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

被引：203

作者：

Kirby, Andrew ^{[1
,2
]}

Gnirke, Andreas ^{[1
]}

Jaffe, David B. ^{[1
]}

Baresova, Veronika ^{[3
]}

Pochet, Nathalie ^{[1
,4
]}

Blumenstiel, Brendan ^{[1
]}

Ye, Chun ^{[1
]}

Aird, Daniel ^{[1
]}

Stevens, Christine ^{[1
]}

Robinson, James T. ^{[1
]}

Cabili, Moran N. ^{[1
,5
]}

Gat-Viks, Irit ^{[1
,6
]}

Kelliher, Edward

Daza, Riza ^{[1
]}

DeFelice, Matthew ^{[1
]}

Hulkova, Helena ^{[3
]}

Sovova, Jana ^{[3
]}

Vylet'al, Petr ^{[3
]}

Antignac, Corinne ^{[7
,8
,9
]}

Guttman, Mitchell ^{[1
]}

Handsaker, Robert E. ^{[1
,10
]}

Perrin, Danielle ^{[1
]}

Steelman, Scott ^{[1
]}

Sigurdsson, Snaevar ^{[1
]}

Scheinman, Steven J. ^{[11
]}

Sougnez, Carrie ^{[1
]}

Cibulskis, Kristian ^{[1
]}

Parkin, Melissa ^{[1
]}

Green, Todd ^{[1
]}

Rossin, Elizabeth ^{[1
]}

Zody, Michael C. ^{[1
]}

Xavier, Ramnik J. ^{[1
,12
,13
]}

Pollak, Martin R. ^{[14
,15
]}

Alper, Seth L. ^{[14
,15
]}

Lindblad-Toh, Kerstin ^{[1
,16
]}

Gabriel, Stacey ^{[1
]}

Hart, P. Suzanne ^{[17
]}

Regev, Aviv ^{[1
]}

Nusbaum, Chad ^{[1
]}

Kmoch, Stanislav ^{[3
]}

Bleyer, Anthony J. ^{[18
]}

Lander, Eric S. ^{[1
]}

Daly, Mark J. ^{[1
,2
]}

机构：

[1] Broad Inst Harvard & MIT, Cambridge, MA USA

[2] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[3] Charles Univ Prague, Fac Med 1, Inst Inherited Metab Disorders, Prague, Czech Republic

[4] Univ Ghent VIB, Dept Plant Syst Biol, Dept Plant Biotechnol & Bioinformat, B-9052 Ghent, Belgium

[5] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA

[6] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Cell Res & Immunol, IL-69978 Tel Aviv, Israel

[7] INSERM, U983, Paris, France

[8] Univ Paris 05, Inst Imagine, Paris, France

[9] Hop Necker Enfants Malad, Assistance Publ Hop Paris, Dept Genet, Paris, France

[10] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[11] Commonwealth Med Coll, Scranton, PA USA

[12] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Ctr Study Inflammatory Bowe, Boston, MA USA

[13] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA

[14] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA

[15] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[16] Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab Uppsala, Uppsala, Sweden

[17] NHGRI, Off Clin Director, US Natl Inst Hlth NIH, Bethesda, MD 20892 USA

[18] Wake Forest Sch Med, Sect Nephrol, Winston Salem, NC 27106 USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 03期

关键词：

GENETIC DIAGNOSIS; CHROMOSOME; 1Q21; REFINEMENT; LINKAGE; LOCUS; MCKD1; MAP;

D O I：

10.1038/ng.2543

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 (similar to 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.

引用

页码：299 / 303

页数：5

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