title: The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Section of Pediatric Neurology, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Davut
authors.initials: D
authors.lastname: Pehlivan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Christine R
authors.initials: CR
authors.lastname: Beck
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Harel
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Zeynep H C
authors.initials: ZH
authors.lastname: Akdemir
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Marjorie A
authors.initials: MA
authors.lastname: Withers
authors.affiliation: Department of Neurology, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey.
authors.forename: Meryem Tuba
authors.identifier: 0000-0003-4418-7906
authors.initials: MT
authors.lastname: Goksungur
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.affiliation: Department of Clinical Neurophysiology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Czesnik
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wiszniewski
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Medizinisch Genetisches Zentrum, Munich, Germany.|Deceased; Obituary-Neuromuscular Disorders 2015;25:725-726..
authors.forename: Bernd
authors.initials: B
authors.lastname: Rautenstrauss
authors.affiliation: Department of Clinical Neurophysiology, University Medical Center Göttingen, Göttingen, Germany.|Max-Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sereda
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.|Texas Children's Hospital, Houston, Texas, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000328:Adult; D017668:Age of Onset; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics*; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D018993:Myelin P0 Protein / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011115:Polyneuropathies / Q000235:genetics* / Q000503:physiopathology
chemical_list: C560547:MPZ protein, human; D024101:Mitochondrial Proteins; D018993:Myelin P0 Protein; D009185:Myelin Proteins; C073687:PMP22 protein, human; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human