The utility of a genetic kidney disease clinic employing a broad range of genomic testing platforms: experience of the Irish Kidney Gene Project

Abstract

Background and aims Genetic testing presents a unique opportunity for diagnosis and management of genetic kidney diseases (GKD). Here, we describe the clinical utility and valuable impact of a specialized GKD clinic, which uses a variety of genomic sequencing strategies. Methods In this prospective cohort study, we undertook genetic testing in adults with suspected GKD according to prespecified criteria. Over 7 years, patients were referred from tertiary centres across Ireland to an academic medical centre as part of the Irish Kidney Gene Project. Results Among 677 patients, the mean age was of 37.2 ± 13 years, and 73.9% of the patients had family history of chronic kidney disease (CKD). We achieved a molecular diagnostic rate of 50.9%. Four genes accounted for more than 70% of identified pathogenic variants: PKD1 and PKD2 (n = 186, 53.4%), MUC1 (8.9%), and COL4A5 (8.3%). In 162 patients with a genetic diagnosis, excluding PKD1/PKD2, the a priori diagnosis was confirmed in 58% and in 13% the diagnosis was reclassified. A genetic diagnosis was established in 22 (29.7%) patients with CKD of uncertain aetiology. Based on genetic testing, a diagnostic kidney biopsy was unnecessary in 13 (8%) patients. Presence of family history of CKD and the underlying a priori diagnosis were independent predictors (P < 0.001) of a positive genetic diagnosis. Conclusions A dedicated GKD clinic is a valuable resource, and its implementation of various genomic strategies has resulted in a direct, demonstrable clinical and therapeutic benefits to affected patients. Graphical abstract

Incorporating Genetics Services into Adult Kidney Disease Care

“…For results considered positive (diagnostic or non-diagnostic) or candidate diagnostic findings, 98 variants in 28 unique genes were identified (Figure 3c, Supplementary Table 3). One patient was found to have variants in two genes associated with Alport syndrome (variants in COL4A4 and COL4A5 ), two patients were found to have dual diagnostic findings, and four patients were found to have both a (Elhassan EAE, 2022)diagnostic or candidate diagnostic finding in addition to a non-diagnostic finding. For two patients, the original results were classified as candidate diagnoses, but since the initial report was issued, the results were upgraded to diagnostic findings by the laboratory.…”

“…With these emerging data, the nephrology medical specialty is increasingly utilizing genomic medicine in clinical practice, similar to other specialties such as oncology (Hampel H, 2015) or cardiology (Hershberger R E, 2018; Mital S, 2016), where genetics clinics have become well integrated into clinical practices and are associated with positive outcomes, such as increased knowledge and positive health behaviors, and decreased anxiety and decisional conflict (Madlensky L, 2017). Newly formed renal genetic clinics have reported their early experiences with genetic testing (Amlie-Wolf L, 2021; Thomas C P, 2020; Mallett A, 2016; Alkanderi S, 2017; Pode-Shakked B, 2022; Lundquist A L, 2020; Elhassan EAE, 2022), utilizing the expertise of clinical geneticists, genetic counselors, and nephrologists to guide the interpretation, clinical assessment, and correlation of genetic findings. The integration of genetic counselors in nephrology aims to address nephrologists’ lack of training and low confidence in interpreting genetic results (Jayasinghe K, 2020; Berns, 2010).…”

Framework for prioritizing variants of unknown significance from clinical genetic testing in kidney disease – utility of multidisciplinary approach to gather evidence of pathogenicity for Hepatocyte Nuclear Factor-1β (HNF1B) p.Arg303His

“…Despite the high utility of genetic testing in CKD, upwards of 10-30% of tests returned a VUS in part because the painstaking work of gathering and adjudicating evidence to determine the pathogenicity (3,(16)(17)(18). Variant classification for CKD-associated variants is disproportionately affected as very few CKD genes are recommended as returnable in incidental findings by the ACMG-AMP guidelines compared to cardiac disease or cancer genes (43).…”

“…A consequence of testing dozens if not hundreds of genes linked to kidney disease is that many variants of unknown significance (VUS) are often detected. In various cohorts, up to 10-30% of genetic results may be VUS, classified according to the American College of Medical Genetics-Association for Molecular Pathology (ACMG-AMP) criteria (3,(16)(17)(18). VUS present a diagnostic and ethical challenge in genetic testing and lack of resolution may result in delays in treatment and management (19).…”

Framework From a Multidisciplinary Approach for Transitioning Variants of Unknown Significance From Clinical Genetic Testing in Kidney Disease to a Definitive Classification

“…In various cohorts, from 10% to 100% of genetic results may be VUS, classified according to the American College of Medical Genetics-Association for Molecular Pathology (ACMG-AMP) criteria. 3,[18][19][20] VUS present a diagnostic and ethical challenge in genetic testing and lack of resolution may result in delays in treatment and management. 21 Variant reclassification from VUS to (likely) benign, or (likely) pathogenic improves as data sharing and variant curation efforts from expert panels (e.g., ClinGen and Genomics England) expand.…”