Copy Number Variations in a Population-Based Study of Charcot-Marie-Tooth Disease

Copy number variations (CNVs) are important in relation to diversity and evolution but can sometimes cause disease. The most common genetic cause of the inherited peripheral neuropathy Charcot-Marie-Tooth disease is thePMP22duplication; otherwise, CNVs have been considered rare. We investigated CNVs in a population-based sample of Charcot-Marie-Tooth (CMT) families. The 81 CMT families had previously been screened for thePMP22duplication and point mutations in 51 peripheral neuropathy genes, and a genetic cause was identified in 37 CMT families (46%). Index patients from the 44 CMT families with an unknown genetic diagnosis were analysed by whole-genome array comparative genomic hybridization to investigate the entire genome for larger CNVs and multiplex ligation-dependent probe amplification to detect smaller intragenomic CNVs inMFN2andMPZ. One patient had the pathogenicPMP22duplication not detected by previous methods. Three patients had potentially pathogenic CNVs in theCNTNAP2,LAMA2, orSEMA5A, that is, genes related to neuromuscular or neurodevelopmental disease. Genotype and phenotype correlation indicated likely pathogenicity for theLAMA2CNV, whereas theCNTNAP2andSEMA5ACNVs remained potentially pathogenic. Except thePMP22duplication, disease causing CNVs are rare but may cause CMT in about 1% (95% CI 0–7%) of the Norwegian CMT families.