title: Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D.
abstract: OBJECTIVE
  Copy-number variations as a mutational mechanism contribute significantly to human disease. Approximately one-half of the patients with Charcot-Marie-Tooth (CMT) disease have a 1.4 Mb duplication copy-number variation as the cause of their neuropathy. However, non-CMT1A neuropathy patients rarely have causative copy-number variations, and to date, autosomal-recessive disease has not been associated with copy-number variation as a mutational mechanism.
  
  
  METHODS
  We performed Agilent 8 × 60 K array comparative genomic hybridization on DNA from 12 recessive Turkish families with CMT disease. Additional molecular studies were conducted to detect breakpoint junctions and to evaluate gene expression levels in a family in which we detected an intragenic duplication copy-number variation.
  
  
  RESULTS
  We detected an ~6.25 kb homozygous intragenic duplication in NDRG1, a gene known to be causative for recessive HMSNL/CMT4D, in three individuals from a Turkish family with CMT neuropathy. Further studies showed that this intragenic copy-number variation resulted in a homozygous duplication of exons 6-8 that caused decreased mRNA expression of NDRG1.
  
  
  CONCLUSIONS
  Exon-focused high-resolution array comparative genomic hybridization enables the detection of copy-number variation carrier states in recessive genes, particularly small copy-number variations encompassing or disrupting single genes. In families for whom a molecular diagnosis has not been elucidated by conventional clinical assays, an assessment for copy-number variations in known CMT genes might be considered.
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 Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
authors.forename: Meryem Tuba
authors.initials: MT
authors.lastname: Goksungur
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, 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: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
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: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Mehmed M
authors.initials: MM
authors.lastname: Atik
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Claudia M B
authors.initials: CMB
authors.lastname: Carvalho
authors.affiliation: Department of Neurology, Istanbul Bilim University, Faculty of Medicine, Istanbul, Turkey.
authors.forename: Zeliha
authors.initials: Z
authors.lastname: Matur
authors.affiliation: Department of Opthalmology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
authors.forename: Serife
authors.initials: S
authors.lastname: Bayraktar
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Boone
authors.affiliation: Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey.
authors.forename: Kaya
authors.initials: K
authors.lastname: Akyuz
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: Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Battaloglu
authors.affiliation: Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
authors.forename: Yesim
authors.initials: Y
authors.lastname: Parman
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; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020440:Gene Duplication; D015870:Gene Expression; D005808:Genes, Recessive; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation; D012035:Refsum Disease / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014421:Turkey; D055815:Young Adult; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein