Biallelic Pathogenic GFRA1 Variants Cause Autosomal Recessive Bilateral Renal Agenesis

Abstract

BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) are one of the most common malformations identified in the fetal stage. Bilateral renal agenesis (BRA) represents the most severe and fatal form of CAKUT. Only three genes have been confirmed to have a causal role in humans (ITGA8, GREB1L, and FGF20).MethodsGenome sequencing within a diagnostic setting and combined data repository analysis identified a novel gene.ResultsTwo patients presented with BRA, detected during the prenatal period, without additional recognizable malformations. They had parental consanguinity and similarly affected, deceased siblings, suggesting autosomal recessive inheritance. Evaluation of homozygous regions in patient 1 identified a novel, nonsense variant in GFRA1 (NM_001348097.1:c.676C>T, p.[Arg226*]). We identified 184 patients in our repository with renal agenesis and analyzed their exome/genome data. Of these 184 samples, 36 were from patients who presented with isolated renal agenesis. Two of them had loss-of-function variants in GFRA1. The second patient was homozygous for a frameshift variant (NM_001348097.1:c.1294delA, p.[Thr432Profs*13]). The GFRA1 gene encodes a receptor on the Wolffian duct that regulates ureteric bud outgrowth in the development of a functional renal system, and has a putative role in the pathogenesis of Hirschsprung disease.ConclusionsThese findings strongly support the causal role of GFRA1-inactivating variants for an autosomal recessive, nonsyndromic form of BRA. This knowledge will enable early genetic diagnosis and better genetic counseling for families with BRA.

A null founder variant in NPNT, encoding nephronectin, causes autosomal recessive renal agenesis

“…In addition, deleterious variants in GFRA1 were recently linked to lethal autosomal recessive BRA. 18,19 Interestingly, ITGA8 encodes the alpha-8 integrin, the receptor to which nephronectin is known to bind with very high affinity as indicated by the subnanomolar dissociation constant. 20 Thus, while knockout animal models have long demonstrated the absolute requirement for both nephronectin and its receptor for kidney formation, the human genetics evidence for the nephronectin role has been lagging.…”

“…Only three genes are currently listed in OMIM with a link to isolated (non‐syndromic) BRA: FGF20 (OMIM# 615721), GREB1L (OMIM# 617805) and ITGA8 (OMIM# 191830). In addition, deleterious variants in GFRA1 were recently linked to lethal autosomal recessive BRA 18,19 . Interestingly, ITGA8 encodes the alpha‐8 integrin, the receptor to which nephronectin is known to bind with very high affinity as indicated by the subnanomolar dissociation constant 20 .…”

A Biallelic Frameshift Mutation in Nephronectin Causes Bilateral Renal Agenesis in Humans

“…To date, the clinical manifestations of .500 syndromes have been found to include renal and urinary tract deformities. 4 Approximately 56 genes (38 dominant and 18 recessive) have been shown to be associated with CAKUT, [5][6][7][8][9][10][11][12] but explain only 20%-25% of cases.…”

Generation of patterned kidney organoids that recapitulate the adult kidney collecting duct system from expandable ureteric bud progenitors

“…In vivo, GDNF secreted by MM cells surrounding UPC-containing branch tips signals via RET, with its co-receptor GFRA1, to maintain the UPC state and stimulate UB branching morphogenesis 2 , 4 . Loss of the activity of these genes results in a CAKUT syndome 2 , 4 , 5 , 58 , 59 . We employed CRISPR/Cas9 system to KO Ret / RET in mouse and human UB organoids predicting as in vivo, UB organoid development in vitro would be Ret/RET -dependent (Fig.…”