Abstract
BACKGROUND: Vesicoureteral reflux (VUR) is a genetically heterogenous disorder. We conducted this pilot study to explore the possibility of genetic discovery in patients with VUR using exome sequencing. METHODS: Whole exome sequencing was performed on the DNA of ten Indian children (nine boys) with bilateral grade IV/V reflux and bilateral renal hypodysplasia (extreme phenotype) as well as that of a family with 2 affected male siblings with bilateral VUR and chronic kidney disease. For prioritization of single nucleotide variations (SNVs) in the ten children with extreme phenotype, extremely rare and deleterious variations were selected from a list of 778 genes of biological relevance. Hypothesis-free prioritization was performed in the VUR family. Copy-number variations (CNV) were also called and prioritized from whole exome data. RESULTS: Among ten patients with extreme phenotype, rare and novel and deleterious variants related to VUR and renal hypodysplasia were identified in 7/10 patients each. At least one prioritized variant in either genes related to VUR per se or renal hypodysplasia was seen in 8/10 patients. All patients carried different variations. Among the remaining two patients, one carried a pathogenic CNV. In the VUR family, a rare and deleterious variant in SLIT1 gene was identified. CONCLUSION: Sharp phenotyping in combination with exome sequencing using a combination of approaches including hypothesis-driven and hypothesis-free for prioritization of SNVs and study of CNVs seems to be an optimal method of genetic discovery of VUR. VUR is genetically heterogenous.