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Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing

(2013) NATURE GENETICS. 45(3). p.299-303
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Abstract
Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (similar to 1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing.
Keywords
LINKAGE, LOCUS, MCKD1, GENETIC DIAGNOSIS, REFINEMENT, CHROMOSOME 1Q21, MAP

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Chicago
Kirby, Andrew, Andreas Gnirke, David B Jaffe, Veronika Barešová, Nathalie Pochet, Brendan Blumenstiel, Chun Ye, et al. 2013. “Mutations Causing Medullary Cystic Kidney Disease Type 1 Lie in a Large VNTR in MUC1 Missed by Massively Parallel Sequencing.” Nature Genetics 45 (3): 299–303.
APA
Kirby, A., Gnirke, A., Jaffe, D. B., Barešová, V., Pochet, N., Blumenstiel, B., Ye, C., et al. (2013). Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. NATURE GENETICS, 45(3), 299–303.
Vancouver
1.
Kirby A, Gnirke A, Jaffe DB, Barešová V, Pochet N, Blumenstiel B, et al. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. NATURE GENETICS. 2013;45(3):299–303.
MLA
Kirby, Andrew et al. “Mutations Causing Medullary Cystic Kidney Disease Type 1 Lie in a Large VNTR in MUC1 Missed by Massively Parallel Sequencing.” NATURE GENETICS 45.3 (2013): 299–303. Print.
@article{4294558,
  abstract     = {Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (similar to 1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing.},
  author       = {Kirby, Andrew and Gnirke, Andreas and Jaffe, David B and Barešová, Veronika and Pochet, Nathalie and Blumenstiel, Brendan and Ye, Chun and Aird, Daniel and Stevens, Christine and Robinson, James T and Cabili, Moran N and Gat-Viks, Irit and Kelliher, Edward and Daza, Riza and DeFelice, Matthew and Hůlková, Helena and Sovová, Jana and Vylet'al, Petr and Antignac, Corinne and Guttman, Mitchell and Handsaker, Robert E and Perrin, Danielle and Steelman, Scott and Sigurdsson, Snaevar and Scheinman, Steven J and Sougnez, Carrie and Cibulskis, Kristian and Parkin, Melissa and Green, Todd and Rossin, Elizabeth and Zody, Michael C and Xavier, Ramnik J and Pollak, Martin R and Alper, Seth L and Lindblad-Toh, Kerstin and Gabriel, Stacey and Hart, P Suzanne and Regev, Aviv and Nusbaum, Chad and Kmoch, Stanislav and Bleyer, Anthony J and Lander, Eric S and Daly, Mark J},
  issn         = {1061-4036},
  journal      = {NATURE GENETICS},
  keywords     = {LINKAGE,LOCUS,MCKD1,GENETIC DIAGNOSIS,REFINEMENT,CHROMOSOME 1Q21,MAP},
  language     = {eng},
  number       = {3},
  pages        = {299--303},
  title        = {Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing},
  url          = {http://dx.doi.org/10.1038/ng.2543},
  volume       = {45},
  year         = {2013},
}

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