The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy

Davut Pehlivan, Christine R. Beck, Yuji Okamoto, Tamar Harel, Zeynep H C Akdemir, Shalini N. Jhangiani, Marjorie A. Withers, Meryem Tuba Goksungur, Claudia M B Carvalho, Dirk Czesnik, Claudia Gonzaga-Jauregui, Wojciech Wiszniewski, Donna M. Muzny, Richard A. Gibbs, Bernd Rautenstrauss, Michael W. Sereda, James R. Lupski

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)443-451
Number of pages9
JournalGenetics in Medicine
Volume18
Issue number5
DOIs
StatePublished - May 1 2016
Externally publishedYes

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Polyneuropathies
Tooth
Nucleotides
Exome
Charcot-Marie-Tooth Disease
Inborn Genetic Diseases
Comparative Genomic Hybridization
Gene Dosage
Peripheral Nervous System
Oligonucleotide Array Sequence Analysis
Molecular Biology
Phenotype
Mutation
Genes

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Pehlivan, D., Beck, C. R., Okamoto, Y., Harel, T., Akdemir, Z. H. C., Jhangiani, S. N., ... Lupski, J. R. (2016). The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy. Genetics in Medicine, 18(5), 443-451. https://doi.org/10.1038/gim.2015.124

The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy. / Pehlivan, Davut; Beck, Christine R.; Okamoto, Yuji; Harel, Tamar; Akdemir, Zeynep H C; Jhangiani, Shalini N.; Withers, Marjorie A.; Goksungur, Meryem Tuba; Carvalho, Claudia M B; Czesnik, Dirk; Gonzaga-Jauregui, Claudia; Wiszniewski, Wojciech; Muzny, Donna M.; Gibbs, Richard A.; Rautenstrauss, Bernd; Sereda, Michael W.; Lupski, James R.

In: Genetics in Medicine, Vol. 18, No. 5, 01.05.2016, p. 443-451.

Research output: Contribution to journalArticle

Pehlivan, D, Beck, CR, Okamoto, Y, Harel, T, Akdemir, ZHC, Jhangiani, SN, Withers, MA, Goksungur, MT, Carvalho, CMB, Czesnik, D, Gonzaga-Jauregui, C, Wiszniewski, W, Muzny, DM, Gibbs, RA, Rautenstrauss, B, Sereda, MW & Lupski, JR 2016, 'The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy', Genetics in Medicine, vol. 18, no. 5, pp. 443-451. https://doi.org/10.1038/gim.2015.124
Pehlivan D, Beck CR, Okamoto Y, Harel T, Akdemir ZHC, Jhangiani SN et al. The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy. Genetics in Medicine. 2016 May 1;18(5):443-451. https://doi.org/10.1038/gim.2015.124
Pehlivan, Davut ; Beck, Christine R. ; Okamoto, Yuji ; Harel, Tamar ; Akdemir, Zeynep H C ; Jhangiani, Shalini N. ; Withers, Marjorie A. ; Goksungur, Meryem Tuba ; Carvalho, Claudia M B ; Czesnik, Dirk ; Gonzaga-Jauregui, Claudia ; Wiszniewski, Wojciech ; Muzny, Donna M. ; Gibbs, Richard A. ; Rautenstrauss, Bernd ; Sereda, Michael W. ; Lupski, James R. / The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy. In: Genetics in Medicine. 2016 ; Vol. 18, No. 5. pp. 443-451.
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AU - Harel, Tamar

AU - Akdemir, Zeynep H C

AU - Jhangiani, Shalini N.

AU - Withers, Marjorie A.

AU - Goksungur, Meryem Tuba

AU - Carvalho, Claudia M B

AU - Czesnik, Dirk

AU - Gonzaga-Jauregui, Claudia

AU - Wiszniewski, Wojciech

AU - Muzny, Donna M.

AU - Gibbs, Richard A.

AU - Rautenstrauss, Bernd

AU - Sereda, Michael W.

AU - Lupski, James R.

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N2 - 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.

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