title: Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies.
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.
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Heon Yung
authors.initials: HY
authors.lastname: Gee
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Toby W
authors.initials: TW
authors.lastname: Hurd
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shazia
authors.initials: S
authors.lastname: Ashraf
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Moumita
authors.initials: M
authors.lastname: Chaki
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Cluckey
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Vega-Warner
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Pawaree
authors.initials: P
authors.lastname: Saisawat
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Katrina A
authors.initials: KA
authors.lastname: Diaz
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Humphrey
authors.initials: H
authors.lastname: Fang
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kohl
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Allen
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Rannar
authors.initials: R
authors.lastname: Airik
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Weibin
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Gokul
authors.initials: G
authors.lastname: Ramaswami
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Janssen
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Clementine
authors.initials: C
authors.lastname: Fu
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Innis
authors.affiliation: Department of Pediatrics, University Children's Hospital, University Essen, Essen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weber
authors.affiliation: Department of Pediatrics, University Children's Hospital, University Essen, Essen, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Vester
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: The Pediatric Nephrology Unit, Alexandria University, Alexandria, Egypt.
authors.forename: Hanan M
authors.initials: HM
authors.lastname: Fathy
authors.affiliation: Zentrum für Kinder- und Jugendmedizin am UKGM, Marburg, Germany.
authors.forename: Nikola
authors.initials: N
authors.lastname: Jeck
authors.affiliation: Zentrum für Kinder- und Jugendmedizin am UKGM, Marburg, Germany.
authors.forename: Gunther
authors.initials: G
authors.lastname: Klaus
authors.affiliation: Department of Pediatric Nephrology, Faculty of Medicine, University of Istanbul, Istanbul, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Nayir
authors.affiliation: Department of Pediatric Nephrology, Children's Hospital King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Khawla A
authors.initials: KA
authors.lastname: Rahim
authors.affiliation: Division of Pediatric Nephrology, Tawam Hospital, UAE University, Al Ain, UAE.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Al Attrach
authors.affiliation: King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Al Hassoun
authors.affiliation: Nephrology, Haseki Training and Research Hospital, Bezmialem Vakif University Faculty of Medicine, Istanbul, Turkey.
authors.forename: Savas
authors.initials: S
authors.lastname: Ozturk
authors.affiliation: Dialysis Unit, Polish-American Children's Hospital, Collegium Medicum of Jagiellonian University, Cracow, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Drozdz
authors.affiliation: Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, University of Hamburg, Hamburg, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Helmchen
authors.affiliation: Division of Nephrology, Department of Internal Medicine, MetroHealth Medical Center, and Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: O'Toole
authors.affiliation: Department of Internal Medicine and Eugene McDermott Center for Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Attanasio
authors.affiliation: Departments of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lewis
authors.affiliation: 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.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Biomedical Research Core Facilities, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Washburn
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: James
authors.initials: J
authors.lastname: MacDonald
authors.affiliation: 1] Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA [2] HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Innis
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.affiliation: 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.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000293:Adolescent; D000328:Adult; D004252:DNA Mutational Analysis; D042241:Early Diagnosis; D059472:Exome; D005808:Genes, Recessive; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D007223:Infant; D052177:Kidney Diseases, Cystic / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D055815:Young Adult