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.

Department of Medicine Dublin Royal College of Surgeons in Ireland Dublin Ireland

Department of Nephrology and Internal Medicine University Hospital Limerick Limerick Ireland

Department of Nephrology and Transplantation Beaumont Hospital Dublin Ireland

Department of Paediatrics Boston Children's Hospital Harvard Medical School Boston MA 02115 USA

Department of Pathology Beaumont Hospital Dublin Ireland

Department of Pathology Royal College of Surgeons in Ireland Dublin Ireland

Division of Nephrology and Hypertension Mayo Clinic Rochester MN USA

Division of Nephrology Department of Medicine London Health Sciences Centre London ON Canada

Nephrology Department Galway University Hospitals Saolta University Healthcare Group Galway Ireland

Regenerative Medicine Institute at CÚRAM Centre for Research in Medical Devices School of Medicine National University of Ireland Galway Ireland

Research Unit for Rare Diseases Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University Prague Prague Czech Republic

School of Pharmacy and Biomolecular Sciences Royal College of Surgeons Dublin Ireland

Schulich School of Medicine and Dentistry University of Western Ontario London ON Canada

Section on Nephrology Wake Forest School of Medicine Winston Salem NC USA

Trinity Health Kidney Centre Trinity Translational Medicine Institute Trinity College Dublin St James' Street Dublin 8 Ireland

Zobrazit více v PubMed

Devuyst O, et al. Rare inherited kidney diseases: challenges, opportunities, and perspectives. Lancet. 2014;383(9931):1844–1859. doi: 10.1016/S0140-6736(14)60659-0. PubMed DOI PMC

Soliman NA. Orphan kidney diseases. Nephron Clin Pract. 2012;120(4):c194–c199. doi: 10.1159/000339785. PubMed DOI

Connaughton DM, et al. The Irish Kidney Gene project-prevalence of family history in patients with kidney disease in Ireland. Nephron. 2015;130(4):293–301. doi: 10.1159/000436983. PubMed DOI

Cocchi E, Nestor JG, Gharavi AG. Clinical genetic screening in adult patients with kidney disease. Clin J Am Soc Nephrol. 2020;15(10):1497–1510. doi: 10.2215/CJN.15141219. PubMed DOI PMC

Thomas CP, et al. Initial experience from a renal genetics clinic demonstrates a distinct role in patient management. Genet Med. 2020;22(6):1025–1035. doi: 10.1038/s41436-020-0772-y. PubMed DOI PMC

Mallett A, et al. A multidisciplinary renal genetics clinic improves patient diagnosis. Med J Aust. 2016;204(2):58–59. doi: 10.5694/mja15.01157. PubMed DOI

IKGP. The Irish Kidney Gene Porject. 2021; Available from: http://www.beaumont.ie/kidneycentre-aboutus-irishkidneygeneproject. Cited 10 Dec 2021

HSE. National Service Plan 2020. 2020; Available from: https://www.hse.ie/eng/services/publications/national-service-plan-2020.pdf. Cited 21 May 2021

Jayasinghe K, et al. Clinical impact of genomic testing in patients with suspected monogenic kidney disease. Genet Med. 2021;23(1):183–191. doi: 10.1038/s41436-020-00963-4. PubMed DOI PMC

Groopman EE, et al. Diagnostic utility of exome sequencing for kidney disease. N Engl J Med. 2019;380(2):142–151. doi: 10.1056/NEJMoa1806891. PubMed DOI PMC

Connaughton DM, et al. Monogenic causes of chronic kidney disease in adults. Kidney Int. 2019;95(4):914–928. doi: 10.1016/j.kint.2018.10.031. PubMed DOI PMC

Lata S, et al. Whole-exome sequencing in adults with chronic kidney disease: a pilot study. Ann Intern Med. 2018;168(2):100–109. doi: 10.7326/M17-1319. PubMed DOI PMC

Ali H, et al. PKD1 duplicated regions limit clinical utility of whole exome sequencing for genetic diagnosis of autosomal dominant polycystic kidney disease. Sci Rep. 2019;9(1):4141. doi: 10.1038/s41598-019-40761-w. PubMed DOI PMC

Bullich G, et al. A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases. Kidney Int. 2018;94(2):363–371. doi: 10.1016/j.kint.2018.02.027. PubMed DOI

Domingo-Gallego A et al. (2021) Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players. Nephrol Dial Transplant PubMed

Mansilla MA, et al. Targeted broad-based genetic testing by next-generation sequencing informs diagnosis and facilitates management in patients with kidney diseases. Nephrol Dial Transplant. 2021;36(2):295–305. doi: 10.1093/ndt/gfz173. PubMed DOI PMC

Eckardt K-U, et al. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management—a KDIGO consensus report. Kidney Int. 2015;88(4):676–683. doi: 10.1038/ki.2015.28. PubMed DOI

Blumenstiel B, et al. Development and validation of a mass spectrometry-based assay for the molecular diagnosis of Mucin-1 kidney disease. J Mol Diagn. 2016;18(4):566–571. doi: 10.1016/j.jmoldx.2016.03.003. PubMed DOI

Murray SL, et al. Utility of genomic testing after renal biopsy. Am J Nephrol. 2020;51(1):43–53. doi: 10.1159/000504869. PubMed DOI PMC

Živná M, et al. Noninvasive immunohistochemical diagnosis and novel MUC1 mutations causing autosomal dominant tubulointerstitial kidney disease. J Am Soc Nephrol. 2018;29(9):2418–2431. doi: 10.1681/ASN.2018020180. PubMed DOI PMC

Cormican S, et al. Autosomal dominant tubulointerstitial kidney disease (ADTKD) in Ireland. Ren Fail. 2019;41(1):832–841. doi: 10.1080/0886022X.2019.1655452. PubMed DOI PMC

Stapleton CP, et al. An exome sequencing study of 10 families with IgA nephropathy. Nephron. 2020;144(2):72–83. doi: 10.1159/000503564. PubMed DOI

Benson KA, et al. The genetic landscape of polycystic kidney disease in Ireland. Eur J Hum Genet. 2021;29(5):827–838. doi: 10.1038/s41431-020-00806-5. PubMed DOI PMC

Lane BM, et al. A rare autosomal dominant variant in regulator of calcineurin type 1 (RCAN1) gene confers enhanced calcineurin activity and may cause FSGS. J Am Soc Nephrol. 2021;32:1682–1695. doi: 10.1681/ASN.2020081234. PubMed DOI PMC

CeGAT (2020)

Vylet'al P, et al. Plasma mucin-1 (CA15–3) levels in autosomal dominant tubulointerstitial kidney disease due to MUC1 mutations. Am J Nephrol. 2021;52:1–10. doi: 10.1159/000513952. PubMed DOI PMC

Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–424. doi: 10.1038/gim.2015.30. PubMed DOI PMC

Central Statistics Office (2021) Census 2016 results

Tan YC, et al. Novel method for genomic analysis of PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease. Hum Mutat. 2009;30(2):264–273. doi: 10.1002/humu.20842. PubMed DOI

Cornec-Le Gall E, et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013;24(6):1006–1013. doi: 10.1681/ASN.2012070650. PubMed DOI PMC

Rossetti S, et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007;18(7):2143–2160. doi: 10.1681/ASN.2006121387. PubMed DOI

Wang M, et al. Contributions of rare gene variants to familial and sporadic FSGS. J Am Soc Nephrol. 2019;30(9):1625–1640. doi: 10.1681/ASN.2019020152. PubMed DOI PMC

Gribouval O, et al. Identification of genetic causes for sporadic steroid-resistant nephrotic syndrome in adults. Kidney Int. 2018;94(5):1013–1022. doi: 10.1016/j.kint.2018.07.024. PubMed DOI

Jarvik GP, et al. Return of genomic results to research participants: the floor, the ceiling, and the choices in between. Am J Hum Genet. 2014;94(6):818–826. doi: 10.1016/j.ajhg.2014.04.009. PubMed DOI PMC

Stokman MF, et al. The expanding phenotypic spectra of kidney diseases: insights from genetic studies. Nat Rev Nephrol. 2016;12(8):472–483. doi: 10.1038/nrneph.2016.87. PubMed DOI

Rare disease gene association discovery in the 100,000 Genomes Project

A Novel Monoallelic ALG5 Variant Causing Late-Onset ADPKD and Tubulointerstitial Fibrosis