Yuji Okamoto1, Meryem Tuba Goksungur2, Davut Pehlivan1, Christine R Beck1, Claudia Gonzaga-Jauregui1, Donna M Muzny3, Mehmed M Atik1, Claudia M B Carvalho1, Zeliha Matur4, Serife Bayraktar5, Philip M Boone1, Kaya Akyuz6, Richard A Gibbs3, Esra Battaloglu6, Yesim Parman2, James R Lupski1,3,7,8. 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.
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.
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.
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