The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation

Abstract

Purpose Chronic kidney disease (CKD) is a major health-care burden. Increasing evidence suggests that a considerable proportion of patients are affected by a monogenic kidney disorder. Methods In this study, the kidney transplantation waiting list at the Charité was screened for patients with undetermined cause of CKD. By next-generation sequencing (NGS) we targeted all 600 genes described and associated with kidney disease or allied disorders. Results In total, 635 patients were investigated. Of these, 245 individuals had a known cause of CKD (38.5%) of which 119 had a proven genetic disease (e.g., ADPKD, Alport). The other 340 patients (53.5%) were classified as undetermined diagnosis, of whom 87 had kidney failure (KF) onset <40 years. To this latter group genetic testing was offered as well as to those patients (n = 29) with focal segmental glomerulosclerosis (FSGS) and all individuals (n = 21) suspicious for thrombotic microangiopathy (TMA) in kidney biopsy. We detected diagnostic variants in 26 of 126 patients (20.6%) of which 14 of 126 (11.1%) were pathogenic or likely pathogenic. In another 12 of 126 (9.5%) patients, variants of unknown significance (VUS) were detected. Conclusion Our study demonstrates the diagnostic value of comprehensive genetic testing among patients with undetermined CKD.

Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations

“…In this study, we utilized different approaches based on next-generation sequencing (NGS) technologies and comprehensive bioinformatic analyses described in detail elsewhere. 18 , 19 …”

Interstitial Nephritis: A Change in Diagnosis With Next-Generation Sequencing

“…We utilized a targeted comprehensive panel approach in our study which has pros and cons compared to an exome-wide approach recently discussed in greater detail elsewhere 6 . Overall, we put major efforts in our NGS methodology to find a compromise and established a customized gene panel that targets all 600 genes described and associated with kidney disease or allied disorders-as well as corresponding flanking intronic sequences.…”

The HIDDEN Protocol: An Australian Prospective Cohort Study to Determine the Utility of Whole Genome Sequencing in Kidney Failure of Unknown Aetiology

“…Previous cohort studies retrospectively applied WES to early-onset (<50-yearold) and paediatric cohorts of KF patients with a diagnostic yield of between 20 and 50% (8,17). In addition, WES and specific kidney gene panel retrospective application to adult and paediatric KF patients on transplant waiting lists similarly revealed a 10-50% diagnostic yield (7,18,19). The application of WES to KF cohorts of unknown genetic disease aetiology harbours some limitations, including difficulty in diagnosis due to broad phenotypic and genetic heterogeneity, and higher rate of detecting variants of uncertain significance (9).…”

“…The prospective, multi-site study design along with consistent application of inclusion criteria through a national clinical referral approval panel enables strong consistency and applicability. Previous studies in KF cohorts applied genomic testing in single centre cross-sectional analyses to understand the diagnostic utility of whole exome sequencing (WES) (7,8). HIDDEN will extend knowledge regarding the diagnostic utility and benefit of genomic testing by prospectively applying WGS in a cohort of KF in a real-world clinical setting.…”

“…Missed or delayed diagnosis potentially affects disease progression and time to KF (3). Genetic diagnosis also significantly impacts kidney transplantation, with between 20 and 51% of transplant recipients under the age of 50 having a monogenic cause for their kidney disease (7,8). Early molecular diagnosis can clarify the risk of primary disease recurrence in kidney transplant recipients, limiting the use of therapies with significant side effect profiles and helping to identify potential unaffected living-related kidney donors (3).…”