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Published on: January 7, 2019
FREM2 as a candidate gene for posterior urethral valves: Evidence from a case-parent cohort
Jyoti Sharma1, Sourabh Kumar1, Himani Pandey2
1All India Institute of Medical Sciences, New Delhi, India.
Insights
Genetic analysis implicates FREM2 as a candidate gene for posterior urethral valves (PUV), a common cause of infant urinary obstruction. Findings suggest a recessive inheritance pattern, offering insights into PUV etiology and potential interventions.
Area of Science:
- Genetics
- Pediatric Urology
- Molecular Biology
Background:
- Posterior urethral valves (PUV) are a leading cause of lower urinary tract obstruction in male infants, potentially leading to end-stage renal disease (ESRD).
- PUV pathogenesis is multifactorial, with both genetic and environmental factors contributing.
- The specific genetic underpinnings of PUV and related congenital anomalies of the kidney and urinary tract (CAKUT) remain largely uncharacterized.
Purpose of the Study:
- To investigate the genetic basis of isolated posterior urethral valves (PUV).
- To identify potential genetic markers associated with PUV through exome analysis.
- To understand the implications of identified genetic variants for disease pathogenesis.
Main Methods:
- Whole-exome sequencing was performed on five patients with isolated PUV and their parents (case-parent trios).
- Genetic variants were filtered based on read depth, minor allele frequency, and predicted functional impact.
- In-silico analyses included pathogenicity prediction, assessment of evolutionary conservation, and domain localization of variants.
Main Results:
- Seven rare variants within the FREM2 gene (13q13.3) were identified across the five PUV patients.
- Two patients presented with identical homozygous FREM2 variants (c.9232A > G; p.Ile3078Val).
- Three patients exhibited compound heterozygous FREM2 variants, with one variant (c.4037G > A; p.Gly1346Glu) showing high predicted pathogenicity.
Conclusions:
- The study identifies FREM2 as a candidate gene implicated in the pathogenesis of posterior urethral valves (PUV).
- Findings suggest a recessive inheritance pattern for PUV, supported by the identification of both homozygous and compound heterozygous variants.
- These results offer novel insights into the genetic etiology of PUV and potential avenues for future diagnostic and therapeutic strategies.
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.
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