Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing
Autor: | Martin R. Pollak, Kerstin Lindblad-Toh, Helena Hůlková, Matthew Defelice, Veronika Baresova, Chun Ye, Melissa Parkin, James T. Robinson, Ramnik J. Xavier, Scott Steelman, Mark J. Daly, Eric S. Lander, Danielle Perrin, Corinne Antignac, Edward Kelliher, Seth L. Alper, Michael C. Zody, Aviv Regev, Robert E. Handsaker, David B. Jaffe, Jana Sovová, Brendan Blumenstiel, Todd Green, Irit Gat-Viks, Petr Vylet'al, Christine Stevens, Mitchell Guttman, Nathalie Pochet, Carrie Sougnez, Snaevar Sigurdsson, Chad Nusbaum, Moran N. Cabili, Steven J. Scheinman, Anthony J. Bleyer, Elizabeth J. Rossin, Daniel Aird, Kristian Cibulskis, Andreas Gnirke, Stacey Gabriel, P. Suzanne Hart, Stanislav Kmoch, Andrew Kirby, Riza M. Daza |
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Přispěvatelé: | Massachusetts Institute of Technology. Department of Biology, Regev, Aviv, Lander, Eric S. |
Rok vydání: | 2013 |
Předmět: |
Male
Kidney Disease Genetic Linkage Minisatellite Repeat 030232 urology & nephrology Sequence assembly Minisatellite Repeats Biology Medullary cystic kidney disease Medical and Health Sciences Cytosine 03 medical and health sciences symbols.namesake 0302 clinical medicine Tandem repeat LINKAGE LOCUS Genetics medicine Humans Polycystic Kidney 2.1 Biological and endogenous factors Aetiology Exome sequencing GENETIC DIAGNOSIS 030304 developmental biology 0303 health sciences Massive parallel sequencing REFINEMENT Mucin-1 Haplotype Biology and Life Sciences High-Throughput Nucleotide Sequencing Biological Sciences medicine.disease 3. Good health Good Health and Well Being MCKD1 Haplotypes Autosomal Dominant Mutation MAP Mendelian inheritance symbols Female CHROMOSOME 1Q21 Biotechnology Developmental Biology |
Zdroj: | Nature genetics, vol 45, iss 3 NATURE GENETICS Regev via Courtney Crummett |
ISSN: | 1546-1718 1061-4036 |
Popis: | 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) |
Databáze: | OpenAIRE |
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