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

Abstract

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.

Graphical abstract

Figure 1.

Diagnostic yield of genomic screen in 733 individuals with COU. Differences between COU subgroups for diagnostics SNV and CNV yield were all P > 0.05 by using the 2×3 chi-squared test. (A) The overall in silico diagnostic yield of candidate pathogenic SNV and CNV in the COU cohort is 10.0% (73 of 733 patients). This proportion of genomic contribution to the etiology of COU is in accordance with other congenital kidney and urinary tract phenotypes. (B) Distribution of COU cases carrying candidate pathogenic/likely pathogenic SNVs based on mode of inheritance. SNVs in genes with an AD mode of inheritance were vastly predominant for all COU subtypes. (C) Distribution of GDs, likely pathogenic CNVs, and candidate microdeletions and microduplications covering known genes in COU exome cases. Because pathogenic deletions were much more frequently found than duplications in all COU subtypes, our data implicate that haploinsufficiency or dominant negative effects are the main molecular mechanisms leading to COU. DEL, deletion; DUP, duplication. Figure 1 can be viewed in color online at www.jasn.org.