Title | Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Sanna-Cherchi, S, Khan, K, Westland, R, Krithivasan, P, Fievet, L, Rasouly, HMilo, Ionita-Laza, I, Capone, VP, Fasel, DA, Kiryluk, K, Kamalakaran, S, Bodria, M, Otto, EA, Sampson, MG, Gillies, CE, Vega-Warner, V, Vukojevic, K, Pediaditakis, I, Makar, GS, Mitrotti, A, Verbitsky, M, Martino, J, Liu, Q, Na, Y-J, Goj, V, Ardissino, G, Gigante, M, Gesualdo, L, Janezcko, M, Zaniew, M, Mendelsohn, CLee, Shril, S, Hildebrandt, F, van Wijk, JAE, Arapovic, A, Saraga, M, Allegri, L, Izzi, C, Scolari, F, Tasic, V, Ghiggeri, GMarco, Latos-Bielenska, A, Materna-Kiryluk, A, Mane, S, Goldstein, DB, Lifton, RP, Katsanis, N, Davis, EE, Gharavi, AG |
Journal | Am J Hum Genet |
Volume | 101 |
Issue | 5 |
Pagination | 789-802 |
Date Published | 2017 Nov 02 |
ISSN | 1537-6605 |
Keywords | Alleles, Animals, Case-Control Studies, Clustered Regularly Interspaced Short Palindromic Repeats, Congenital Abnormalities, Exome, Female, Genetic Heterogeneity, Genome-Wide Association Study, Genotype, Heredity, Homozygote, Humans, Kidney, Kidney Diseases, Male, Membrane Proteins, Mice, Mutation, Neoplasm Proteins, Phenotype, RNA, Long Noncoding, Urinary Tract, Urogenital Abnormalities, Zebrafish |
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 for novel LOF, increased to p = 4.1 × 10 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). 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. |
DOI | 10.1016/j.ajhg.2017.09.018 |
Alternate Journal | Am. J. Hum. Genet. |
PubMed ID | 29100090 |
PubMed Central ID | PMC5673636 |
Grant List | UM1 HG006504 / HG / NHGRI NIH HHS / United States R01 DK105124 / DK / NIDDK NIH HHS / United States P30 DK096493 / DK / NIDDK NIH HHS / United States R01 DK088767 / DK / NIDDK NIH HHS / United States P50 DK096415 / DK / NIDDK NIH HHS / United States U54 HG006504 / HG / NHGRI NIH HHS / United States R01 DK108805 / DK / NIDDK NIH HHS / United States U54 DK104309 / DK / NIDDK NIH HHS / United States R01 DK080099 / DK / NIDDK NIH HHS / United States UL1 TR000040 / TR / NCATS NIH HHS / United States R01 DK103184 / DK / NIDDK NIH HHS / United States R01 MH095797 / MH / NIMH NIH HHS / United States |