Autosomal dominant tubulointerstitial kidney disease (ADTKD) in Ireland

Cormican, Sarah; Connaughton, Dervla M.; Kennedy, Claire; Murray, Susan; Živná, Martina; Kmoch, Stanislav; Fennelly, Neil K.; O’Kelly, Patrick; Benson, Katherine; Conlon, Eoin T.; Cavalleri, Gianpiero L.; Foley, Claire; Doyle, Brendan; Dorman, Anthony; Little, Mark A.; Lavin, Peter; Kidd, Kendrah; Bleyer, Anthony J.; Conlon, Peter J.

doi:10.1080/0886022x.2019.1655452

Cited by 21 publications

(16 citation statements)

References 30 publications

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“…Interpolating to the total GCKD cohort, while assuming complete enrichment through our criteria, this would mean a prevalence of 0.13% (7/5,217). Interestingly, this figure is similar to another recent study with the estimate of 0.54% for patients with ADTKD in the complete ESRD cohort of Ireland 52 and the diagnostic yield for ADTKD variants reported by Groopman et al with 0.39% (13/3,315). Importantly, none of the 7 individuals with diagnostic ADTKD mutations were originally grouped as suffering from a “hereditary disorder”.…”

Section: Discussionsupporting

confidence: 91%

Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study

Popp

Ekici

Knaup

et al. 2021

Preprint

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Exome sequencing (ES) studies in chronic kidney disease (CKD) cohorts could identify pathogenic variants in ~10% of patients. This implies underdiagnosis of hereditary CKD. Tubulointerstitial kidney diseases, showing no typical clinical/histologic finding but tubulointerstitial fibrosis, are particularly difficult to diagnose. We used a custom designed targeted panel (29 genes) and MUC1-SNaPshot to sequence 271 DNA samples, selected by clinical criteria from 5,217 individuals in the German Chronic Kidney Disease (GCKD) cohort. We identified 33 pathogenic small variants. Of these 27 (81.8%) were in COL4-genes, the largest group being 15 COL4A5-variants with nine unrelated individuals carrying c.1871G>A, p.(Gly624Asp). We found three cysteine variants in UMOD, a novel missense, and a novel splice variant in HNF1B and the homoplastic MTTF variant m.616T>C. Copy-number analysis identified a heterozygous COL4A5-deletion, and a HNF1B-duplication/-deletion, respectively. Overall, pathogenic variants were present in 12.5% (34/271) and variants of unknown significance in 9.6% (26/271) of selected individuals. Bioinformatic predictions paired with gold standard diagnostics for MUC1 (SNaPshot) could not identify the typical cytosine duplication ('c.428dupC') in any individual, implying that ADTKD-MUC1 is rare. Our study shows that >10% of individuals with certain clinical features carry disease variants in genes associated with tubulointerstitial kidney diseases. COL4-genes constitute the largest fraction, implying they are overlooked using clinical Alport-syndrome criteria. We also identified variants easily missed by some ES pipelines. Finally, our results indicate that the filtering criteria applied enrich for an underlying genetic disorder.

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Section: Discussionsupporting

confidence: 91%

Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study

Popp

Ekici

Knaup

et al. 2021

Preprint

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“…The families, individuals, and grafts included in this report are summarized in Table . Mutation details have been reported elsewhere . Transplants were performed between 1980 and the present day with 15 performed before 2000 and a further 21 performed thereafter.…”

Section: Resultsmentioning

confidence: 99%

“…Polycystic kidney disease accounts for the majority of these patients, but there are also approximately 160 “Rare Kidney Diseases” which result from genetic mutations and frequently progress to ESRD . ADTKD is one such condition, and we have reported separately on the clinical characteristics of Irish individuals with ADTKD . Recently, the use of whole‐exome sequencing has been used to evaluate Irish individuals with a suspected rare genetic cause of kidney disease …”

Section: Discussionmentioning

confidence: 99%

“…23 ADTKD is one such condition, and we have reported separately on the clinical characteristics of Irish individuals with ADTKD. 20 Recently, the use of whole-exome sequencing has been used to evaluate Irish individuals with a suspected rare genetic cause of kidney disease. 24 There are, at present, no specific therapies to delay CKD progression in patients with ADTKD.…”

Section: Discussionmentioning

confidence: 99%

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Renal transplant outcomes in patients with autosomal dominant tubulointerstitial kidney disease

Cormican

Kennedy

Connaughton

et al. 2020

Clinical Transplantation

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Introduction Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of chronic kidney disease (CKD) and end‐stage renal disease (ESRD). We aimed to compare renal transplant outcomes in people with ESRD due to ADTKD to those with other causes of renal failure. Methods Patients with clinical characteristics consistent with ADTKD by the criteria outlined in the 2015 KDIGO consensus were included. We compared ADTKD transplant outcomes with those of 4633 non‐ADTKD renal transplant recipients. Results We included 31 patients who met diagnostic criteria for ADTKD in this analysis, 23 of whom had an identified mutation (28 were categorized as definite‐ADTKD and 3 as suspected ADTKD). Five patients received a second transplant during follow‐up. In total, 36 grafts were included. We did not identify significant differences between groups in terms of graft or patient survival after transplantation. Twenty‐five transplant biopsies were performed during follow‐up, and none of these showed signs of recurrent ADTKD post‐transplant. Conclusion In patients with ESRD due to ADTKD, we demonstrate that transplant outcomes are comparable with the general transplant population. There is no evidence that ADTKD can recur after transplantation.

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“…This was considered to be the case if they had an acute rise in creatinine and a diagnosis on biopsy of acute tubular necrosis (ATN) or acute interstitial nephritis (AIN) -They had a positive ANCA and a biopsy showing pauci-immune vasculitis -They were a known diabetic and had a diagnosis consistent with diabetic nephropathy DNA was extracted from blood lymphocytes. Genomic sequencing was performed in-house, with library preparation using a previously described targeted renal disease gene panel (Cormican et al 2019). This sequencing method is unable to detect small insertions and deletions in the variable number tandem repeat region of MUC1.…”

Section: Methodsmentioning

confidence: 99%

Diagnostic utility of genetic testing in patients undergoing renal biopsy

Benson

Murray

Doyle

et al. 2020

Cold Spring Harb Mol Case Stud

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High-throughput DNA testing is becoming established as a standard diagnostic test in the renal clinic. Previously published studies on cohorts of patients with unexplained chronic kidney disease of a suspected genetic aetiology have suggested a diagnostic yield for genomic sequencing of up to 18%. Here we determine the yield of targeted gene panel in a clinically unscreened cohort of patients referred for percutaneous native renal biopsy. Patients who underwent renal biopsy for investigation of chronic kidney disease were sequenced using a genomic sequencing panel covering 227 genes in which variation is known to be associated with monogenic chronic kidney disease (CKD). Candidate disease-causing variants were assessed for pathogenicity using guidelines from the American College for Medical Genetics and Genomics. Fifty CKD patients were recruited and sequenced. A molecular diagnosis was obtained for two patients (4%). A molecular diagnosis is possible using genomic testing in ∼4% of clinically unscreened patients undergoing renal biopsy. Genetic screening may be useful for diagnosis in a subset of CKD patients but is most valuable when applied to patients with suspected heritable forms of kidney disease.

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Autosomal dominant tubulointerstitial kidney disease (ADTKD) in Ireland

Cited by 21 publications

References 30 publications

Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study

Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study

Renal transplant outcomes in patients with autosomal dominant tubulointerstitial kidney disease

Diagnostic utility of genetic testing in patients undergoing renal biopsy

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