Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux

Abstract

Vesicoureteric reflux (VUR) is the commonest urological anomaly in children. Despite treatment improvements, associated renal lesions – congenital dysplasia, acquired scarring or both – are a common cause of childhood hypertension and renal failure. Primary VUR is familial, with transmission rate and sibling risk both approaching 50%, and appears highly genetically heterogeneous. It is often associated with other developmental anomalies of the urinary tract, emphasising its etiology as a disorder of urogenital tract development. We conducted a genome-wide linkage and association study in three European populations to search for loci predisposing to VUR. Family-based association analysis of 1098 parent-affected-child trios and case/control association analysis of 1147 cases and 3789 controls did not reveal any compelling associations, but parametric linkage analysis of 460 families (1062 affected individuals) under a dominant model identified a single region, on 10q26, that showed strong linkage (HLOD = 4.90; ZLRLOD = 4.39) to VUR. The ~9Mb region contains 69 genes, including some good biological candidates. Resequencing this region in selected individuals did not clearly implicate any gene but FOXI2, FANK1 and GLRX3 remain candidates for further investigation. This, the largest genetic study of VUR to date, highlights the 10q26 region as a major genetic contributor to VUR in European populations.

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux

“…9 Segregation analyses and linkage studies suggested the contribution of rare variants with large effects and multiple modes of inheritance. [12][13][14][15][16][17][18][19] Urinary tract formation in the mouse begins at E9, when nephric ducts form and extend, joining the cloaca. Cloacal septation separates the hindgut from the urogenital sinus (UGS) between E11 and E14.…”

Children with vesico-ureteric reflux have joint hypermobility and occasional TNXB sequence variants

“…While VUR remains a common pediatric disorder, the ability for clinicians to determine who will develop recurrent urinary tract infections, who will develop renal scarring, and how these patients should be managed remains unclear. An additional challenge is the fact that VUR is both genetically 30,31,32,33,34 and phenotypically heterogeneous. The purpose of this paper was to ascertain if VUR with joint hypermobility is a common phenotype and to determine if children with VUR and joint hypermobility might be at higher risk for recurrent urinary tract infections and/or renal scars.…”

Envisioning treating genetically-defined urinary tract malformations with viral vector-mediated gene therapy

“…The latter may become more widely adopted, especially by families who already have a child with a genetically defined urinary tract malformation, and even more so if specific treatments were to become available. Although these are rare diseases, commoner urinary tract anomalies may have genetic causes, including non-syndromic primary vesicoureteric reflux [28].…”