PUBLICATION
Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations
- Authors
- Sanna-Cherchi, S., Khan, K., Westland, R., Krithivasan, P., Fievet, L., Rasouly, H.M., Ionita-Laza, I., Capone, V.P., Fasel, D.A., Kiryluk, K., Kamalakaran, S., Bodria, M., Otto, E.A., Sampson, M.G., Gillies, C.E., Vega-Warner, V., Vukojevic, K., Pediaditakis, I., Makar, G.S., Mitrotti, A., Verbitsky, M., Martino, J., Liu, Q., Na, Y.J., Goj, V., Ardissino, G., Gigante, M., Gesualdo, L., Janezcko, M., Zaniew, M., Mendelsohn, C.L., Shril, S., Hildebrandt, F., van Wijk, J.A.E., Arapovic, A., Saraga, M., Allegri, L., Izzi, C., Scolari, F., Tasic, V., Ghiggeri, G.M., Latos-Bielenska, A., Kiryluk, A.M., Mane, S., Goldstein, D.B., Lifton, R.P., Katsanis, N., Davis, E.E., Gharavi, A.G.
- ID
- ZDB-PUB-171104-1
- Date
- 2017
- Source
- American journal of human genetics 101: 789-802 (Journal)
- Registered Authors
- Davis, Erica, Hildebrandt, Friedhelm, Katsanis, Nicholas
- Keywords
- CAKUT, EYA1, GATA3, HNF1B, HSPA4L, PAX2, SETBP1, SIX5, T, WNT5A
- MeSH Terms
-
- Alleles
- Animals
- Case-Control Studies
- Clustered Regularly Interspaced Short Palindromic Repeats/genetics
- Congenital Abnormalities/genetics*
- Exome/genetics*
- Female
- Genetic Heterogeneity
- Genome-Wide Association Study/methods
- Genotype
- Heredity/genetics
- Homozygote
- Humans
- Kidney/abnormalities*
- Kidney Diseases/congenital*
- Kidney Diseases/genetics
- Male
- Membrane Proteins/genetics
- Mice
- Mutation/genetics*
- Neoplasm Proteins/genetics*
- Phenotype
- RNA, Long Noncoding/genetics
- Urinary Tract/abnormalities
- Urogenital Abnormalities/genetics
- Zebrafish
- PubMed
- 29100090 Full text @ Am. J. Hum. Genet.
Citation
Sanna-Cherchi, S., Khan, K., Westland, R., Krithivasan, P., Fievet, L., Rasouly, H.M., Ionita-Laza, I., Capone, V.P., Fasel, D.A., Kiryluk, K., Kamalakaran, S., Bodria, M., Otto, E.A., Sampson, M.G., Gillies, C.E., Vega-Warner, V., Vukojevic, K., Pediaditakis, I., Makar, G.S., Mitrotti, A., Verbitsky, M., Martino, J., Liu, Q., Na, Y.J., Goj, V., Ardissino, G., Gigante, M., Gesualdo, L., Janezcko, M., Zaniew, M., Mendelsohn, C.L., Shril, S., Hildebrandt, F., van Wijk, J.A.E., Arapovic, A., Saraga, M., Allegri, L., Izzi, C., Scolari, F., Tasic, V., Ghiggeri, G.M., Latos-Bielenska, A., Kiryluk, A.M., Mane, S., Goldstein, D.B., Lifton, R.P., Katsanis, N., Davis, E.E., Gharavi, A.G. (2017) Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations. American journal of human genetics. 101:789-802.
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.
Errata / Notes
This article is corrected by ZDB-PUB-220906-89 .
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping