Alternative titles; symbols
ORPHA: 289365; DO: 9620;
Cytogenetic location: 1p13 Genomic coordinates (GRCh38): 1:106,700,001-117,200,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p13 | Vesicoureteral reflux 1 | 193000 | Autosomal dominant | 2 |
Vesicoureteral reflux (VUR) is characterized by the reflux of urine from the bladder into the ureters and sometimes into the kidneys. It is a risk factor for urinary tract infections. Primary VUR results from a developmental defect of the ureterovesical junction (UVJ). In combination with intrarenal reflux, the resulting inflammatory reaction may result in renal injury or scarring, also called reflux nephropathy (RN). Extensive renal scarring impairs renal function and may predispose patients to hypertension, proteinuria, and renal insufficiency (summary by Lu et al., 2007).
Genetic Heterogeneity of Vesicoureteral Reflux
A locus designated VUR1 maps to chromosome 1p13. VUR2 (610878) is caused by mutation in the ROBO2 gene (602431) on chromosome 3p12; VUR3 (613674) is caused by mutation in the SOX17 gene (610928) on chromosome 8q11; VUR4 (614317) maps to chromosome 5; VUR5 (614318) maps to chromosome 13; VUR6 (614319) maps to chromosome 18; VUR7 (615390) maps to chromosome 12; and VUR8 (615963) is caused by mutation in the TNXB gene (600985) on chromosome 6p21. A possible X-linked form has been reported (VURX; 314550).
Mulcahy et al. (1970) described a high familial incidence. The disorder is rare in blacks. Burger (1972) found 23 families with 2 or more affected first-degree relatives and added 7 more containing a total of 20 affected first-degree relatives. The anatomic substrate was thought to be abnormally short intravesical ureter. Mother and at least 1 child were affected in 4 families.
Fried et al. (1975) described 2 families, each with several affected children. In 1 family the mother had unilateral reflux. Investigating relatives is important because if the disorder is not treated, progressive renal damage may occur. Lewy and Belman (1975) observed vesicoureteral reflux in father and 3 sons.
Van den Abbeele et al. (1987) studied 60 asymptomatic sibs of patients known to have vesicoureteral reflux, using radionuclide voiding cystography. Vesicoureteral reflux was detected in 27 of the 60 (45%). Reflux was unilateral in 15 and bilateral in 12. Van den Abbeele et al. (1987) stated that the gonadal dose with radionuclide cystography is low and recommended that this procedure should be used in screening all sibs of patients with known vesicoureteral reflux.
Connolly et al. (1996) studied the natural history of vesicoureteral reflux as revealed by the clinical records and radionuclide cystograms of 76 girls and 32 boys of mean age 21 months with reflux detected in a sib screening program. Reflux resolved in 52.8% of cases at a mean follow-up of 18.5 months. Yearly resolution rates exceeded 28%. Predictors of the likelihood of resolution were not identified. By showing that spontaneous resolution is likely for children with this disorder, this study supported nonsurgical management with annual imaging evaluation.
Lu et al. (2007) stated that VUR has an incidence of approximately 1 in 100 infants.
Reflux nephropathy resulting from vesicoureteral reflux is said to account for as much as 15% of end-stage renal disease in children and young adults (Kincaid-Smith et al., 1984). In sibs and offspring of affected persons, the prevalence is as high as 50% (Van den Abbeele et al., 1987; Noe et al., 1992).
VUR may be multifactorial (Burger, 1972; Fried et al., 1975) rather than autosomal dominant.
Chapman et al. (1985) applied complex segregation analysis to data from 88 families with at least 1 person with VUR. They concluded that a single major locus is the most important causal factor. The mutant allele was estimated to be dominant with a frequency of about 0.16%. As adults, about 45% of persons with the gene would have VUR and/or reflux nephropathy and 15% develop renal failure, compared to 0.05% and 0.001%, respectively, for persons without the gene. Whether this disorder is multifactorial or mendelian, the analysis points up the importance of studying asymptomatic relatives of persons with VUR.
Peeden and Noe (1992) found 18 patients with vesicoureteral reflux among 48 children with urinary tract infections. All 24 sibs of these 18 index patients were studied for the presence of reflux which was found in 11 (46%). Kenda et al. (1991) had reported similar findings. Using data from a review of records in 2 medical centers, Wan et al. (1996) reported an overall reflux rate in 27% of 622 sibs, with a 33% rate in females. Twin sibs (zygosity unspecified) had the highest reflux rates (67%). Most sibs with reflux were younger than 7 years; less than 5% were older than 10 years, yet the older sibs comprised a significant proportion of those with RN. Nearly 14% of sibs had renal scarring, which did not correlate with reflux grade. The severity of sib reflux was usually low and was more common in the lesser grades (I, II, III).
Robson et al. (1994, 1995) suggested that multicystic dysplasia of kidneys (143400), ureteropelvic junction obstruction, and VUR may have a common genetic cause.
Devriendt et al. (1998) reviewed the evidence that VUR is an autosomal dominant condition with reduced penetrance. They suggested that since VUR can be seen in the contralateral side of individuals with syndromic or nonsyndromic multicystic renal dysplasia, ureterovesical junction obstruction, pelviureteral junction obstruction, ureteral duplication, renal hypoplasia, and renal aplasia, these different urologic malformations not only have a related pathogenesis, but may be caused by mutations in the same genes.
Feather et al. (2000) performed a genomewide search in 7 European families with apparently dominant inheritance of VUR/RN. The most positive locus spanned 20 cM on 1p13 between 2 specific markers, giving a nonparametric lod score of 5.76 (P = 0.0002) and a parametric lod score of 3.16. Saturation with markers at 1-cM intervals increased the nonparametric lod score to 5.94 (P = 0.00009). There was evidence of genetic heterogeneity, and 12 additional loci were identified genomewide, with P less than 0.05. They found no positive results in areas that had previously been reported as renal malformation loci, including 6p (see 143400) and 10q, the site of the PAX2 gene (167409).
Van Eerde et al. (2007) was unable to confirm linkage to the locus on chromosome 1p13 in 4 unrelated Dutch families with VUR. Further analysis excluded linkage to any loci or gene, indicating genetic heterogeneity.
Associations Pending Confirmation
By genomewide analysis of 104 primarily Irish families with primary VUR, Kelly et al. (2007) identified a candidate locus on chromosome 2q37.1-q37.3 (maximum nonparametric lod score of 4.10).
Among French Canadian VUR patients, Yang et al. (2008) observed a significant association between primary VUR and a G691S polymorphism (rs1799939) in the RET gene (164762) on chromosome 10q11. The rare A allele was identified in 83 of 118 unrelated probands with VUR; 2 affected sibs were homozygous for the variant. The frequency of the A allele was 0.145 in controls and 0.360 in patients. Yang et al. (2008) hypothesized that the variant may result in local conformational changes and altered phosphorylation status of RET. As Skinner et al. (2008) observed an association between variants in the RET gene and renal adysplasia, VUR may be a manifestation of that disorder.
Choi et al. (1998) studied 23 affected individuals from 8 families with primary familial VUR. Sanyanusin et al. (1995) demonstrated mutations in the PAX2 gene (167409.0001) in renal coloboma syndrome (120330), of which VUR is a part. By use of SSCP, Choi et al. (1998) found no mutations in exons 2 to 5 of the PAX2 gene. In addition, a polymorphic dinucleotide repeat marker located within the PAX2 gene segregated independently of the disease. Choi et al. (1998) concluded that mutation in the PAX2 gene is not a major cause of primary familial reflux.
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