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

Simone Sanna-Cherchi, Kamal Khan, Rik Westland, Priya Krithivasan, Lorraine Fievet, Hila Milo Rasouly, Iuliana Ionita-Laza, Valentina P. Capone, David A. Fasel, Krzysztof Kiryluk, Sitharthan Kamalakaran, Monica Bodria, Edgar A. Otto, Matthew G. Sampson, Christopher E. Gillies, Virginia Vega-Warner, Katarina Vukojevic, Igor Pediaditakis, Gabriel S. Makar, Adele MitrottiMiguel Verbitsky, Jeremiah Martino, Qingxue Liu, Young Ji Na, Vinicio Goj, Gianluigi Ardissino, Maddalena Gigante, Loreto Gesualdo, Magdalena Janezcko, Marcin Zaniew, Cathy Lee Mendelsohn, Shirlee Shril, Friedhelm Hildebrandt, Joanna A.E. van Wijk, Adela Arapovic, Marijan Saraga, Landino Allegri, Claudia Izzi, Francesco Scolari, Velibor Tasic, Gian Marco Ghiggeri, Anna Latos-Bielenska, Anna Materna Kiryluk, Shrikant Mane, David B. Goldstein, Richard P. Lifton, Nicholas Katsanis, Erica E. Davis, Ali G. Gharavi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)789-802
Number of pages14
JournalAmerican Journal of Human Genetics
Volume101
Issue number5
DOIs
Publication statusPublished - Nov 2 2017

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Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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., ... Gharavi, A. G. (2017). Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations. American Journal of Human Genetics, 101(5), 789-802. https://doi.org/10.1016/j.ajhg.2017.09.018