Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D

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 ha...

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Bibliographic Details
Published in:Genetics in medicine 2014-05, Vol.16 (5), p.386-394
Main Authors: Okamoto, Yuji, Goksungur, Meryem Tuba, Pehlivan, Davut, Beck, Christine R, Gonzaga-Jauregui, Claudia, Muzny, Donna M, Atik, Mehmed M, Carvalho, Claudia M B, Matur, Zeliha, Bayraktar, Serife, Boone, Philip M, Akyuz, Kaya, Gibbs, Richard A, Battaloglu, Esra, Parman, Yesim, Lupski, James R
Format: Article
Language:English
Subjects:
Adult
Base Sequence
Cell Cycle Proteins - genetics
Charcot-Marie-Tooth Disease - genetics
Comparative Genomic Hybridization
DNA Copy Number Variations - genetics
Female
Gene Duplication
Gene Expression
Genes
Genes, Recessive
Humans
Intracellular Signaling Peptides and Proteins - genetics
Male
Mutation
Refsum Disease - genetics
Sequence Analysis, DNA
Turkey
Young Adult
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Summary: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. 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. 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. 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.
ISSN:1098-3600
1530-0366
DOI:10.1038/gim.2013.155