Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players

Abstract

Background Inherited kidney diseases are one of the leading causes of chronic kidney disease (CKD) that manifests before the age of 30 years. Precise clinical diagnosis of early-onset CKD is complicated due to the high phenotypic overlap, but genetic testing is a powerful diagnostic tool. We aimed to develop a genetic testing strategy to maximize the diagnostic yield for patients presenting with early-onset CKD and to determine the prevalence of the main causative genes. Methods We performed genetic testing of 460 patients with early-onset CKD of suspected monogenic cause using next-generation sequencing of a custom-designed kidney disease gene panel in addition to targeted screening for c.428dupC MUC1. Results We achieved a global diagnostic yield of 65% (300/460), which varied depending on the clinical diagnostic group: 77% in cystic kidney diseases, 76% in tubulopathies, 67% in autosomal dominant tubulointerstitial kidney disease, 61% in glomerulopathies, and 38% in congenital anomalies of the kidney and urinary tract. Among the 300 genetically diagnosed patients, the clinical diagnosis was confirmed in 77%, a specific diagnosis within a clinical diagnostic group was identified in 15%, and 7% of cases were reclassified. Of the 64 causative genes identified in our cohort, seven (COL4A3, COL4A4, COL4A5, HNF1B, PKD1, PKD2, and PKHD1) accounted for 66% (198/300) of the genetically diagnosed patients. Conclusions Two-thirds of patients with early-onset CKD in this cohort had a genetic cause. Just seven genes were responsible for the majority of diagnoses. Establishing a genetic diagnosis is crucial to define the precise etiology of CKD, which allows accurate genetic counseling and improved patient management.

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

“…We identified disease-causing variants in 46.5% (233/501) of GKD families (51.4% (348/677) of patients). The diagnostic yield in our cohort was consistent with several earlier studies [5,14,15], but higher than other studies [9,10]. There are several factors that would explain our relatively high yield.…”

“…Indeed, WES has been described as ineffective for diagnosis of ADPKD, the most common form of GKD [13]. NGS-based targeted gene panels may be considered as an alternative, with several studies reporting diagnostic rates ranging from 20 to 78% [14][15][16]. Other techniques may be required for specific genetic diseases.…”

Genetic kidney diseases as an underrecognized cause of chronic kidney disease: the key role of international registry reports

“…patients with cystic kidney diseases, tubulopathies or suspected monogenic glomerulopathies have a likely monogenic cause of the disease [ 50 ]…”

“…kidney disease of unknown aetiology in patients <25–30 years of age; at least 20% of CKD patients under the age of 25 years have an IKD [ 9 , 50 ]…”

Interpreting ciliopathy-associated missense variants of uncertain significance (VUS) in an animal model

“…OMIM#602152). Variants in TMEM67 have also been identified in patients with non-syndromic conditions including cystic kidney disease24 and congenital liver fibrosis25 .More than 60% of reported missense variants in TMEM67 have uncertain or conflicting interpretations of their clinical significance (84/137=61.3%, accessed from ClinVar26 on April 17, 2021). The abundance of human VUS alleles makes TMEM67 an excellent candidate to explore if modelling VUS in C. elegans can generate evidence about their pathogenicity.…”