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


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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Figure 1: Linkage of six families with MCKD1 to chromosome 1.
Figure 2: Discovery of a cytosine insertion in a coding VNTR of MUC1.
Figure 3: Detection of MUC1 cytosine insertion by probe-extension assay.
Figure 4: Immunohistochemical and immunofluorescence studies of the MUC1-fs protein.


  1. Bleyer, A.J., Hart, P.S. & Kmoch, S. Hereditary interstitial kidney disease. Semin. Nephrol. 30, 366–373 (2010).

    Article  Google Scholar 

  2. Castro, A.F. & Coresh, J. CKD surveillance using laboratory data from the population-based National Health and Nutrition Examination Survey (NHANES). Am. J. Kidney Dis. 53, S46–S55 (2009).

    Article  Google Scholar 

  3. Christodoulou, K. et al. Chromosome 1 localization of a gene for autosomal dominant medullary cystic kidney disease. Hum. Mol. Genet. 7, 905–911 (1998).

    Article  CAS  Google Scholar 

  4. Wolf, M.T.F. et al. Medullary cystic kidney disease type 1: mutational analysis in 37 genes based on haplotype sharing. Hum. Genet. 119, 649–658 (2006).

    Article  CAS  Google Scholar 

  5. Fuchshuber, A. et al. Refinement of the gene locus for autosomal dominant medullary cystic kidney disease type 1 (MCKD1) and construction of a physical and partial transcriptional map of the region. Genomics 72, 278–284 (2001).

    Article  CAS  Google Scholar 

  6. Kiser, R.L. et al. Medullary cystic kidney disease type 1 in a large Native-American kindred. Am. J. Kidney Dis. 44, 611–617 (2004).

    Article  CAS  Google Scholar 

  7. Wolf, M.T. et al. Telomeric refinement of the MCKD1 locus on chromosome 1q21. Kidney Int. 66, 580–585 (2004).

    Article  CAS  Google Scholar 

  8. Choi, M. et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc. Natl. Acad. Sci. USA 106, 19096–19101 (2009).

    Article  CAS  Google Scholar 

  9. Al-Romaih, K.I. et al. Genetic diagnosis in consanguineous families with kidney disease by homozygosity mapping coupled with whole-exome sequencing. Am. J. Kidney Dis. 58, 186–195 (2011).

    Article  CAS  Google Scholar 

  10. 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  11. Gemayel, R., Vinces, M.D., Legendre, M. & Verstrepen, K.J. Variable tandem repeats accelerate evolution of coding and regulatory sequences. Annu. Rev. Genet. 44, 445–477 (2010).

    Article  CAS  Google Scholar 

  12. Legendre, M., Pochet, N., Pak, T. & Verstrepen, K.J. Sequence-based estimation of minisatellite and microsatellite repeat variability. Genome Res. 17, 1787–1796 (2007).

    Article  CAS  Google Scholar 

  13. Horne, A.W. et al. MUC 1: a genetic susceptibility to infertility? Lancet 357, 1336–1337 (2001).

    Article  CAS  Google Scholar 

  14. Fowler, J.C., Teixeira, A.S., Vinall, L.E. & Swallow, D.M. Hypervariability of the membrane-associated mucin and cancer marker MUC1. Hum. Genet. 113, 473–479 (2003).

    Article  CAS  Google Scholar 

  15. Brayman, M., Thathiah, A. & Carson, D.D. MUC1: a multifunctional cell surface component of reproductive tissue epithelia. Reprod. Biol. Endocrinol. 2, 4 (2004).

    Article  Google Scholar 

  16. Levitin, F. et al. The MUC1 SEA module is a self-cleaving domain. J. Biol. Chem. 280, 33374–33386 (2005).

    Article  CAS  Google Scholar 

  17. Auranen, M., Ala-Mello, S., Turunen, J.A. & Järvelä, I. Further evidence for linkage of autosomal-dominant medullary cystic kidney disease on chromosome 1q21. Kidney Int. 60, 1225–1232 (2001).

    Article  CAS  Google Scholar 

  18. Spicer, A.P., Rowse, G.J., Lidner, T.K. & Gendler, S.J. Delayed mammary tumor progression in Muc-1 null mice. J. Biol. Chem. 270, 30093–30101 (1995).

    Article  CAS  Google Scholar 

  19. Lander, E. & Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet. 11, 241–247 (1995).

    Article  CAS  Google Scholar 

  20. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  21. Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardonl, L.R. Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101 (2002).

    Article  CAS  Google Scholar 

  22. Korn, J.M. et al. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat. Genet. 40, 1253–1260 (2008).

    Article  CAS  Google Scholar 

  23. Handsaker, R.E., Korn, J.M., Nemesh, J. & McCarroll, S.A. Discovery and genotyping of genome structural polymorphism by sequencing on a population scale. Nat. Genet. 43, 269–276 (2011).

    Article  CAS  Google Scholar 

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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.

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Authors and Affiliations



A.J.B., E.S.L. and M.J.D. jointly supervised the research. R.J.X., M.R.P. and S.L.A. provided study design and interpretation advice. C.A., S.J.S., P.S.H. and A.J.B. performed sample collection. C. Stevens managed the project. C. Sougnez and K.C. provided early genotyping and sequencing support. Linkage analysis was performed by A.K. on the basis of previous work by P.S.H. A.K. and M.J.D. developed variation discovery and analysis methods. A.K., J.T.R. and R.E.H. analyzed structural variation. T.G. performed CNV analysis. S.G. supervised the sequencing. S. Sigurdsson and K.L.-T. designed the custom capture array. M.P. performed direct PCR of the polymorphic VNTR candidates selected by N.P. A.G. and D.A. performed Southern blot and long-range PCR of the MUC1 VNTR. C.N. supervised the MUC1 VNTR sequencing approach. A.G. performed VNTR allele cloning and generation of sequencing libraries. E.K., R.D., D.P. and S. Steelman performed Sanger sequencing. D.B.J. assembled and analyzed VNTR Sanger sequencing. M.G. provided RNA-seq support. S.K. supervised the immunohistochemistry and immunofluorescence work performed by V.B., H.H., J.S. and P.V. A.K., B.B. and M.D. developed the C-insertion genotype assay. M.C.Z. provided informatic and sequencing consultation. A.R. provided informatic and analysis consultation. C.Y., J.T.R., M.N.C., I.G.-V., R.E.H. and E.R. provided informatic support. The manuscript was written primarily by A.K., A.G., A.J.B., E.S.L. and M.J.D. The supplementary information was prepared mainly by A.K., A.G., D.B.J., B.B., R.E.H., S. Sigurdsson, S.K. and A.J.B.

Corresponding authors

Correspondence to Anthony J Bleyer, Eric S Lander or Mark J Daly.

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Competing interests

A.K., A.G., B.B. and M.D. are listed as inventors on the C-insertion genotyping assay under patent review, filed by the Broad Institute. The other authors declare no competing interests.

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Kirby, A., Gnirke, A., Jaffe, D. et al. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nat Genet 45, 299–303 (2013).

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