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

TitleExonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D.
Publication TypeJournal Article
Year of Publication2014
AuthorsOkamoto, Y, Goksungur, MTuba, Pehlivan, D, Beck, CR, Gonzaga-Jauregui, C, Muzny, DM, Atik, MM, Carvalho, CMB, Matur, Z, Bayraktar, S, Boone, PM, Akyuz, K, Gibbs, RA, Battaloglu, E, Parman, Y, Lupski, JR
JournalGenet Med
Date Published2014 May
KeywordsAdult, Base Sequence, Cell Cycle Proteins, Charcot-Marie-Tooth Disease, Comparative Genomic Hybridization, DNA Copy Number Variations, Female, Gene Duplication, Gene Expression, Genes, Recessive, Humans, Intracellular Signaling Peptides and Proteins, Male, Mutation, Refsum Disease, Sequence Analysis, DNA, Turkey, Young Adult

PURPOSE: 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.

CONCLUSION: 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.

Alternate JournalGenet. Med.
PubMed ID24136616
PubMed Central IDPMC4224029
Grant ListU54-HG003273 / HG / NHGRI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 NS058529 / NS / NINDS NIH HHS / United States