FREM2 as a candidate gene for posterior urethral valves: Evidence from a case-parent cohort.

BACKGROUND

Posterior urethral valves (PUV) are the most common cause of lower urinary tract obstruction in male infants, occurring in 1 in 4000 live male births and constituting a significant cause of urinary obstruction, long-term complications and end-stage renal disease (ESRD) in children. PUV is a multifactorial pathology, involving both genetic and environmental contributions. Congenital anomalies of the kidney and urinary tract (CAKUT), such as renal agenesis, hypoplasia and vesicoureteral reflux, share etiological and phenotypic overlap with PUV. While CAKUT can arise from monogenic causes, the specific genetic factors remain poorly understood.

OBJECTIVE

To investigate the genetic basis of PUV by identifying potential genetic markers through exome analysis in case-parent trio and their implications for disease pathogenesis.

METHODS

Five patients with isolated PUV presenting with relatively severe clinical manifestations underwent whole-exome sequencing in case-parent trio. Variants were filtered based on read depth, minor allele frequency and functional impact. In-silico analysis included pathogenicity prediction, evolutionary conservation and domain localization.

RESULTS

Seven rare variants in FREM2 (13q13.3) were identified across all five patients. Two patients harbored identical homozygous variants (c.9232A > G; p.Ile3078Val), while three patients exhibited compound heterozygosity. The variants showed variable pathogenicity, with c.4037G > A; p.Gly1346Glu demonstrating high impact (CADD score 21.6) and consistent deleterious predictions. Four variants affected highly conserved regions of the FREM2 and all but one resulted in significant physicochemical amino acid changes.

CONCLUSIONS

This study proposes the role of FREM2 as a candidate gene in PUV pathogenesis, highlighting its role in urinary tract development through extracellular matrix interactions. The identification of both homozygous and compound heterozygous variants supports a recessive inheritance pattern for PUV. These findings provide new insights into the genetic etiology of PUV and potential targets for future diagnostic and therapeutic interventions. Further research is necessary to elucidate the functional impact of these variants and explore their potential in genetic counselling and therapeutic interventions.