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.
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We thank T.L. Hatte for reagent use. We thank D. Altshuler, T. Carter and J. Schlondorff for useful discussions and M. Cortes, M. Ilzarbe and M. Betancourt for helpful project management. We also thank F. Letendre, M. Coole, R.P. Frere, C. Bonnet, L. Mulrain, N. Norbui and H. Arachchi for Sanger sequencing. This work was conducted as part of the Slim Initiative for Genomic Medicine, a joint United States–Mexico project funded by the Carlos Slim Health Institute. This research was supported in part by the Intramural Research Program of the US NIH, National Human Genome Research Institute (NHGRI). S.K., H.H., J.S. and V.B. were funded by Charles University programs PRVOUK-P24/LF1/3 and UNCE 204011, and their work was supported by grants LH12015 and NT13116-4/2012 from the Ministry of Education and the Ministry of Health of the Czech Republic. S.L.A. was supported by US NIH grant DK34854 (The Harvard Digestive Diseases Center). N.P. is a Broad Fellow of the Broad Institute and a postdoctoral research fellow of the Fund for Scientific Research–Flanders (FWO Vlaanderen, Belgium). I.G.-V. was supported by the Human Frontier Science Program, Alon, the Israeli Centers of Research Excellence (I-CORE) and the Edmond J. Safra Center for Bioinformatics at Tel Aviv University.
Supplementary Note, Supplementary Figures 1–5 and Supplementary Tables 1–3
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Der Nephrologe (2018)