Familial Vesicoureteral Reflux: Testing Replication of Linkage in Seven New Multigenerational Kindreds

Abstract

Vesicoureteral reflux (VUR) (OMIM %193000), a common cause of childhood renal failure, is strongly influenced by hereditary factors. Familial VUR most closely conforms to autosomal-dominant inheritance, but because of variable penetrance and expressivity, large multigenerational pedigrees tractable to linkage analysis have been difficult to ascertain. A single genome-wide study of familial VUR has demonstrated linkage to chromosome 1p13, with 78% locus heterogeneity. Previous studies in humans have also suggested loci on chromosomes 6p21, 10q26, and 19q13, whereas mutations in ROBO2 were recently reported in some patients with VUR. Replication of these studies was attempted in seven previously undescribed families from Italy and the United States. Simulation studies, assuming 50% locus heterogeneity, showed that these kindreds had 85% power to replicate linkage and 53% power to achieve genome-wide significance at candidate intervals. Thirty-five markers on chromosomes 1p13, 3p12, 6p21, 10q26, and 19q13 were genotyped and analysis of linkage under a variety of models was performed. Parametric analysis excluded linkage to all candidate loci under genetic homogeneity; moreover, the data did not support statistically significant linkage under models of locus heterogeneity. Similarly, nonparametric, allele-sharing analysis did not reveal any evidence of linkage at any of the loci tested. Thus, despite sufficient power, linkage of familial VUR to previously reported candidate intervals could not be replicated. These data demonstrate substantial genetic heterogeneity of VUR and suggest that mapping strategies relying on a large number of kindreds or single "loaded" pedigrees will be most effective to achieve replication or detection of linkage.

ROBO2 gene variants in children with primary nonsyndromic vesicoureteral reflux with or without renal hypoplasia/dysplasia

“…Three linkage studies, however, have been unable to support these findings. One study on Italian and American kinships with VUR, one on four Dutch families with VUR, and one on UK and Slovenian data sets with VUR found no linkage to the locus of ROBO2 (6,8,11). In this study, syndromic cases of VUR were excluded, and the cases of primary nonsyndromic VUR accompanied by RHD were studied separately.…”

“…Recent studies have identified variants of the roundabout, axon guidance receptor, homolog 2 (ROBO2) gene in patients with VUR and VUR accompanied by other CAKUT, but their conclusions are contradictory on whether or not mutations of the ROBO2 gene are a causative factor of VUR or VUR-other CAKUT (6)(7)(8)(9)(10)(11)(12)(13)(14).…”

Genetics of vesicoureteral reflux

“…24,105,106 roBo2/sliT2 to date, two groups have reported ROBO2 gene missense mutations associated with vur, 107,108 and a further study has supported the hypothesis that variations in ROBO2 and SLIT2 are rare causes of vur in humans. 109 However, subsequent candidate gene linkage studies including the ROBO2 locus found no evidence for linkage, 23 and similar study has found no evidence of linkage at SLIT2. 24 …”

“…two attempts to replicate their findings were unsuccessful. 23,24 this may be explained by the fact that the map positions of some of the markers linked to vur by Feather et al 22 have since been revised-the marker defining one side of their reviews…”

“…it has become increasingly evident that the familial clustering of vur must have a genetic basis; however, to date there has been no agreement on the mode of inheritance. a range of inheritance patterns have been suggested, including autosomal dominant with incomplete penetrance, [20][21][22][23][24] autosomal recessive, 25,26 X-linked 27,28 and polygenic, 29 and a substantial amount of work has evaluated candidate genes and conducted genome-wide scans. However, an understanding of the genetics of primary vur remains elusive.…”