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
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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