Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing
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 dis...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2013
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| Online Access: | http://hdl.handle.net/1721.1/80712 https://orcid.org/0000-0001-8567-2049 |
| _version_ | 1811085504770211840 |
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| author | Kirby, Andrew Gnirke, Andreas Jaffe, David B. Baresova, Veronika Pochet, Nathalie Blumenstiel, Brendan Ye, Chun Aird, Daniel Stevens, Christine Robinson, James T. Cabili, Moran N. Gat-Viks, Irit Kelliher, Edward Daza, Riza DeFelice, Matthew Hulkova, Helena Sovova, Jana Vylet'al, Petr Antignac, Corinne Guttman, Mitchell Handsaker, Robert E. Perrin, Danielle Steelman, Scott Sigurdsson, Snaevar Scheinman, Steven J. Sougnez, Carrie Cibulskis, Kristian Parkin, Melissa Green, Todd Rossin, Elizabeth Zody, Michael C. Xavier, Ramnik J. Pollak, Martin R. Alper, Seth L. Lindblad-Toh, Kerstin Gabriel, Stacey B. Hart, P. Suzanne Regev, Aviv Nusbaum, Chad Kmoch, Stanislav Bleyer, Anthony J. Daly, Mark J. Lander, Eric Steven |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Kirby, Andrew Gnirke, Andreas Jaffe, David B. Baresova, Veronika Pochet, Nathalie Blumenstiel, Brendan Ye, Chun Aird, Daniel Stevens, Christine Robinson, James T. Cabili, Moran N. Gat-Viks, Irit Kelliher, Edward Daza, Riza DeFelice, Matthew Hulkova, Helena Sovova, Jana Vylet'al, Petr Antignac, Corinne Guttman, Mitchell Handsaker, Robert E. Perrin, Danielle Steelman, Scott Sigurdsson, Snaevar Scheinman, Steven J. Sougnez, Carrie Cibulskis, Kristian Parkin, Melissa Green, Todd Rossin, Elizabeth Zody, Michael C. Xavier, Ramnik J. Pollak, Martin R. Alper, Seth L. Lindblad-Toh, Kerstin Gabriel, Stacey B. Hart, P. Suzanne Regev, Aviv Nusbaum, Chad Kmoch, Stanislav Bleyer, Anthony J. Daly, Mark J. Lander, Eric Steven |
| author_sort | Kirby, Andrew |
| collection | MIT |
| description | 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 (~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. |
| first_indexed | 2024-09-23T13:10:38Z |
| format | Article |
| id | mit-1721.1/80712 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:10:38Z |
| publishDate | 2013 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/807122022-09-28T12:24:42Z Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing Kirby, Andrew Gnirke, Andreas Jaffe, David B. Baresova, Veronika Pochet, Nathalie Blumenstiel, Brendan Ye, Chun Aird, Daniel Stevens, Christine Robinson, James T. Cabili, Moran N. Gat-Viks, Irit Kelliher, Edward Daza, Riza DeFelice, Matthew Hulkova, Helena Sovova, Jana Vylet'al, Petr Antignac, Corinne Guttman, Mitchell Handsaker, Robert E. Perrin, Danielle Steelman, Scott Sigurdsson, Snaevar Scheinman, Steven J. Sougnez, Carrie Cibulskis, Kristian Parkin, Melissa Green, Todd Rossin, Elizabeth Zody, Michael C. Xavier, Ramnik J. Pollak, Martin R. Alper, Seth L. Lindblad-Toh, Kerstin Gabriel, Stacey B. Hart, P. Suzanne Regev, Aviv Nusbaum, Chad Kmoch, Stanislav Bleyer, Anthony J. Daly, Mark J. Lander, Eric Steven Massachusetts Institute of Technology. Department of Biology Regev, Aviv Lander, Eric S. Regev, Aviv 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 (~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. National Institutes of Health (U.S.) (Intramural Research Program) National Human Genome Research Institute (U.S.) Charles University (program UNCE 204011) Charles University (program PRVOUK-P24/LF1/3) Czech Republic. Ministry of Education, Youth, and Sports (grant NT13116-4/2012) Czech Republic. Ministry of Health (grant NT13116-4/2012) Czech Republic. Ministry of Health (grant LH12015) National Institutes of Health (U.S.) (Harvard Digestive Diseases Center, grant DK34854) 2013-09-13T14:10:11Z 2013-09-13T14:10:11Z 2013-02 2012-05 Article http://purl.org/eprint/type/JournalArticle 1061-4036 1546-1718 http://hdl.handle.net/1721.1/80712 Kirby, Andrew, Andreas Gnirke, David B Jaffe, Veronika Barešová, Nathalie Pochet, Brendan Blumenstiel, Chun Ye, 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, no. 3 (February 10, 2013): 299-303. https://orcid.org/0000-0001-8567-2049 en_US http://dx.doi.org/10.1038/ng.2543 Nature Genetics Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Nature Publishing Group Regev via Courtney Crummett |
| spellingShingle | Kirby, Andrew Gnirke, Andreas Jaffe, David B. Baresova, Veronika Pochet, Nathalie Blumenstiel, Brendan Ye, Chun Aird, Daniel Stevens, Christine Robinson, James T. Cabili, Moran N. Gat-Viks, Irit Kelliher, Edward Daza, Riza DeFelice, Matthew Hulkova, Helena Sovova, Jana Vylet'al, Petr Antignac, Corinne Guttman, Mitchell Handsaker, Robert E. Perrin, Danielle Steelman, Scott Sigurdsson, Snaevar Scheinman, Steven J. Sougnez, Carrie Cibulskis, Kristian Parkin, Melissa Green, Todd Rossin, Elizabeth Zody, Michael C. Xavier, Ramnik J. Pollak, Martin R. Alper, Seth L. Lindblad-Toh, Kerstin Gabriel, Stacey B. Hart, P. Suzanne Regev, Aviv Nusbaum, Chad Kmoch, Stanislav Bleyer, Anthony J. Daly, Mark J. Lander, Eric Steven Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing |
| title | Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing |
| title_full | Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing |
| title_fullStr | Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing |
| title_full_unstemmed | Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing |
| title_short | Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing |
| title_sort | mutations causing medullary cystic kidney disease type 1 lie in a large vntr in muc1 missed by massively parallel sequencing |
| url | http://hdl.handle.net/1721.1/80712 https://orcid.org/0000-0001-8567-2049 |
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