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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 Portfolio; Volume: 45; Issue: 3 Linguagem: Inglês

10.1038/ng.2543

1546-1718

Andrew Kirby, Andreas Gnirke, David B. Jaffe, Veronika Barešová, Nathalie Pochet, Brendan Blumenstiel, Chun Ye, Daniel Aird, Christine Stevens, James Robinson, Moran N. Cabili, Irit Gat‐Viks, Edward Kelliher, Riza M. Daza, Matthew DeFelice, Helena Hůlková, Jana Sovová, Petr Vyleťal, Corinne Antignac, Mitchell Guttman, Robert E. Handsaker, Danielle Perrin, Scott Steelman, Snævar Sigurðsson, Steven J. Scheinman, Carrie Sougnez, Kristian Cibulskis, Melissa Parkin, Todd J. Green, Elizabeth J. Rossin, Michael C. Zody, Ramnik J. Xavier, Martin R. Pollak, Seth L. Alper, Kerstin Lindblad‐Toh, Stacey B. Gabriel, P. Suzanne Hart, Aviv Regev, Chad Nusbaum, Stanislav Kmoch, Anthony J. Bleyer, Eric S. Lander, Mark J. Daly,

Genomic variations and chromosomal abnormalities

Anthony Bleyer, Eric Lander, Mark Daly and colleagues show that frameshift mutations in a large VNTR of MUC1 cause medullary cystic kidney disease type 1. Their discovery sheds light on the biology of this disease and highlights challenges in using massively parallel sequencing technologies to characterize certain types of sequence variants. 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.