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 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.

ATAV: a comprehensive platform for population-scale genomic analyses

“…The collapsing framework of ATAV has enabled the confirmation of known and the discovery of novel genes in a wide range of diseases such as epilepsies [28,29], sudden unexplained death in epilepsy [30], congenital kidney malformations [31], chronic kidney disease [32], amyotrophic lateral sclerosis [33,34], Alzheimer's disease [27], retinal dystrophy [35], and idiopathic pulmonary fibrosis [26]. Furthermore the diagnostic framework has helped to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes in a wide range of diseases including stillbirth [36], rare undiagnosed genetic disorders [37,38], epilepsies [39][40][41],…”

“…ATAV has an external data plugin code structure, which allows quick code integration of gene based, site based and variant based data. [10][11][12][13][14][15][16][17][18][19]; c [20][21][22][23][24][25][26][27][28][29]; d [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49]; e [50-199]; f >=200. A run-length encoding procedure is used to further compress data within fixed 1000 bp block regions (see Figure 3).…”

Hypoparathyroidism, deafness, and renal dysplasia syndrome: 20 Years after the identification of the firstGATA3mutations

“…NGS screening of patients with congenital anomalies of the kidney and urinary tract has also identified GATA3 mutations in 1 of 202 patients (Sanna-Cherchi et al, 2017) and 2 of 650 patients (Hwang et al, 2014),…”

“…respectively. However, it should be noted that the great majority of patients with isolated hypoparathyroidism or isolated renal dysplasia that were found to have GATA3 mutations, either had incomplete clinical information about other organs or were found to have other features of HDR when examined more closely (e.g., by carrying out formal hearing evaluation) (Hwang et al, 2014;Kim et al, 2015;Sanna-Cherchi et al, 2017;Y. Wang et al, 2019).…”

Genetic basis of human congenital anomalies of the kidney and urinary tract

“…Finally, with the availability of large exome control data sets, exome-wide association studies are feasible. This approach, combined with functional in vivo modeling in zebrafish, recently led to the discovery of loss-of-function mutations in GREB1L as a new cause of autosomal dominant RHD (116). GREB1L (growth regulation by estrogen in breast cancer 1 like) encodes a protein with a poorly understood function, but its role in the pathogenesis CAKUT has recently been validated by others (117).…”