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Significance Statement Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. Background Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. Methods We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction (n=321), ureterovesical junction obstruction/congenital megaureter (n=178), and COU not otherwise specified (COU-NOS ; n=234). Results We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. Conclusions We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.

INTRODUCTION The neurogenic bladder in children is caused primarily by neural tube defects, which include: myelomeningocele (MMC), meningocele, closed spina bifida, lipomeningoceles, caudal agenesis, tethered cord associated with imperforate anus, malformations of the cloaca. Other minor causes are: spinal cord injury, infectious diseases, cancer, malformations and vascular insults. The neurogenic bladder can be caused by injury affecting different levels of the nervous system, which can determine different clinical conditions: overactive bladder (OAB) with detrusor/sphincter dyssynergia (DSD), detrusor hyperactivity and ipereflexia or areflexia of urethral sphincter, loss of bladder contractility. The diagnosis of neurogenic bladder can be difficult especially in cases of closed spina bifida. In the very first months of the children there may be no clinical signs of disease indeed, but there could be only the presence of cutaneous markers on the lower back. The neurogenic bladder diagnosis is made by clinical and instrumental exams. Videourodynamics is the gold standard for diagnosis, but if this is not available, then a filling cystometry continuing into a pressure flow study should be performed. Approximately 50% of children with MMC and 25% of children with closed spina bifida, have overactive bladder and detrusor/sphincter dyssynergia (DSD) and thus a higher risk of having high intravesical pressures that cause progressive renal damage. For this reason is necessary to start medical treatment (with clean intermittent catheterization and antimuscarinic drugs) and neurogenic bowel management as soon as possible to preserve renal function and to prevent other complications. AIM OF THE STUDY The aim of the study is the therapeutic outcome of oxybutynin ER evaluation in a group of patients with spina bifida, already treated with clean intermittent catheterization (CIP) and oxybutynin immediate release, for neurogenic bladder. MATERIALS AND METHODS This study included 12 patients (5 male and 7 female), aged 6 to 17 years (mean age 9,8 years) with neurogenic bladder referred to our hospital. All these patients are already performing clean intermittent catheterization (CIP) and had undergone medical treatment with oxybutynin immediate release since at least one year. All 12 pts have received a cystomanometry, has filled the frequency volume chart and the Child Behavior Checklist (CBLC/618). All 12 patients enrolled were subjected to treatment with oxybutynin ER with an initial dose of 5 mg/day. It has been necessary to raise the dose to 15 mg/day gradually for following 3 weeks for 7/12 pts. Patients evaluation started 46 weeks after giving of oxybutynin ER. Parameters used for patient assessment were: clinical improvement; improving urodynamic examination, occurrence of side effects, treatment compliance by patients and parents and changes in the score obtained with the CBLC/618. The clinical improvement was evaluated on the basis of the following parameters: number of episodes of urinary incontinence and/or the amount of urine lost involuntarily, urge incontinence and reduction of the frequency of urinary tract infections. The compliance of the therapy was evaluated by filling out the drug intake form. All the parents of the 12 pts have to refill again the CBLC/618 to detect changes. RESULTS 8/12 children (66%) had a reduction of incontinence. The 2 pts (17%) who have had urge incontinence have slightly improved but not resolved the symptoms. Only 3 of 12 pts (25%), 2 females and 1 male, have had febrile infections of the upper urinary tract infections (UTIs), which were treated with antibiotics administered orally for 7 days, with rapid defervescence of fever and negativity of urine test on the third day of therapy. However, the incidence of febrile UTIs has not changed with the administration of oxybutynin ER. Only 7/12 pts had a urodynamic examination control. For 4/7 pts it was observed an improvement of urodynamic path relative to a better bladder compliance related to an improvement of the maximum cystometric capacity (MCC) and reduction of abdominal leak point pressure. The administration of oxybutynin ER didn’t show any new side effect and those already present has not got worse. Among children with dry mouth, 3/12 pts (25%) reported disappearance of the symptom, while 2/12 pts (17%) describe a slight improvement. The ophthalmic xerosis, described by 1 patient out of 12 (8%), has not improved with the new therapy. Within 7/12 pts (58%) with constipation, after the new therapy, 4/12 pts (33%) reported a slight improvement, while the remaining 3/12 pts (25%) not. Also they have not reported other side effects. Only 17% (2/12 ptz) does not appear to have taken the therapy correctly; so the compliance of the therapy is good and results to be 95%. Finally the analysis of the first and second CBCL/618 forms did not show significant differences. CONCLUSIONS The results from this study agree with data reported in the literature. Especially if we refer both to the better adhesion of parents/patients to therapy with oxybutynin ER, both to the appearance of minor side effects (and/or milder side effects) compared to the use of oxybutynin IR. In patients with neurogenic bladder it's important to preserve renal function and ensure early urinary continence, not only to get life expectancy, but also to improve life quality. Increased patient adherence to therapy allows you to have better control on the lower urinary tract by reducing the risk of developing kidney damage.