ABSTRACT
Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853∗]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage.
Subject(s)
Chromosome Aberrations , DNA-Binding Proteins/genetics , Fetal Diseases/genetics , Mutation , Urinary Bladder Neck Obstruction/congenital , Urinary Bladder Neck Obstruction/genetics , Adult , Animals , Child , Female , Fetal Diseases/pathology , Genes, Dominant , Gestational Age , Humans , Male , Mice , Middle Aged , Pedigree , Pregnancy , Urinary Bladder Neck Obstruction/pathology , ZebrafishABSTRACT
OBJECTIVE: The aim of the present study was to investigate genetic effects in the formation of congenital lower urinary tract obstruction (LUTO) comprising posterior urethral valves (PUV), urethral atresia, and urethras with variable degrees of stenosis. METHODS: A classic twin study was performed by assessing LUTO twin pairs from the literature. Furthermore, data regarding 3 previously unreported twin pairs with PUV from University of Bonn, Essen and Wroclaws own in-house databases were added. Both pair- and probandwise concordance rates were calculated and compared for monozygotic (MZ) and dizygotic (DZ) twin pairs. RESULTS: The pairwise concordance rates for all LUTO were 53% (95% confidence interval [CI] 32%-73%) and 17% (95% CI 3%-56%) for MZ and DZ twin pairs, respectively (P = .180). The probandwise concordance rates were 69% (95% CI 51%-83%) and 29% (CI 95% 8%-64%) for MZ and DZ twin pairs respectively (P = .084). The MZ/DZ ratios of the pair- and probandwise concordance rates were 3.1 and 2.4, respectively. CONCLUSION: The present study did not show significant differences in comparisons of concordance rates of MZ and DZ twin pairs, probably due to the small number of twin pairs reported. However, the more than 2-fold higher pair- and probandwise concordance rates for MZ versus DZ twin pairs are very suggestive of a contribution of genetic factors to the development of LUTO.
Subject(s)
Diseases in Twins/congenital , Urethral Stricture/congenital , Child , Diseases in Twins/epidemiology , Humans , Infant, Newborn , Male , Twins, Dizygotic/statistics & numerical data , Twins, Monozygotic/statistics & numerical data , Urethra/abnormalities , Urethral Stricture/epidemiologyABSTRACT
This study reviews the outcomes of a model developed to improve the quality of care of residents living within residential aged care facilities (RACF). The Southcare Geriatric Flying Squad saw a total of 640 acutely unwell RACF residents over an 18-month period. Of these, 578 (90.3%) were managed in the RACF avoiding emergency department. Only 35 (5.5%) patients required emergency department transfer and 27 (4.2%) were directly admitted to a medical ward. The service may have reduced emergency presentations by offering rapid assessment and management, choice in place of treatment and level of interventions.