The genetic landscape of polycystic kidney disease in Ireland

Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype

“…Screening was performed using either a 137 or 357 gene tNGS panel containing known and candidate PKD and ciliopathy genes, 38,46 and for the 35 IKGP and 69 Brest/Genkyst individuals, as described, respectively, with IFT140 added to the French panel. 17,43 As indicated in Figure 1, causative variants in PKD1 or PKD2 were not found in previous testing of 352 families, while 834 families had not been previously screened. Library preparation, sequencing, read-alignment, and variant calling were performed as previously described.…”

“…Details of the study participants and their recruitment sites are summarized in Figure 1. Subjects were recruited from ADPKD clinical trials: HALT-PKD (n ¼ 49), 36,37 TAME-PKD (n ¼ 83), 38 and DIPAK (n ¼ 12); 39 observational ADPKD studies: Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) (n ¼ 11), 40 Genkyst (n ¼ 10), 41 and DIPAK Observational Study (n ¼ 137); 42 genetic studies of ADPKD: ADKPD Modifier Study (n ¼ 49), the Mayo PKD Center (n ¼ 737), and the Irish Kidney Gene Project (IKGP; n ¼ 35); 43 and from other academic centers studying ADPKD. The relevant institutional review boards or ethics committees approved all studies, and participants gave informed consent.…”

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

“…AS Alport syndrome, CAKUT congenital anomalies of the kidney and urinary tract, CKD Chronic kidney disease, ESKD end stage kidney disease, GKD genetic kidney disease, IQR Interquartile range, FHx family history, FSGS focal segmental glomerulosclerosis, GN glomerulonephritis, PKD polycystic kidney disease, uCKD CKD of uncertain aetiology, TIKD tubulointerstitial kidney disease, Yrs years 1 In total, 677 patients were reviewed in the genetic kidney disease (GKD) clinic, recruited and bio-banked for the evaluation and management of nephropathy. Included in this large cohort, two groups of patients were previously published in the Monogenic Kidney Disease Study [11] and PKD study [23]; these are grouped separately for clarity 2 A positive family history of kidney disease that was reported by the patient (either a 1st-degree relative (parent, child, or sibling) or a 2nd -degree relative (grandparent, aunt, uncle, niece, nephew, or cousin) Non-Cystic GKD: Among 313 families with non-cystic GKD, the diagnostic yield was 27.1%. The diagnostic yield varied within each diagnostic subgroup (Table 2, Supplementary Fig.…”

“…1 More than 475 known chronic kidney disease genes; see references [11,25]. 2 Roche SeqCap EZ Choice (227 genes panel) and Roche NimbleGen HeatSeq panel (11 genes panel); see reference [23] found to have a known monogenic disorder, bringing their diagnostic odyssey to an end, and emphasising the difficulties in making a clinical diagnosis in these very rare conditions without genetics support (Supplementary Table S1). In patients with a priori diagnosis of CAKUT, we detected 11 pathogenic/likely pathogenic variants in 11 individuals, corresponding to 7 of 73 families (9.6%).…”

“…In this prospective study, we describe our overall experience of the IKGP over the 7-year period from 2014 to 2020 and the clinical impact of GKDC on patients, including some patient subsets that have been previously described [11,[19][20][21][22][23][24].…”