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

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J Neurol. 2009 Dec 1.

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

disease.

Huang J, Wu X, Montenegro G, Price J, Wang G, Vance JM, Shy ME, Züchner S.

Hussman Institute for Human Genomics, School of Medicine, University of

Miami, Miami, USA.

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.