Abstract: SA-PO584
Rare GREB1L Mutations Contribute to the Genetic Heterogeneity of Congenital Kidney Malformations
Session Information
- Noncystic Mendelian Diseases
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Genetic Diseases of the Kidney
- 802 Non-Cystic Mendelian Diseases
Authors
- Sanna-Cherchi, Simone, Columbia University, New York, New York, United States
- Khan, Kamal, Duke University, Durham, North Carolina, United States
- Westland, Rik, VU University Medical Center, Amsterdam, Netherlands
- Krithivasan, Priya, Columbia University, New York, New York, United States
- Milo Rasouly, Hila, Columbia University, New York, New York, United States
- Ionita-Laza, Iuliana, Columbia University, New York, New York, United States
- Fasel, David, Columbia University Medical Center, New York, New York, United States
- Kiryluk, Krzysztof, Columbia University, New York, New York, United States
- Bodria, Monica, G. Gaslini Children Hospital, Genoa, Italy
- Otto, Edgar A., University of Michigan, Ann Arbor, Michigan, United States
- Sampson, Matt G., University of Michigan, Ann Arbor, Michigan, United States
- Gillies, C., University of Michigan, Ann Arbor, Michigan, United States
- Mitrotti, Adele, Columbia University, New York, New York, United States
- Gesualdo, Loreto, University of Bari, Altamura, BARI, Italy
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
- Van Wijk, Joanna, VU University Medical Center, Amsterdam, Netherlands
- Saraga, Marijan, University Hospital in Split, Split, Croatia
- Scolari, Francesco, University of Brescia, Montichiari (Brescia), Italy
- Tasic, Velibor, University Children's Hospital, Skopje, Macedonia (the former Yugoslav Republic of)
- Ghiggeri, Gian Marco, G. Gaslini Children Hospital, Genoa, Italy
- Materna-Kiryluk, Anna, Poznan University of Medical Sciences, Poznan, Poland
- Goldstein, David B., Columbia University, New York, New York, United States
- Katsanis, Nicholas, Duke University, Durham, North Carolina, United States
- Davis, Erica, Duke University Medical Center, Durham, North Carolina, United States
- Gharavi, Ali G., Columbia University, New York, New York, United States
Background
Renal agenesis and hypodysplasia (RHD) are a major cause of pediatric end-stage renal disease.
Methods
We conducted whole exome sequencing in 203 patients with RHD and identified diagnostic pathogenic mutations in 8/203 patients. In another 6 patients, we found non-recurrent novel loss-of-function (LOF) variants in genes associated with rare syndromes that include kidney defects (SETBP1, WNT5A), or in genes whose inactivation results in kidney malformations in the mouse (SLIT3, HSPA4L, T, SCTR).
Results
To define novel genetic drivers in the remaining cohort of 195 patients, we compared their LOF burden with 6,905 controls. We identified rare LOF variants in GREB1L (P=2.04x10-5), a gene ubiquitously expressed in the developing mouse kidney. Expansion of our model with novel deleterious missense variants resulted in exome-wide significance for GREB1L (P=4.08x10-6). Three mutations (2 LOF and 1 missense) segregated in an autosomal dominant fashion and one predicted deleterious missense was de novo (joint value for burden, inheritance and de novo occurrence: P<1.0x10-8). In a replication cohort of 410 RHD cases, we identified 8 more qualifying LOF/missense variants in GREB1L. To directly test our genetic findings, we generated a greb1l zebrafish model. Knockdown and CRISPR/Cas9 deletion of greb1l in zebrafish showed specific pronephric defects that could be rescued by introduction of wild-type human mRNA. Randomized testing of missense alleles by in vivo complementation showed that 4/4 alleles found exclusively in patients were unable to rescue the phenotype.
Conclusion
Taken together, our study provides new insight into the genetic landscape of renal malformations and identifies GREB1L as a novel susceptibility gene for RHD.
Funding
- NIDDK Support