Scientific Publications

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

Publication TypeJournal Article
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., Hart PS, Regev A., Nusbaum C., Kmoch S., Bleyer AJ, Lander E. S., and Daly M. J.
AbstractAlthough 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.
Year of Publication2013
JournalNature genetics
Volume45
Issue3
Pages299-303
Date Published (YYYY/MM/DD)2013/03/01
ISSN Number1061-4036
DOI10.1038/ng.2543
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/23396133?dopt=Abstract