clinical phenotype of an individual in certain diseases. In this review, we discuss the recent updates on somatic mosaicism in Mendelian diseases, types of somatic mutations, and methods to detect these somatic mutations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. MoDBD Foundation. Global report on birth defects: the hidden toll of dying and disabled children. White Plains: March of Dimes; 2006.

    Google Scholar 

  2. Baird PA, Anderson TW, Newcombe HB, Lowry RB. Genetic disorders in children and young adults: a population study. Am J Hum Genet. 1988;42(5):677–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  3. •• Poduri A, Evrony GD, Cai X, Walsh CA. Somatic mutation, genomic variation, and neurological disease. Science. 2013;341(6141):1237758. This reference reviews the literature around somatic mosaicism in neurological disorders.

  4. •• Biesecker LG, Spinner NB. A genomic view of mosaicism and human disease. Nat Rev Genet. 2013;14(5):307–20. This reference reviews the literature around somatic mosaicism in Mendelian disorders.

  5. Kennedy SR, Loeb LA, Herr AJ. Somatic mutations in aging, cancer and neurodegeneration. Mech Ageing Dev. 2012;133(4):118–26.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. • Jamuar SS, Lam AT, Kircher M, et al. Somatic mutations in cerebral cortical malformations. N Engl J Med. 2014;371(8):733–43. A systematic approach to quantifying the prevalence of somatic mosaicism in undiagnosed brain malformation using deep sequencing.

  7. Watson IR, Takahashi K, Futreal PA, Chin L. Emerging patterns of somatic mutations in cancer. Nat Rev Genet. 2013;14(10):703–18.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Gardner RJS, G.R.; Shaffer, L.G. Chromosome abnormalities and Genetic Counseling. Chromosome abnormalities and Genetic Counseling. Oxford: Oxford University Press; 2011.

  9. Greenman C, Stephens P, Smith R, et al. Patterns of somatic mutation in human cancer genomes. Nature. 2007;446(7132):153–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Pleasance ED, Cheetham RK, Stephens PJ, et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2010;463(7278):191–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med. 1991;325(24):1688–95.

    Article  CAS  PubMed  Google Scholar 

  12. Lindhurst MJ, Sapp JC, Teer JK, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med. 2011;365(7):611–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368(21):1971–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Niida Y, Stemmer-Rachamimov AO, Logrip M, et al. Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions. Am J Hum Genet. 2001;69(3):493–503.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Smahi A, Courtois G, Vabres P, et al. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature. 2000;405(6785):466–72.

    Article  CAS  PubMed  Google Scholar 

  16. Gleeson JG, Minnerath S, Kuzniecky RI, et al. Somatic and germline mosaic mutations in the doublecortin gene are associated with variable phenotypes. Am J Hum Genet. 2000;67(3):574–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Sicca F, Kelemen A, Genton P, et al. Mosaic mutations of the LIS1 gene cause subcortical band heterotopia. Neurology. 2003;61(8):1042–6.

    Article  CAS  PubMed  Google Scholar 

  18. 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. 2004;5(3):191–6.

    Article  CAS  PubMed  Google Scholar 

  19. Guerrini R, Mei D, Sisodiya S, et al. Germline and mosaic mutations of FLN1 in men with periventricular heterotopia. Neurology. 2004;63(1):51–6.

    Article  CAS  PubMed  Google Scholar 

  20. Beck JA, Poulter M, Campbell TA, et al. Somatic and germline mosaicism in sporadic early-onset Alzheimer’s disease. Hum Mol Genet. 2004;13(12):1219–24.

    Article  CAS  PubMed  Google Scholar 

  21. Alzualde A, Moreno F, Martinez-Lage P, et al. Somatic mosaicism in a case of apparently sporadic Creutzfeldt-Jakob disease carrying a de novo D178 N mutation in the PRNP gene. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(7):1283–91.

    Article  CAS  PubMed  Google Scholar 

  22. Proukakis C, Houlden H, Schapira AH. Somatic alpha-synuclein mutations in Parkinson’s disease: hypothesis and preliminary data. Mov Disord. 2013;28(6):705–12.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971;68(4):820–3.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Garcia-Linares C, Fernandez-Rodriguez J, Terribas E, et al. Dissecting loss of heterozygosity (LOH) in neurofibromatosis type 1-associated neurofibromas: importance of copy neutral LOH. Hum Mutat. 2011;32(1):78–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Qin W, Chan JA, Vinters HV, 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. 2010;20(6):1096–105.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Hashida H, Goto J, Suzuki T, et al. Single cell analysis of CAG repeat in brains of dentatorubral-pallidoluysian atrophy (DRPLA). J Neurol Sci. 2001;190(1–2):87–93.

    Article  CAS  PubMed  Google Scholar 

  27. Hellenbroich Y, Schwinger E, Zuhlke C. Limited somatic mosaicism for Friedreich’s ataxia GAA triplet repeat expansions identified by small pool PCR in blood leukocytes. Acta Neurol Scand. 2001;103(3):188–92.

    Article  CAS  PubMed  Google Scholar 

  28. Ito Y, Tanaka F, Yamamoto M, et al. Somatic mosaicism of the expanded CAG trinucleotide repeat in mRNAs for the responsible gene of Machado-Joseph disease (MJD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA). Neurochem Res. 1998;23(1):25–32.

    Article  CAS  PubMed  Google Scholar 

  29. Scheffer IE, Heron SE, Regan BM, et al. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol. 2014;75(5):782–7.

    Article  CAS  PubMed  Google Scholar 

  30. Poduri A. DEPDC5 does it all: shared genetics for diverse epilepsy syndromes. Ann Neurol. 2014;75(5):631–3.

    Article  CAS  PubMed  Google Scholar 

  31. van der Meulen MA, van der Meulen MJ, te Meerman GJ. Recurrence risk for germinal mosaics revisited. J Med Genet. 1995;32(2):102–4.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Campbell IM, Yuan B, Robberecht C, et al. Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders. Am J Hum Genet. 2014;95(2):173–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Bakker E, Veenema H, Den Dunnen JT, et al. Germinal mosaicism increases the recurrence risk for ‘new’ Duchenne muscular dystrophy mutations. J Med Genet. 1989;26(9):553–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Helderman-van den Enden AT, de Jong R, den Dunnen JT, et al. Recurrence risk due to germ line mosaicism: Duchenne and Becker muscular dystrophy. Clin Genet. 2009;75(5):465–72.

  35. Conlin LK, Kramer W, Hutchinson AL, et al. Molecular analysis of ring chromosome 20 syndrome reveals two distinct groups of patients. J Med Genet. 2011;48(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  36. Hsu LY, Yu MT, Richkind KE, et al. Incidence and significance of chromosome mosaicism involving an autosomal structural abnormality diagnosed prenatally through amniocentesis: a collaborative study. Prenat Diagn. 1996;16(1):1–28.

    Article  CAS  PubMed  Google Scholar 

  37. Gijsbers AC, Dauwerse JG, Bosch CA, et al. Three new cases with a mosaicism involving a normal cell line and a cryptic unbalanced autosomal reciprocal translocation. Eur J Med Genet. Jul-Aug. 2011;54(4):e409–12.

    Article  Google Scholar 

  38. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. • Cheung SW, Shaw CA, Scott DA, et al. Microarray-based CGH detects chromosomal mosaicism not revealed by conventional cytogenetics. Am J Med Genet A. 2007;143A(15):1679–86. Important in demonstrating role of microarray to detect mosaic copy number variants.

  40. Ballif BC, Rorem EA, Sundin K, et al. Detection of low-level mosaicism by array CGH in routine diagnostic specimens. Am J Med Genet A. 2006;140(24):2757–67.

    Article  PubMed  Google Scholar 

  41. Conlin LK, Thiel BD, Bonnemann CG, et al. Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis. Hum Mol Genet. 2010;19(7):1263–75.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Cai X, Evrony GD, Lehmann HS, et al. Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep. 2014;8(5):1280–9.

  43. Poduri A, Evrony GD, Cai X, et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron. 2012;74(1):41–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Conti V, Pantaleo M, Barba C, et al. Focal dysplasia of the cerebral cortex and infantile spasms associated with somatic 1q21.1-q44 duplication including the AKT3 gene. Clin Genet. 2014. doi:10.1111/cge.12476.

  45. Liu J, Reeves C, Michalak Z, et al. Evidence for mTOR pathway activation in a spectrum of epilepsy-associated pathologies. Acta Neuropathol Commun. 2014;2:71.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Piotrowski A, Bruder CE, Andersson R, et al. Somatic mosaicism for copy number variation in differentiated human tissues. Hum Mutat. 2008;29(9):1118–24.

    Article  PubMed  Google Scholar 

  47. Bruder CE, Piotrowski A, Gijsbers AA, et al. Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am J Hum Genet. 2008;82(3):763–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Lee JH, Huynh M, Silhavy JL, et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet. 2012;44(8):941–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Riviere JB, Mirzaa GM, O’Roak BJ, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet. 2012;44(8):934–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Kurek KC, Luks VL, Ayturk UM, et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet. 2012;90(6):1108–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Couto JA, Vivero MP, Kozakewich HP, et al. A somatic MAP3K3 mutation is associated with verrucous venous malformation. Am J Hum Genet. 2015;96(3):480–6.

    Article  CAS  PubMed  Google Scholar 

  52. Kousoulidou L, Tanteles G, Moutafi M, Sismani C, Patsalis PC, Anastasiadou V. 263.4 kb deletion within the TCF4 gene consistent with Pitt–Hopkins syndrome, inherited from a mosaic parent with normal phenotype. Eur J Med Genet. 2013;56(6):314–8.

    Article  PubMed  Google Scholar 

  53. Topcu M, Akyerli C, Sayi A, et al. Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy. Eur J Hum Genet. Jan 2002;10(1):77–81.

    Article  CAS  PubMed  Google Scholar 

  54. Huisman SA, Redeker EJ, Maas SM, Mannens MM, Hennekam RC. High rate of mosaicism in individuals with Cornelia de Lange syndrome. J Med Genet. May 2013;50(5):339–44.

    Article  CAS  PubMed  Google Scholar 

  55. Ansari M, Poke G, Ferry Q, et al. Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism. J Med Genet. Oct 2014;51(10):659–68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Borgulova I, Mazanec R, Sakmaryova I, Havlova M, Safka Brozkova D, Seeman P. Mosaicism for GJB1 mutation causes milder Charcot–Marie–Tooth X1 phenotype in a heterozygous man than in a manifesting heterozygous woman. Neurogenetics. 2013;14(3–4):189–95.

    Article  CAS  PubMed  Google Scholar 

  57. Diebold B, Delepine C, Nectoux J, Bahi-Buisson N, Parent P, Bienvenu T. Somatic mosaicism for a FOXG1 mutation: diagnostic implication. Clin Genet. 2014;85(6):589–91.

    Article  CAS  PubMed  Google Scholar 

  58. Milh M, Lacoste C, Cacciagli P, et al. Variable clinical expression in patients with mosaicism for KCNQ2 mutations. Am J Med Genet A. 2015. doi:10.1002/ajmg.a.37152.

  59. Simons C, Rash LD, Crawford J, et al. Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy. Nat Genet. 2015;47(1):73–7.

    Article  CAS  PubMed  Google Scholar 

  60. Fu XJ, Nozu K, Kaito H, et al. Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome. Eur J Hum Genet. 2015. doi:10.1038/ejhg.2015.113.

  61. Rehen SK, Yung YC, McCreight MP, et al. Constitutional aneuploidy in the normal human brain. J Neurosci. 2005;25(9):2176–80.

    Article  CAS  PubMed  Google Scholar 

  62. •• Knouse KA, Wu J, Whittaker CA, Amon A. Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci USA. 2014;111(37):13409–14. Review on structural mosaic variants and techniques to detect mosaicism.

  63. Dumanski JP, Piotrowski A. Structural genetic variation in the context of somatic mosaicism. Methods Mol Biol. 2012;838:249–72.

    Article  CAS  PubMed  Google Scholar 

  64. Rodriguez-Santiago B, Malats N, Rothman N, et al. Mosaic uniparental disomies and aneuploidies as large structural variants of the human genome. Am J Hum Genet. 2010;87(1):129–38.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. • Pham J, Shaw C, Pursley A, et al. Somatic mosaicism detected by exon-targeted, high-resolution aCGH in 10,362 consecutive cases. Eur J Hum Genet. 2014;22(8):969–78. Used single cell sequencing to demonstrate that L1 retrotransposition is a rare event in human brain, unlike what was considered previously.

  66. • Evrony GD, Cai X, Lee E, et al. Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell. 2012;151(3):483–96. Used single cell sequencing to demonstrate somatic CNVs in “normal” human brain.

  67. Cai X, Evrony GD, Lehmann HS, et al. Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep. 2014;8(5):1280–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Pinheiro LB, Coleman VA, Hindson CM, et al. Evaluation of a droplet digital polymerase chain reaction format for DNA copy number quantification. Anal Chem. 2012;84(2):1003–11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Heyries KA, Tropini C, Vaninsberghe M, et al. Megapixel digital PCR. Nat Methods. 2011;8(8):649–51.

    Article  CAS  PubMed  Google Scholar 

  70. Abyzov A, Mariani J, Palejev D, et al. Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature. 2012;492(7429):438–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Rohlin A, Wernersson J, Engwall Y, Wiklund L, Bjork J, Nordling M. Parallel sequencing used in detection of mosaic mutations: comparison with four diagnostic DNA screening techniques. Hum Mutat. 2009;30(6):1012–20.

    Article  CAS  PubMed  Google Scholar 

  72. Ng SB, Turner EH, Robertson PD, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature. 2009;461(7261):272–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Ng SB, Buckingham KJ, Lee C, et al. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010;42(1):30–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Pagnamenta AT, Lise S, Harrison V, et al. Exome sequencing can detect pathogenic mosaic mutations present at low allele frequencies. J Hum Genet. 2012;57(1):70–2.

    Article  CAS  PubMed  Google Scholar 

  75. Pritchard CC, Smith C, Marushchak T, et al. A mosaic PTEN mutation causing Cowden syndrome identified by deep sequencing. Genet Med. 2013;15(12):1004–7.

    Article  CAS  PubMed  Google Scholar 

  76. Gilissen C, Hehir-Kwa JY, Thung DT, et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014;511(7509):344–7.

    Article  CAS  PubMed  Google Scholar 

  77. Tapper WJ, Foulds N, Cross NC, et al. Megalencephaly syndromes: exome pipeline strategies for detecting low-level mosaic mutations. PLoS ONE. 2014;9(1):e86940.

    Article  PubMed Central  PubMed  Google Scholar 

  78. Gabriel S, Ziaugra L, Tabbaa D. SNP genotyping using the Sequenom MassARRAY iPLEX platform. Curr Protoc Hum Genet. 2009;Chapter 2:Unit 2 12.

  79. Lee JH, Huynh M, Silhavy JL, et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet. 2012;44(8):941–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

Dr Saumya Shekhar Jamuar is supported by the Nurturing Clinician Scientist Scheme, Paediatrics Academic Clinical Programme, Singhealth Duke-NUS Graduate Medical School, Singapore.

Disclosure

TW Ting, R Shahdadpuri, and SS Jamuar all declare no conflicts of interest.

Human and Animal Rights and Informed Consent

All studies by Saumya Shekhar Jamuar involving animal and/or human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.

Author information

Authors and Affiliations

  1. Singhealth Duke-NUS Paediatric Academic Clinical Programme, Department of Paediatrics, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore, 229899, Singapore

    Teck Wah Ting, Raveen Shahdadpuri & Saumya Shekhar Jamuar

Authors
  1. Teck Wah Ting
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raveen Shahdadpuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saumya Shekhar Jamuar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Saumya Shekhar Jamuar.

Additional information

This article is part of the Topical Collection on Clinical Genetics.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ting, T.W., Shahdadpuri, R. & Jamuar, S.S. Mosaicism in Traditional Mendelian Diseases. Curr Genet Med Rep 3, 101–109 (2015). https://doi.org/10.1007/s40142-015-0071-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40142-015-0071-0

Keywords

Search

Navigation