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


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.

SUBMITTER: Sanna-Cherchi S 

PROVIDER: S-EPMC5673636 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Sanna-Cherchi Simone S   Khan Kamal K   Westland Rik R   Krithivasan Priya P   Fievet Lorraine L   Rasouly Hila Milo HM   Ionita-Laza Iuliana I   Capone Valentina P VP   Fasel David A DA   Kiryluk Krzysztof K   Kamalakaran Sitharthan S   Bodria Monica M   Otto Edgar A EA   Sampson Matthew G MG   Gillies Christopher E CE   Vega-Warner Virginia V   Vukojevic Katarina K   Pediaditakis Igor I   Makar Gabriel S GS   Mitrotti Adele A   Verbitsky Miguel M   Martino Jeremiah J   Liu Qingxue Q   Na Young-Ji YJ   Goj Vinicio V   Ardissino Gianluigi G   Gigante Maddalena M   Gesualdo Loreto L   Janezcko Magdalena M   Zaniew Marcin M   Mendelsohn Cathy Lee CL   Shril Shirlee S   Hildebrandt Friedhelm F   van Wijk Joanna A E JAE   Arapovic Adela A   Saraga Marijan M   Allegri Landino L   Izzi Claudia C   Scolari Francesco F   Tasic Velibor V   Ghiggeri Gian Marco GM   Latos-Bielenska Anna A   Materna-Kiryluk Anna A   Mane Shrikant S   Goldstein David B DB   Lifton Richard P RP   Katsanis Nicholas N   Davis Erica E EE   Gharavi Ali G AG  

American journal of human genetics 20171101 5


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  ...[more]

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