Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis.

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.

Smell - Adding a New Dimension to Urinalysis.

BACKGROUND: Urinary tract infections (UTI) are among the most common infections in children. The primary tool to detect UTI is dipstick urinalysis; however, this has limited sensitivity and specificity. Therefore, urine culture has to be performed to confirm a UTI. Urinary volatile organic compounds (VOC) may serve as potential biomarker for diagnosing UTI. Previous studies on urinary VOCs focused on detection of UTI in a general population; therefore, this proof-of-principle study was set up in a clinical high-risk pediatric population. METHODS: This study was performed at a tertiary nephro-urological clinic. Patients included were 0-18 years, clinically suspected of a UTI, and had abnormal urinalysis. Urine samples were divided into four groups, i.e., urine without bacterial growth, contamination, colonization, and UTI. VOC analysis was performed using an electronic nose (eNose) (Cyranose 320®) and VOC profiles of subgroups were compared. RESULTS: Urinary VOC analysis discriminated between UTI and non-UTI samples (AUC 0.70; p = 0.048; sensitivity 0.67, specificity 0.70). The diagnostic accuracy of VOCs improved when comparing urine without bacterial growth versus with UTI (AUC 0.80; p = 0.009, sensitivity 0.79, specificity 0.75). CONCLUSIONS: In an intention-to-diagnose high-risk pediatric population, UTI could be discriminated from non-UTI by VOC profiling, using an eNose. Since eNose can be used as bed-side test, these results suggest that urinary VOC analysis may serve as an adjuvant in the diagnostic work-up of UTI in children.