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

Elhussein Elhassan ,Mark A Little,Caragh Stapleton,Matthew D Griffin,Martina Živná,Cliona Cowhig,Gianpiero L Cavalleri,Friedhelm Hildebrandt,Dervla M Connaughton,Claire Kennedy,Anthony J Bleyer,Susan Murray ,Neil K Fennelly,Sarah Cormican,Anthony Dorman,Kendrah Kidd,Peter C Harris,Liam F Casserly ,Katherine Benson ,Brendan Doyle,Stanislav Kmoch,Peter J Conlon

doi:10.1007/s40620-021-01236-2

Abstract

Background and aimsGenetic 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.MethodsIn 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.ResultsAmong 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.ConclusionsA 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

Highlights

Testing for genetic kidney diseases (GKD), encompasses an array of more than 150 rare monogenic disorders, uncovers new horizons for diagnosis and management of patients and their families [1, 2]
Recent studies have focused on the utility of whole-exome sequencing (WES) in diagnosing genetic kidney dis‐ eases (GKD), with a diagnostic yield of 9–37% for monogenic disease depending on the patient population [9,10,11,12]
Twenty-one patients were excluded from analysis as they declined participation, were deemed not to require testing upon referral assessment, or did not provide a sample for analysis (Fig. 1)

Summary

Introduction

Testing for genetic kidney diseases (GKD), encompasses an array of more than 150 rare monogenic disorders, uncovers new horizons for diagnosis and management of patients and their families [1, 2]. To determine the efficacy of genomic sequencing technologies, including next-generation sequenc‐ ing (NGS), and the underlying genetic cause of disease in patients with suspected GKD, we established a research program known as the Irish Kidney Gene Project (IKGP) and an associated clinical service called the Genetic Kid‐ ney Disease Clinic (GKDC), at Beaumont Hospital, Dublin, Ireland [7, 8]. Recent studies have focused on the utility of whole-exome sequencing (WES) in diagnosing GKD, with a diagnostic yield of 9–37% for monogenic disease depending on the patient population [9,10,11,12].

Methods

Results

Conclusion