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Genet Med. 2014 May;16(5):386-394. doi: 10.1038/gim.2013.155. Epub 2013 Oct 17.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
2
Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
3
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
4
Department of Neurology, Istanbul Bilim University, Faculty of Medicine, Istanbul, Turkey.
5
Department of Opthalmology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
6
Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey.
7
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
8
Texas Children's Hospital, Houston, Texas, USA.
#
Contributed equally

Erratum in

  • Genet Med. 2014 Feb;16(2):203.

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 × 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.

PMID:
24136616
PMCID:
PMC4224029
DOI:
10.1038/gim.2013.155
[Indexed for MEDLINE]
Free PMC Article

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