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.
Copy number variation Charcot-Marie-Tooth disease CMT1A Peripheral neuropathies
This is a preview of subscription content, log in to check access.
This study was supported by the National Institute of Neurological Disorders and Stroke (5R01NS052767-04, to S.Z.) and the Charcot-Marie-Tooth Association (to S.Z.).
Walsh T (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320:539–543CrossRefPubMedGoogle Scholar
Xu B (2008) Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet 40:880–885CrossRefPubMedGoogle Scholar
The International Schizophrenia Consortium (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455:237–241CrossRefGoogle Scholar
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
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
Patel PI, Isaya G (2001) Friedreich ataxia: from GAA triplet-repeat expansion to frataxin deficiency. Am J Hum Genet 69:15–24CrossRefPubMedGoogle Scholar
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