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Am J Hum Genet. 2017 Nov 2;101(5):789-802. doi: 10.1016/j.ajhg.2017.09.018.

Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations.

Author information

1
Division of Nephrology, Columbia University, New York, NY 10032, USA. Electronic address: ss2517@cumc.columbia.edu.
2
Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA.
3
Division of Nephrology, Columbia University, New York, NY 10032, USA; Department of Pediatric Nephrology, VU University Medical Center, Amsterdam 1007 MB, the Netherlands.
4
Division of Nephrology, Columbia University, New York, NY 10032, USA.
5
Department of Biostatistics, Columbia University, New York, NY 10032, USA.
6
Institute for Genomic Medicine, Columbia University Medical Center, New York, NY 10032, USA.
7
Division of Nephrology, Dialysis, Transplantation, and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Genoa 16147, Italy.
8
University of Michigan School of Medicine, Department of Internal Medicine-Nephrology, Ann Arbor, MI 48109, USA.
9
University of Michigan School of Medicine, Department of Pediatrics-Nephrology, Ann Arbor, MI 48109, USA.
10
Department of Anatomy, Histology, and Embryology, School of Medicine, University of Split, Split 21000, Croatia.
11
Pediatric Unit, Fatebenefratelli Hospital, Milan 20121, Italy.
12
Pediatric Nephrology and Dialysis Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico Milano, 20122 Milan, Italy.
13
Department of Medical and Surgical Sciences, University of Foggia, Foggia 71121, Italy.
14
Section of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70121, Italy.
15
Department of Medical Genetics, Chair of Pediatrics, Jagiellonian University, Collegium Medicum, Krakow 31-008, Poland.
16
Children's Hospital, Poznan 61-825, Poland.
17
Department of Urology, Pathology and Cell Biology, Genetics and Development, Columbia University, New York, NY 10032, USA.
18
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
19
Department of Pediatric Nephrology, VU University Medical Center, Amsterdam 1007 MB, the Netherlands.
20
Department of Pediatrics, University Hospital of Split, Split 21000, Croatia.
21
Department of Pediatrics, University Hospital of Split, Split 21000, Croatia; School of Medicine, University of Split, Split 21000, Croatia.
22
Department of Medicine and Surgery, University of Parma, Parma 43100, Italy.
23
Cattedra di Nefrologia, Università di Brescia, Seconda Divisione di Nefrologia Azienda Ospedaliera Spedali Civili di Brescia Presidio di Montichiari, Brescia 25018, Italy; Dipartimento Ostetrico Ginecologico, Azienda Ospedaliera Spedali Civili di Brescia, Brescia 25018, Italy.
24
Cattedra di Nefrologia, Università di Brescia, Seconda Divisione di Nefrologia Azienda Ospedaliera Spedali Civili di Brescia Presidio di Montichiari, Brescia 25018, Italy.
25
Department of Pediatric Nephrology, University Children's Hospital, Medical Faculty of Skopje, Skopje 1000, Macedonia.
26
Department of Medical Genetics, Poznan University of Medical Sciences, and Center for Medical Genetics GENESIS, Poznan 61-701, Poland.
27
Department of Human Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
28
Department of Human Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
29
Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA. Electronic address: erica.davis@duke.edu.

Abstract

Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional affected individual with RHD and a congenital heart defect, we found a homozygous loss-of-function (LOF) variant in SLIT3, recapitulating phenotypes reported with Slit3 inactivation in the mouse. To identify genes associated with RHD, we performed an exome-wide association study with 195 unresolved case subjects and 6,905 control subjects. The top signal resided in GREB1L, a gene implicated previously in Hoxb1 and Shha signaling in zebrafish. The significance of the association, which was p = 2.0 × 10-5 for novel LOF, increased to p = 4.1 × 10-6 for LOF and deleterious missense variants combined, and augmented further after accounting for segregation and de novo inheritance of rare variants (joint p = 2.3 × 10-7). Finally, CRISPR/Cas9 disruption or knockdown of greb1l in zebrafish caused specific pronephric defects, which were rescued by wild-type human GREB1L mRNA, but not mRNA containing alleles identified in case subjects. Together, our study provides insight into the genetic landscape of kidney malformations in humans, presents multiple candidates, and identifies SLIT3 and GREB1L as genes implicated in the pathogenesis of RHD.

KEYWORDS:

CAKUT; EYA1; GATA3; HNF1B; HSPA4L; PAX2; SETBP1; SIX5; T; WNT5A

PMID:
29100090
PMCID:
PMC5673636
DOI:
10.1016/j.ajhg.2017.09.018
[Indexed for MEDLINE]
Free PMC Article

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