title: Copy number variations in a population-based study of Charcot-Marie-Tooth disease.
abstract: 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 the PMP22 duplication; 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 the PMP22 duplication 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 in MFN2 and MPZ. One patient had the pathogenic PMP22 duplication not detected by previous methods. Three patients had potentially pathogenic CNVs in the CNTNAP2, LAMA2, or SEMA5A, that is, genes related to neuromuscular or neurodevelopmental disease. Genotype and phenotype correlation indicated likely pathogenicity for the LAMA2 CNV, whereas the CNTNAP2 and SEMA5A CNVs remained potentially pathogenic. Except the PMP22 duplication, disease causing CNVs are rare but may cause CMT in about 1% (95% CI 0-7%) of the Norwegian CMT families.
authors: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway ; Head and Neck Research Group, Research Centre, Akershus University Hospital, 1478 Lørenskog, Norway ; Campus Akershus University Hospital, University of Oslo, 1474 Nordbyhagen, Norway.
authors: Helle
authors: H
authors: Høyer
authors: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway ; Head and Neck Research Group, Research Centre, Akershus University Hospital, 1478 Lørenskog, Norway ; Campus Akershus University Hospital, University of Oslo, 1474 Nordbyhagen, Norway.
authors: Geir J
authors: GJ
authors: Braathen
authors: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway.
authors: Anette K
authors: AK
authors: Eek
authors: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway.
authors: Gry B N
authors: GB
authors: Nordang
authors: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway.
authors: Camilla F
authors: CF
authors: Skjelbred
authors: Head and Neck Research Group, Research Centre, Akershus University Hospital, 1478 Lørenskog, Norway ; Campus Akershus University Hospital, University of Oslo, 1474 Nordbyhagen, Norway.
authors: Michael B
authors: MB
authors: Russell
mesh_terms: D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002648:Child; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D005838:Genotype; D006801:Humans; D007797:Laminin / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010523:Peripheral Nervous System Diseases / Q000235:genetics; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D039961:Semaphorins
chemical_list: C403049:CNTNAP2 protein, human; D007797:Laminin; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C491228:SEMA5A protein, human; D039961:Semaphorins; C102645:laminin alpha 2
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