The genetic contribution of copy number variants to hereditary peripheral neurop

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(Oral presentation at the Antwerp Consortium July 2009)

The genetic contribution of copy number variants to hereditary peripheral

neuropathies.

J. Huang1, J. Pn•ce1,G. MontenegrIo, G. Wlang, X. Wu2 ,J. Vance1, M. Shy2

andS.Ziichner1 IMiami Institute for Human Genomics, School of Medicine,

University of Miami,USA; 2Department of

Neurology, School of Medicine, Wayne State University, USA

Background: Hereditary peripheral neuropathies present a group of clinically and

genetically heterogeneous entities.. All known formss, including the various

forms of Charcot-Marie-Tooth disease (CMT) are chacterized as Mendelian traits

and over 30 genes have been

identified thus far. It is well known that copy number variants (CNV) may

involved in many diseases, including CMT type IA, We speculate that hereditary

peripheral neuropathy patients without missense mutations might instead carry

rare CNVs in known genes, causing

the disease phenotype.

Methods: In this study, we performed the first high-density CNV study in CMT

tageting 34 genomic regions hmboring known genes fOr hereditamy peripheral

neuropathies, including the 17pl2 duplication region. We screened a sample of 97

clinically heterogeneous index

patients applying custom NimbleGen 4-plex 385K CGH arrays. All results were

confirmed byqPCR.

Results: We identified common and rare CNVs, of which five affect coding exons

of CMT genes. We identified six CNVs that affected coding exons. A novel shorter

form of a PMP22 duplication was detected in a CMTIA family previously tested

negative in a commercial test. Moreover, we have evidence that this CNV

represents a triplication of the PMP22 gene. Two other CNVs in MTMR2 and

ARHGEFIO are likely not disease associated. Our results indicate that CNVs are a

rare cause for CMT. Their potential relevance as disease modifiers

remains to be evaluated. The present study design cannot rule out that specific

CMT forms exist were CNVs play a larger role.