TY - JOUR
T1 - Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations
AU - Sanna-Cherchi, Simone
AU - Khan, Kamal
AU - Westland, Rik
AU - Krithivasan, Priya
AU - Fievet, Lorraine
AU - Rasouly, Hila Milo
AU - Ionita-Laza, Iuliana
AU - Capone, Valentina P.
AU - Fasel, David A.
AU - Kiryluk, Krzysztof
AU - Kamalakaran, Sitharthan
AU - Bodria, Monica
AU - Otto, Edgar A.
AU - Sampson, Matthew G.
AU - Gillies, Christopher E.
AU - Vega-Warner, Virginia
AU - Vukojevic, Katarina
AU - Pediaditakis, Igor
AU - Makar, Gabriel S.
AU - Mitrotti, Adele
AU - Verbitsky, Miguel
AU - Martino, Jeremiah
AU - Liu, Qingxue
AU - Na, Young Ji
AU - Goj, Vinicio
AU - Ardissino, Gianluigi
AU - Gigante, Maddalena
AU - Gesualdo, Loreto
AU - Janezcko, Magdalena
AU - Zaniew, Marcin
AU - Mendelsohn, Cathy Lee
AU - Shril, Shirlee
AU - Hildebrandt, Friedhelm
AU - van Wijk, Joanna A.E.
AU - Arapovic, Adela
AU - Saraga, Marijan
AU - Allegri, Landino
AU - Izzi, Claudia
AU - Scolari, Francesco
AU - Tasic, Velibor
AU - Ghiggeri, Gian Marco
AU - Latos-Bielenska, Anna
AU - Materna-Kiryluk, Anna
AU - Mane, Shrikant
AU - Goldstein, David B.
AU - Lifton, Richard P.
AU - Katsanis, Elias Nicholas
AU - Davis, Erica Ellen
AU - Gharavi, Ali G.
N1 - Funding Information:
We thank all individuals with RHD and their family members for participating to this study. This work was supported by grants from the National Institutes of Health ( R01DK103184 and UL1 TR000040 to S.S.-C.; R01DK108805 to M.G.S.; R01DK088767 to F.H.; P50DK096415 to N.K.; P30DK096493 to N.K. and E.E.D.; R01DK080099 to A.G.G.; U54DK104309 to A.G.G.; R01DK105124 to K. Kiryluk), the American Heart Association grant-in-aid 13GRNT14680075 to S.S.-C., the Joint Italian Ministry of Health and NIH Young Investigators Finalized Research 2012 to S.S.-C. and G.M.G., the National Human Genome Research Institute Centers for Mendelian Genomics ( HG006504 to R.P.L.), and the Fondazione Malattie Renali nel Bambino (to G.M.G.). M.G.S. is supported by the Charles Woodson Clinical Research Fund . A.-M.K. and A.L.-B. are funded by the Polish Ministry of Health . We acknowledge the Polish Kidney Genetics Network (POLYGENES) , the Polish Registry of Congenital Malformations (PRCM) , the NZOZ Center for Medical Genetics (GENESIS) in Poznań, Poland , and the Dutch Kidney Foundation for the Kolff post-doc abroad grant ( 15OKK95 to R.W.). The list of contributors for the 6,905 exome controls used in this study is available in the Supplemental Data .
Publisher Copyright:
© 2017 American Society of Human Genetics
PY - 2017/11/2
Y1 - 2017/11/2
N2 - 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.
AB - 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.
KW - CAKUT
KW - EYA1
KW - GATA3
KW - HNF1B
KW - HSPA4L
KW - PAX2
KW - SETBP1
KW - SIX5
KW - T
KW - WNT5A
UR - http://www.scopus.com/inward/record.url?scp=85033593238&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85033593238&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2017.09.018
DO - 10.1016/j.ajhg.2017.09.018
M3 - Article
C2 - 29100090
AN - SCOPUS:85033593238
SN - 0002-9297
VL - 101
SP - 789
EP - 802
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -
