A genome search for primary vesicoureteral reflux shows further evidence for genetic heterogeneity

Pediatric Nephrology, Jan 2008

Vesicoureteral reflux (VUR) is the most common disease of the urinary tract in children. In order to identify gene(s) involved in this complex disorder, we performed a genome-wide search in a selected sample of 31 patients with primary VUR from eight families originating from southern Italy. Sixteen additional families with 41 patients were included in a second stage. Nonparametric, affected-only linkage analysis identified four genomic areas on chromosomes 1, 3, and 4 (p < 0.05); the best result corresponded to the D3S3681-D3S1569 interval on chromosome 3 (nonparametric linkage score, NPL = 2.75, p = 0.008). This region was then saturated with 26 additional markers, tested in the complete group of 72 patients from 24 families (NPL = 2.01, p = 0.01). We identified a genomic area on 3q22.2–23, where 26 patients from six multiplex families shared overlapping haplotypes. However, we did not find evidence for a common ancestral haplotype. The region on chromosome 1 was delimited to 1p36.2–34.3 (D1S228-D1S255, max. NPL = 1.70, p = 0.03), after additional fine typing. Furthermore, on chromosome 22q11.22–12.3, patients from a single family showed excess allele sharing (NPL = 3.35, p = 0.015). Only the chromosome 3q region has been previously reported in the single genome-wide screening available for primary VUR. Our results suggest the presence of several novel loci for primary VUR, giving further evidence for the genetic heterogeneity of this disorder.

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A genome search for primary vesicoureteral reflux shows further evidence for genetic heterogeneity

Maria Luisa Conte 0 Aida M. Bertoli-Avella 0 Bianca M. de Graaf 0 Francesca Punzo 0 Giuliana Lama 0 Angela La Manna 0 Carolina Grassia 0 Pier Francesco Rambaldi 0 Ben A. Oostra 0 Silverio Perrotta 0 0 P. F. Rambaldi Department of Radiological Sciences, Nuclear Medicine, Second University of Naples , Naples, Italy Vesicoureteral reflux (VUR) is the most common disease of the urinary tract in children. In order to identify gene(s) involved in this complex disorder, we performed a genome-wide search in a selected sample of 31 patients with primary VUR from eight families originating from southern Italy. Sixteen additional families with 41 patients were included in a second stage. Nonparametric, affected-only linkage analysis identified four genomic areas on chromosomes 1, 3, and 4 (p <0.05); the best result corresponded to the D3S3681-D3S1569 interval on chromosome 3 (nonparametric linkage score, NPL= 2.75, p = 0.008). This region was then saturated with 26 additional markers, tested in the complete group of 72 patients from 24 families (NPL= 2.01, p = 0.01). We identified a genomic area on 3q22.2-23, where 26 patients from six multiplex families shared overlapping haplotypes. However, we did not find Financial support: This work was in part supported by the Nierstichting Nederland (grant number C05.2146) and Fondo per gli Investimenti della Ricerca di Base (FIRB). - Vesicoureteral reflux (VUR) (OMIM 193000) is the most common disease of the urinary tract in children and affects 12% of the Caucasian population [1]. VUR may be associated with both acquired postinfectious and congenital parenchymal damage, currently known as reflux nephropathy (RN) [2, 3]. The most serious consequence of RN is chronic renal insufficiency (CRI), leading to end-stage renal failure (ESRF), dialysis, and/or renal transplantation: 25.4% of children affected with CRI have RN [4]. As a consequence, the impact of VUR on public health is considerable and, despite medical and surgical interventions for the past decades, the incidence of VUR-related renal failure has not decreased [5]. The reflux may occur isolated or in association with other congenital abnormalities of kidney/urinary tract (CAKUT) or as part of syndromic entities, such as renalcoloboma or branchio-oto-renal syndromes [68]. The exact etiology of primary VUR is not known, but it is probably related to an abnormal morphogenesis of the ureteral bud, leading to a defect of the ureterovesical junction [9]. The initial evidence suggesting a genetic origin of primary VUR came from twin studies, showing an 80100% concordance for VUR in monozygotic twins vs. a 3550% concordance in dizygotic twins [10, 11]. Subsequent evidence included familial clustering of VUR [12], ethnic differences between affected and nonaffected individuals [13], and an increased risk (3050%) of developing VUR in first-degree relatives of an index case [1416]. From family studies, a range of inheritance patterns was reported, including autosomal dominant with incomplete penetrance [1720], autosomal recessive [21], polygenic [22], and even X-linked [23]. Previous studies suggest a urinary tract malformation locus on chromosome 6p [24, 25]. Studies of humans with chromosomal abnormalities also suggest candidate loci or genes on chromosomes 10q26 [26], 19q13 (USF2 gene) [27], and 13q3334 [28]. Because mutations in PAX2 on 10q24 cause renal-coloboma syndrome, a rare autosomal dominant disease with kidney anomalies that include VUR, this gene was also proposed as a candidate [6, 7]. However, none of these loci or genes has been shown causally related to primary VUR [19, 20]. Recently, Lu et al. [29] showed that mutations in the ROBO2 gene contribute to the pathogenesis of VUR/CAKUT in a small proportion of families. In the only genome-wide linkage study reported to date, Feather et al. [18] demonstrated linkage to chromosome 1p13 for primary VUR under a model of autosomal dominant inheritance with reduced penetrance. Here, we describe the results of the second genome-wide scan for primary VUR. Differently from previous studies and aiming to collect a homogeneous sample set, our patients were ascertained in a single geographic region. Our results suggest the presence of several novel loci for primary VUR, giving further evidence for the genetic heterogeneity of this disorder. Patients and families Fifty-one pedigrees with multiple patients with VUR coming from Campania (southern Italy) were enrolled in the study (Fig. 1). All families were ascertained through an index case, with VUR documented by voiding cystourethrography (VCUG) in males and direct radionuclide cystography (RNC) in females and family members. Three pediatric nephrologists and one radiologist assessed the patients. RN was diagnosed by DMSA scintigraphy (dimercaptosuccinic acid labeled with Technetium-99 m) and defined as focal defects of radionuclide uptake and/or by one-kidney differential uptake below 43% [30]. VUR grading was made accordi (...truncated)


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Maria Luisa Conte, Aida M. Bertoli-Avella, Bianca M. de Graaf, Francesca Punzo, Giuliana Lama, Angela La Manna, Carolina Grassia, Pier Francesco Rambaldi, Ben A. Oostra, Silverio Perrotta. A genome search for primary vesicoureteral reflux shows further evidence for genetic heterogeneity, Pediatric Nephrology, 2008, pp. 587-595, Volume 23, Issue 4, DOI: 10.1007/s00467-007-0675-z