@article {285, title = {Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D.}, journal = {Genet Med}, volume = {16}, year = {2014}, month = {2014 May}, pages = {386-394}, 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 {\texttimes} 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.

}, keywords = {Adult, 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}, issn = {1530-0366}, doi = {10.1038/gim.2013.155}, author = {Okamoto, Yuji and Goksungur, Meryem Tuba and Pehlivan, Davut and Beck, Christine R and Gonzaga-Jauregui, Claudia and Muzny, Donna M and Atik, Mehmed M and Carvalho, Claudia M B and Matur, Zeliha and Bayraktar, Serife and Boone, Philip M and Akyuz, Kaya and Gibbs, Richard A and Battaloglu, Esra and Parman, Yesim and Lupski, James R} } @article {301, title = {Deletions of recessive disease genes: CNV contribution to carrier states and disease-causing alleles.}, journal = {Genome Res}, volume = {23}, year = {2013}, month = {2013 Sep}, pages = {1383-94}, abstract = {

Over 1200 recessive disease genes have been described in humans. The prevalence, allelic architecture, and per-genome load of pathogenic alleles in these genes remain to be fully elucidated, as does the contribution of DNA copy-number variants (CNVs) to carrier status and recessive disease. We mined CNV data from 21,470 individuals obtained by array-comparative genomic hybridization in a clinical diagnostic setting to identify deletions encompassing or disrupting recessive disease genes. We identified 3212 heterozygous potential carrier deletions affecting 419 unique recessive disease genes. Deletion frequency of these genes ranged from one occurrence to 1.5\%. When compared with recessive disease genes never deleted in our cohort, the 419 recessive disease genes affected by at least one carrier deletion were longer and located farther from known dominant disease genes, suggesting that the formation and/or prevalence of carrier CNVs may be affected by both local and adjacent genomic features and by selection. Some subjects had multiple carrier CNVs (307 subjects) and/or carrier deletions encompassing more than one recessive disease gene (206 deletions). Heterozygous deletions spanning multiple recessive disease genes may confer carrier status for multiple single-gene disorders, for complex syndromes resulting from the combination of two or more recessive conditions, or may potentially cause clinical phenotypes due to a multiply heterozygous state. In addition to carrier mutations, we identified homozygous and hemizygous deletions potentially causative for recessive disease. We provide further evidence that CNVs contribute to the allelic architecture of both carrier and recessive disease-causing mutations. Thus, a complete recessive carrier screening method or diagnostic test should detect CNV alleles.

}, keywords = {Alleles, Comparative Genomic Hybridization, Databases, Genetic, DNA Copy Number Variations, Gene Deletion, Gene Frequency, Genes, Dominant, Genes, Recessive, Genetic Diseases, Inborn, Homozygote, Humans}, issn = {1549-5469}, doi = {10.1101/gr.156075.113}, author = {Boone, Philip M and Campbell, Ian M and Baggett, Brett C and Soens, Zachry T and Rao, Mitchell M and Hixson, Patricia M and Patel, Ankita and Bi, Weimin and Cheung, Sau Wai and Lalani, Seema R and Beaudet, Arthur L and Stankiewicz, Pawel and Shaw, Chad A and Lupski, James R} }