Biallelic Pathogenic GFRA1 Variants Cause Autosomal Recessive Bilateral Renal Agenesis

Significance Statement Bilateral renal agenesis (BRA) represents the most severe form of congenital anomalies of the kidney and the urinary tract. Currently, only three genes are known to cause nonsyndromic BRA in humans. The rarity and the high mortality of BRA make it challenging to identify additional loci. Genome sequencing identified a novel causal association of GFRA1 variants with BRA in humans. Two homozygous, putative, loss-of-function variants (p.Arg226* and p.Thr432Profs*) were found in index cases with BRA from two unrelated consanguineous families by prioritizing homozygous variants and conducting a dedicated database search. These findings have implications for early genetic diagnosis and genetic counseling for families with BRA. Background Congenital 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 ). Methods Genome sequencing within a diagnostic setting and combined data repository analysis identified a novel gene. Results Two 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. Conclusions These 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.