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Kidney Int. 2014 Apr;85(4):880-7. doi: 10.1038/ki.2013.450. Epub 2013 Nov 20.

Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies.

Author information

1
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
3
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
4
Department of Pediatrics, University Children's Hospital, University Essen, Essen, Germany.
5
Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
6
The Pediatric Nephrology Unit, Alexandria University, Alexandria, Egypt.
7
Zentrum für Kinder- und Jugendmedizin am UKGM, Marburg, Germany.
8
Department of Pediatric Nephrology, Faculty of Medicine, University of Istanbul, Istanbul, Turkey.
9
Department of Pediatric Nephrology, Children's Hospital King Fahad Medical City, Riyadh, Saudi Arabia.
10
Division of Pediatric Nephrology, Tawam Hospital, UAE University, Al Ain, UAE.
11
King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.
12
Nephrology, Haseki Training and Research Hospital, Bezmialem Vakif University Faculty of Medicine, Istanbul, Turkey.
13
Dialysis Unit, Polish-American Children's Hospital, Collegium Medicum of Jagiellonian University, Cracow, Poland.
14
Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, University of Hamburg, Hamburg, Germany.
15
Division of Nephrology, Department of Internal Medicine, MetroHealth Medical Center, and Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
16
Department of Internal Medicine and Eugene McDermott Center for Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
17
Departments of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA.
18
Cologne Center for Genomics, Center for Molecular Medicine Cologne, and Cologne Excellence Cluster on Cellular Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
19
Biomedical Research Core Facilities, University of Michigan, Ann Arbor, Michigan, USA.
20
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
21
1] Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA [2] HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
22
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
23
1] Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Abstract

Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.

PMID:
24257694
PMCID:
PMC3972265
DOI:
10.1038/ki.2013.450
[Indexed for MEDLINE]
Free PMC Article

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