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 asso- ciated with RHD in 7/202 case subjects. In an additional affected individual with RHD and a congenital heart defect, we found a homo- zygous 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 sub- jects. 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 1⁄4 2.0 3 105 for novel LOF, increased to p 1⁄4 4.1 3 106 for LOF and deleterious missense variants com- bined, and augmented further after accounting for segregation and de novo inheritance of rare variants (joint p 1⁄4 2.3 3 107). 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 land- scape of kidney malformations in humans, presents multiple candidates, and identifies SLIT3 and GREB1L as genes implicated in the pathogenesis of RHD.
Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations / Simone, Sanna-Cherchi; Kamal Khan, ∗; Westland, Rik; Krithivasan, Priya; Fievet, Lorraine; Milo Rasouly, Hila; Ionita-Laza, Iuliana; Capone, Valentina P.; Fasel, David A.; Kiryluk, Krzysztof; Kamalakaran, Sitharthan; Bodria, Monica; Otto, Edgar A.; Sampson, Matthew G.; Gillies, Christopher E.; Vega-Warner, Virginia; Vukojevic, Katarina; Pediaditakis, Igor; Makar, Gabriel S.; Mitrotti, Adele; Verbitsky, Miguel; Martino, Jeremiah; Liu, Qingxue; Na, Young-Ji; Goj, Vinicio; Ardissino, Gianluigi; Gigante, Maddalena; Gesualdo, Loreto; Janezcko, Magdalena; Zaniew, Marcin; Lee Mendelsohn, Cathy; Shril, Shirlee; Hildebrandt, Friedhelm; van Wijk, Joanna A. E.; Arapovic, Adela; Saraga, Marijan; Allegri, Landino; Izzi, Claudia; Scolari, Francesco; Tasic, Velibor; Ghiggeri, GIAN MARCO; Latos-Bielenska, Anna; Materna-Kiryluk, Anna; Mane, Shrikant; Goldstein, David B.; Lifton, Richard P.; Katsanis, Nicholas; Davis, Erica E.; Gharavi, ∗∗ and Ali G.. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - 101(2017), pp. 1034-1039. [10.1016/j.ajhg.2017.11.003]
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