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.

Diagnostic Utility of Exome Sequencing for Kidney Disease.

BACKGROUND: Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally. METHODS: We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings. RESULTS: In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management. CONCLUSIONS: Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases. (Funded by the National Institutes of Health and others.).

Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study.

PURPOSE: Recruitment of participants from diverse backgrounds is crucial to the generalizability of genetic research, but has proven challenging. We retrospectively evaluated recruitment methods used for a study on return of genetic results. METHODS: The costs of study design, development, and participant enrollment were calculated, and the characteristics of the participants enrolled through the seven recruitment methods were examined. RESULTS: A total of 1118 participants provided consent, a blood sample, and questionnaire data. The estimated cost across recruitment methods ranged from $579 to $1666 per participant and required a large recruitment team. Recruitment methods using flyers and staff networks were the most cost-efficient and resulted in the highest completion rate. Targeted sampling that emphasized the importance of Latino/a participation, utilization of translated materials, and in-person recruitments contributed to enrolling a demographically diverse sample. CONCLUSIONS: Although all methods were deployed in the same hospital or neighborhood and shared the same staff, each recruitment method was different in terms of cost and characteristics of the enrolled participants, suggesting the importance of carefully choosing the recruitment methods based on the desired composition of the final study sample. This analysis provides information about the effectiveness and cost of different methods to recruit adults for genetic research.

Correction: Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study.

The original version of this Article contained an error in the undergraduate degree awarded to the author Ian Halim, which was incorrectly given as BS. This has now been corrected to BA in both the PDF and HTML versions of the Article.

Implementation and Feasibility of Clinical Genome Sequencing Embedded Into the Outpatient Nephrology Care for Patients With Proteinuric Kidney Disease.

Introduction: The diagnosis and management of proteinuric kidney diseases such as focal segmental glomerulosclerosis (FSGS) are challenging. Genetics holds the promise to improve clinical decision making for these diseases; however, it is often performed too late to enable timely clinical action and it is not implemented within routine outpatient nephrology visits. Methods: We sought to test the implementation and feasibility of clinical rapid genome sequencing (GS) in guiding decision making in patients with proteinuric kidney disease in real-time and embedded in the outpatient nephrology setting. Results: We enrolled 10 children or young adults with biopsy-proven FSGS (9 cases) or minimal change disease (1 case). The mean age at enrollment was 16.2 years (range 2-30). The workflow did not require referral to external genetics clinics but was conducted entirely during the nephrology standard-of-care appointments. The total turn-around-time from enrollment to return-of-results and clinical decision averaged 21.8 days (12.4 for GS), which is well within a time frame that allows clinically relevant treatment decisions. A monogenic or APOL1-related form of kidney disease was diagnosed in 5 of 10 patients. The genetic findings resulted in a rectified diagnosis in 6 patients. Both positive and negative GS findings determined a change in pharmacological treatment. In 3 patients, the results were instrumental for transplant evaluation, donor selection, and the immunosuppressive treatment. All patients and families received genetic counseling. Conclusion: Clinical GS is feasible and can be implemented in real-time in the outpatient care to help guiding clinical management. Additional studies are needed to confirm the cost-effectiveness and broader utility of clinical GS across the phenotypic and demographic spectrum of kidney diseases.

Persistent Disease Activity in Patients With Long-Standing Glomerular Disease.

INTRODUCTION: Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease. METHODS: Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort, n = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy <5 years before enrollment drawn from the Cure Glomerulonephropathy Network (CureGN cohort, n = 1182; CUMC-CureGN cohort, n = 362). Disease activity was defined by (i) Kidney Disease: Improving Global Outcomes-recommended threshold criteria for initiation of immunosuppression in primary glomerulonephropathy (GN) and (ii) CureGN's Disease Activity Working Group definitions for activity. RESULTS: No significant differences were detected among the 3 cohorts in terms of age, sex, serum creatinine, and urinary protein-to-creatinine ratio. For each GN subtype, disease activity in the OLD cohort was comparable with disease activity in the entire CureGN and the CUMC-CureGN cohort. When limiting our comparisons to disease activity in incident CUMC-CureGN patients (first diagnostic biopsy within 6 months of enrollment), OLD patients demonstrated similar activity rates as incident patients. CONCLUSION: Disease activity did not differ among patients with shorter versus longer duration of disease. Such survivor patients, with long-term but persistent disease, are potentially highly informative for understanding the clinical course and pathogenesis of GN and may help identify factors mediating more chronic subtypes of disease.