Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing
Andrew Kirby, Andreas Gnirke, David B Jaffe, Veronika Barešová, Nathalie Pochet, Brendan Blumenstiel, Chun Ye, Daniel Aird, Christine Stevens, James T Robinson, Moran N Cabili, Irit Gat-Viks, Edward Kelliher, Riza Daza, Matthew DeFelice, Helena Hůlková, Jana Sovová, Petr Vylet'al, Corinne Antignac, Mitchell Guttman, Robert E Handsaker, Danielle Perrin, Scott Steelman, Snaevar Sigurdsson, Steven J Scheinman, Carrie Sougnez, Kristian Cibulskis, Melissa Parkin, Todd Green, Elizabeth Rossin, Michael C Zody, Ramnik J Xavier, Martin R Pollak, Seth L Alper, Kerstin Lindblad-Toh, Stacey Gabriel, P Suzanne Hart, Aviv Regev, Chad Nusbaum, Stanislav Kmoch, Anthony J Bleyer, Eric S Lander, Mark J Daly, Andrew Kirby, Andreas Gnirke, David B Jaffe, Veronika Barešová, Nathalie Pochet, Brendan Blumenstiel, Chun Ye, Daniel Aird, Christine Stevens, James T Robinson, Moran N Cabili, Irit Gat-Viks, Edward Kelliher, Riza Daza, Matthew DeFelice, Helena Hůlková, Jana Sovová, Petr Vylet'al, Corinne Antignac, Mitchell Guttman, Robert E Handsaker, Danielle Perrin, Scott Steelman, Snaevar Sigurdsson, Steven J Scheinman, Carrie Sougnez, Kristian Cibulskis, Melissa Parkin, Todd Green, Elizabeth Rossin, Michael C Zody, Ramnik J Xavier, Martin R Pollak, Seth L Alper, Kerstin Lindblad-Toh, Stacey Gabriel, P Suzanne Hart, Aviv Regev, Chad Nusbaum, Stanislav Kmoch, Anthony J Bleyer, Eric S Lander, Mark J Daly
Abstract
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.
Conflict of interest statement
COMPETING FINANCIAL INTERESTS
Andrew Kirby, Andreas Gnirke, Brendan Blumenstiel and Matthew DeFelice are listed as inventors on the C-insertion genotyping assay under patent review. The other authors declare no competing interests.
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References
- Bleyer AJ, Hart PS, Kmoch S. Hereditary interstitial kidney disease. Semin Nephrol. 2010;30:366–373.
- Castro AF, Coresh J. CKD surveillance using laboratory data from the population-based National Health and Nutrition Examination Survey (NHANES) Am J Kidney Dis. 2009;53:S46–55.
- Christodoulou K, et al. Chromosome 1 localization of a gene for autosomal dominant medullary cystic kidney disease. Hum Mol Genet. 1998;7:905–911.
- Wolf MTF, et al. Medullary cystic kidney disease type 1: mutational analysis in 37 genes based on haplotype sharing. Hum Genet. 2006;119:649–658.
- Serafini-Cessi F, Malagolini N, Cavallone D. Tamm-Horsfall glycoprotein: biology and clinical relevance. Am J Kidney Dis. 2003;42:658–676.
- Vylet’al P, et al. Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome. Kidney Int. 2006;70:1155–1169.
- Scolari F, et al. Uromodulin storage diseases: clinical aspects and mechanisms. Am J Kidney Dis. 2004;44:987–999.
- Choi M, et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A. 2009;106:19096–19101.
- Al-Romaih KI, et al. Genetic diagnosis in consanguineous families with kidney disease by homozygosity mapping coupled with whole-exome sequencing. Am J Kidney Dis. 2011;58:186–195.
- A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061–1073.
- Gemayel R, Vinces MD, Legendre M, Verstrepen KJ. Variable tandem repeats accelerate evolution of coding and regulatory sequences. Annu Rev Genet. 2010;44:445–477.
- Legendre M, Pochet N, Pak T, Verstrepen KJ. Sequence-based estimation of minisatellite and microsatellite repeat variability. Genome Res. 2007;17:1787–1796.
- Horne AW, et al. MUC 1: a genetic susceptibility to infertility? Lancet. 2001;357:1336–1337.
- Fowler JC, Teixeira AS, Vinall LE, Swallow DM. Hypervariability of the membrane-associated mucin and cancer marker MUC1. Hum Genet. 2003;113:473–479.
- Auranen M, Ala-Mello S, Turunen JA, Järvelä I. Further evidence for linkage of autosomal-dominant medullary cystic kidney disease on chromosome 1q21. Kidney Int. 2001;60:1225–1232.
- Spicer AP, Rowse GJ, Lidner TK, Gendler SJ. Delayed mammary tumor progression in Muc-1 null mice. J Biol Chem. 1995;270:30093–30101.
- Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995;11:241–247.
- Purcell S, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575.
- Abecasis GR, Cherny SS, Cookson WO, Cardon LR. Merlin--rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet. 2002;30:97–101.
- Korn JM, et al. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat Genet. 2008;40:1253–1260.
- Handsaker RE, Korn JM, Nemesh J, McCarroll SA. Discovery and genotyping of genome structural polymorphism by sequencing on a population scale. Nat Genet. 2011;43:269–276.
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