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

Author(s)
Yuji Okamoto, Meryem Tuba Goksungur, Davut Pehlivan, Christine R. Beck, Claudia Gonzaga-Jauregui, Donna M. Muzny, Mehmed M. Atik, Claudia M B Carvalho, Zeliha Matur, Serife Bayraktar, Philip M. Boone, Kaya Akyuz, Richard A. Gibbs, Esra Battaloglu, Yesim Parman, James R. Lupski
Abstract

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 × 60K 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.

Organisation(s)
External organisation(s)
Baylor College of Medicine, Istanbul University, Istanbul Bilim University, Boğaziçi University (BU), Texas Children's Hospital Houston
Journal
Genetics in Medicine
Volume
16
Pages
386-394
No. of pages
9
ISSN
1098-3600
DOI
https://doi.org/10.1038/gim.2013.155
Publication date
2014
Peer reviewed
Yes
Austrian Fields of Science 2012
Genetics
Keywords
ASJC Scopus subject areas
,
Portal url
https://ucris.univie.ac.at/portal/en/publications/exonic-duplication-cnv-of-ndrg1-associated-with-autosomalrecessive-hmsnlomcmt4d(be77075c-f4ef-4784-a63c-0bae59b85cd7).html