Journal of Neurology

, Volume 257, Issue 5, pp 735–741 | Cite as

Copy number variations are a rare cause of non-CMT1A Charcot-Marie-Tooth disease

  • Jia Huang
  • Xingyao Wu
  • Gladys Montenegro
  • Justin Price
  • Gaofeng Wang
  • Jeffery M. Vance
  • Michael E. Shy
  • Stephan Züchner
Original Communication

Abstract

Hereditary peripheral neuropathies present a group of clinically and genetically heterogeneous entities. All known forms, including the various forms of Charcot-Marie-Tooth disease (CMT) are characterized as Mendelian traits and over 35 genes have been identified thus far. The mutational mechanism of the most common CMT type, CMT1A, is a 1.5 Mb chromosomal duplication at 17p12 that contains the gene PMP22. Only recently it has been realized that such copy number variants (CNV) are a widespread phenomenon and important for disease. However, it is not known whether CNVs play a wider role in hereditary peripheral neuropathies outside of CMT1A. In a phenotypically heterogeneous sample of 97 patients, we performed the first high-density CNV study of 34 genomic regions harboring known genes for hereditary peripheral neuropathies including the 17p12 duplication region, with comparative genomic hybridization (CGH) microarrays. We identified three CNVs that affected coding exons. A novel shorter form of a PMP22 duplication was detected in a CMT1A family previously tested negative in a commercial test. Two other CNVs in MTMR2 and ARHGEF10 are likely not disease associated. Our results indicate that CNVs are a rare cause for non-CMT1A CMT. Their potential relevance as disease modifiers remains to be evaluated. The present study design cannot rule out that specific CMT forms exist where CNVs play a larger role.

Keywords

Copy number variation Charcot-Marie-Tooth disease CMT1A Peripheral neuropathies 

Supplementary material

415_2009_5401_MOESM1_ESM.pdf (12 kb)
Supplementary material 1 (PDF 12 kb)
415_2009_5401_MOESM2_ESM.pdf (11 kb)
Supplementary material 2 (PDF 11 kb)
415_2009_5401_MOESM3_ESM.pdf (67 kb)
Supplementary material 3 (PDF 66 kb)

References

  1. 1.
    Skre H (1974) Genetic and clinical aspects of Charcot-Marie-Tooth’s disease. Clin Genet 6:98–118PubMedCrossRefGoogle Scholar
  2. 2.
    Chance PF, Alderson MK, Leppig KA et al (1993) DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell 72:143–151CrossRefPubMedGoogle Scholar
  3. 3.
    Lupski JR, de Oca-Luna RM, Slaugenhaupt S et al (1991) DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66:219–232CrossRefPubMedGoogle Scholar
  4. 4.
    Iafrate AJ, Feuk L, Rivera MN et al (2004) Detection of large-scale variation in the human genome. Nat Genet 36:949–951CrossRefPubMedGoogle Scholar
  5. 5.
    Redon R, Ishikawa S, Fitch KR et al (2006) Global variation in copy number in the human genome. Nature 444:444–454CrossRefPubMedGoogle Scholar
  6. 6.
    Sebat J, Lakshmi B, Troge J et al (2004) Large-scale copy number polymorphism in the human genome. Science 305:525–528CrossRefPubMedGoogle Scholar
  7. 7.
    Sebat J (2007) Strong association of de novo copy number mutations with autism. Science 316:445–449CrossRefPubMedGoogle Scholar
  8. 8.
    Marshall CR (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82:477–488CrossRefPubMedGoogle Scholar
  9. 9.
    Morrow EM (2008) Identifying autism loci and genes by tracing recent shared ancestry. Science 321:218–223CrossRefPubMedGoogle Scholar
  10. 10.
    Stefansson H (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455:232–236CrossRefPubMedGoogle Scholar
  11. 11.
    Walsh T (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320:539–543CrossRefPubMedGoogle Scholar
  12. 12.
    Xu B (2008) Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet 40:880–885CrossRefPubMedGoogle Scholar
  13. 13.
    The International Schizophrenia Consortium (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455:237–241CrossRefGoogle Scholar
  14. 14.
    Beetz C Fau-Nygren AOH, Nygren Ao Fau-Schickel J, Schickel J Fau-Auer-Grumbach M et al (2006) High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia. Neurology 66(3):421–423Google Scholar
  15. 15.
    Verhoeven K, De Jonghe P, Van de Putte T et al (2003) Slowed conduction and thin myelination of peripheral nerves associated with mutant rho Guanine-nucleotide exchange factor 10. Am J Hum Genet 73:926–932CrossRefPubMedGoogle Scholar
  16. 16.
    Patel PI, Isaya G (2001) Friedreich ataxia: from GAA triplet-repeat expansion to frataxin deficiency. Am J Hum Genet 69:15–24CrossRefPubMedGoogle Scholar
  17. 17.
    Pentao L, Wise CA, Chinault AC, Patel PI, Lupski JR (1992) Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nat Genet 2:292–300CrossRefPubMedGoogle Scholar
  18. 18.
    Gu W, Zhang F, Lupski JR (2008) Mechanisms for human genomic rearrangements. Pathogenetics 1:4CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Jia Huang
    • 1
  • Xingyao Wu
    • 2
  • Gladys Montenegro
    • 1
  • Justin Price
    • 1
  • Gaofeng Wang
    • 1
  • Jeffery M. Vance
    • 1
  • Michael E. Shy
    • 2
  • Stephan Züchner
    • 1
    • 3
  1. 1.Hussman Institute for Human Genomics, Miller School of MedicineUniversity of MiamiMiamiUSA
  2. 2.Department of Neurology, School of MedicineWayne State UniversityDetroitUSA
  3. 3.Department of Human Genetics, Hussman Institute for Human GenomicsUniversity of Miami Miller School of MedicineMiamiUSA

Personalised recommendations