Whole Exome Sequencing Reveals Promising Genes Associated with Congenital Renal Parenchymal Anomalies in Greek Children

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) comprise a broad spectrum of malformations and constitute the leading cause of end-stage kidney disease (ESKD) in childhood. Despite extensive research, a monogenic cause is identified in only ~10% of cases, while variable penetrance and expressivity suggest a more complex disease mechanism. Epigenetic and environmental factors have also been implicated, further complicating efforts to elucidate the etiology of these anomalies. Methods: Whole exome sequencing (WES) was performed in 47 individuals with isolated, non-syndromic congenital renal parenchymal anomalies. Results: Variants in four genes (BBS1, PKHD1, XPNPEP3, and KCTD1) were identified, each of which has an established role in nephrogenesis and is implicated in syndromic disorders in which CAKUT can occur as part of the clinical spectrum. In addition, a variant in GREB1L was detected, a gene previously associated with CAKUT. The WES analysis identified candidate variants in 10.6% of patients, consistent with diagnostic yields reported in comparable CAKUT studies. The genes harboring variants are involved in key biological processes, including signaling pathways, ciliary function, and mitochondrial biology, supporting their relevance for further investigation. Conclusions: Our findings support WES as a valuable tool for identifying clinically relevant variants and expanding the genetic landscape of CAKUT.