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Nat Genet DOI:10.1038/ng.2543

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

Publication TypeJournal Article
Year of Publication2013
AuthorsKirby, A, Gnirke, A, Jaffe, DB, Barešová, V, Pochet, N, Blumenstiel, B, Ye, C, Aird, D, Stevens, C, Robinson, JT, Cabili, MN, Gat-Viks, I, Kelliher, E, Daza, R, DeFelice, M, Hůlková, H, Sovová, J, Vylet'al, P, Antignac, C, Guttman, M, Handsaker, RE, Perrin, D, Steelman, S, Sigurdsson, S, Scheinman, SJ, Sougnez, C, Cibulskis, K, Parkin, M, Green, T, Rossin, E, Zody, MC, Xavier, RJ, Pollak, MR, Alper, SL, Lindblad-Toh, K, Gabriel, S, P Hart, S, Regev, A, Nusbaum, C, Kmoch, S, Bleyer, AJ, Lander, ES, Daly, MJ
JournalNat Genet
Date Published2013 Mar
KeywordsCytosine, Female, Genetic Linkage, Haplotypes, High-Throughput Nucleotide Sequencing, Humans, Male, Minisatellite Repeats, Mucin-1, Mutation, Polycystic Kidney, Autosomal Dominant

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.


Alternate JournalNat. Genet.
PubMed ID23396133
PubMed Central IDPMC3901305
Grant ListP30 DK034854 / DK / NIDDK NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
DK34854 / DK / NIDDK NIH HHS / United States