Genetic discovery in vesicoureteral reflux using exome sequencing: A pilot study

Area of Science:

• Genetics
• Pediatric Nephrology
• Molecular Biology

Background:

• Vesicoureteral reflux (VUR) is a complex genetic disorder.
• Understanding the genetic underpinnings of VUR is crucial for diagnosis and treatment.
• Previous studies suggest VUR is genetically heterogeneous.

Purpose of the Study:

• To investigate the potential for genetic discovery in patients with VUR using whole exome sequencing.
• To identify genetic variants associated with severe VUR and renal hypodysplasia.
• To explore genetic causes in a family with VUR and chronic kidney disease.

Main Methods:

• Whole exome sequencing was performed on ten Indian children with severe VUR and renal hypodysplasia, and a family with VUR.
• Prioritization of single nucleotide variations (SNVs) involved selecting rare, deleterious variants in biologically relevant genes.
• Copy-number variations (CNVs) were analyzed, and hypothesis-free and hypothesis-driven approaches were used for variant prioritization.

Main Results:

• Rare and novel deleterious variants linked to VUR and renal hypodysplasia were found in 70% of patients with the extreme phenotype.
• At least one prioritized variant in VUR or renal hypodysplasia-related genes was identified in 80% of these patients.
• A pathogenic CNV was found in one patient, and a rare deleterious variant in the SLIT1 gene was identified in the VUR family.

Conclusions:

• Combining precise phenotyping with exome sequencing, utilizing both hypothesis-driven and hypothesis-free methods, is an effective strategy for genetic discovery in VUR.
• The findings reinforce that VUR is a genetically heterogeneous disorder.
• This approach aids in identifying novel genetic factors contributing to VUR.