|Title||The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Pehlivan, D, Beck, CR, Okamoto, Y, Harel, T, Akdemir, ZHC, Jhangiani, SN, Withers, MA, Goksungur, MTuba, Carvalho, CMB, Czesnik, D, Gonzaga-Jauregui, C, Wiszniewski, W, Muzny, DM, Gibbs, RA, Rautenstrauss, B, Sereda, MW, Lupski, JR|
|Date Published||2016 05|
|Keywords||Adult, Age of Onset, Charcot-Marie-Tooth Disease, Child, Preschool, Comparative Genomic Hybridization, DNA Copy Number Variations, Exome, Female, Genetic Predisposition to Disease, GTP Phosphohydrolases, High-Throughput Nucleotide Sequencing, Humans, Male, Mitochondrial Proteins, Motor Neurons, Myelin P0 Protein, Myelin Proteins, Neural Conduction, Polymorphism, Single Nucleotide, Polyneuropathies|
PURPOSE: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders of the peripheral nervous system. Copy-number variants (CNVs) contribute significantly to CMT, as duplication of PMP22 underlies the majority of CMT1 cases. We hypothesized that CNVs and/or single-nucleotide variants (SNVs) might exist in patients with CMT with an unknown molecular genetic etiology.
METHODS: Two hundred patients with CMT, negative for both SNV mutations in several CMT genes and for CNVs involving PMP22, were screened for CNVs by high-resolution oligonucleotide array comparative genomic hybridization. Whole-exome sequencing was conducted on individuals with rare, potentially pathogenic CNVs.
RESULTS: Putatively causative CNVs were identified in five subjects (~2.5%); four of the five map to known neuropathy genes. Breakpoint sequencing revealed Alu-Alu-mediated junctions as a predominant contributor. Exome sequencing identified MFN2 SNVs in two of the individuals.
CONCLUSION: Neuropathy-associated CNV outside of the PMP22 locus is rare in CMT. Nevertheless, there is potential clinical utility in testing for CNVs and exome sequencing in CMT cases negative for the CMT1A duplication. These findings suggest that complex phenotypes including neuropathy can potentially be caused by a combination of SNVs and CNVs affecting more than one disease-associated locus and contributing to a mutational burden.Genet Med 18 5, 443-451.
|Alternate Journal||Genet. Med.|
|PubMed Central ID||PMC5322766|
|Grant List||U54 HG006542 / HG / NHGRI NIH HHS / United States |
T32 GM007526 / GM / NIGMS NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
K23 NS078056 / NS / NINDS NIH HHS / United States
R01 GM106373 / GM / NIGMS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States