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Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is common, with a prevalence of 1/1000 and predominantly caused by disease-causing variants in PKD1 or PKD2. Clinical diagnosis is usually by age-dependent imaging criteria, which is challenging in patients with atypical clinical features, without family history, or younger age. However, there is increasing need for definitive diagnosis of ADPKD with new treatments available. Sequencing is complicated by six pseudogenes that share 97% homology to PKD1 and by recently identified phenocopy genes. Whole-genome sequencing can definitively diagnose ADPKD, but requires validation for clinical use. We initially performed a validation study, in which 42 ADPKD patients underwent sequencing of PKD1 and PKD2 by both whole-genome and Sanger sequencing, using a blinded, cross-over method. Whole-genome sequencing identified all PKD1 and PKD2 germline pathogenic variants in the validation study (sensitivity and specificity 100%). Two mosaic variants outside pipeline thresholds were not detected. We then examined the first 144 samples referred to a clinically-accredited diagnostic laboratory for clinical whole-genome sequencing, with targeted-analysis to a polycystic kidney disease gene-panel. In this unselected, diagnostic cohort (71 males :73 females), the diagnostic rate was 70%, including a diagnostic rate of 81% in patients with typical ADPKD (98% with PKD1/PKD2 variants) and 60% in those with atypical features (56% PKD1/PKD2; 44% PKHD1/HNF1B/GANAB/ DNAJB11/PRKCSH/TSC2). Most patients with atypical disease did not have clinical features that predicted likelihood of a genetic diagnosis. These results suggest clinicians should consider diagnostic genomics as part of their assessment in polycystic kidney disease, particularly in atypical disease.

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Fig. 1: Flowchart of validation cohort analysis.
Fig. 2: Variants identified in PKD1 and PKD2 across the validation and diagnostic cohorts.
Fig. 3: Overall Results in the Diagnostic Cohort.
Fig. 4: Diagnostic Cohort Results by Clinical Features and Gene.

References

  1. 1.

    Lanktree M, Haghighi A, Guiard E, Harris PC, Paterson AD, Pei Y. Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing. J Am Soc Nephrol. 2018;29:2593–600.

    Google Scholar 

  2. 2.

    Cornec-Le Gall E, Torres VE, Harris PC. Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases. J Am Soc Nephrol. 2018;29:13–23.

    Google Scholar 

  3. 3.

    Pei Y, Obaji J, Dupuis A, Paterson AD, Magistroni R, Dicks E, et al. Unified Criteria for Ultrasonographic Diagnosis of ADPKD. J Am Soc Nephrol. 2009;20:205–12.

    Google Scholar 

  4. 4.

    Iliuta I-A, Kalatharan V, Wang K, Cornec-Le Gall E, Conklin J, Pourafkari M, et al. Polycystic Kidney Disease without an Apparent Family History. J Am Soc Nephrol. 2017;28:2768–76.

    Google Scholar 

  5. 5.

    Pei Y, Hwang YH, Conklin J, Sundsbak JL, Heyer CM, Chan W, et al. Imaging-Based Diagnosis of Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol. 2015;26:746–53.

    Google Scholar 

  6. 6.

    Porath B, Gainullin VG, Gall EC-L, Dillinger EK, Heyer CM, Hopp K, et al. Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease. Am J Hum Genet. 2016;98:1193–207.

    Google Scholar 

  7. 7.

    Cornec-Le Gall E, Olson RJ, Besse W, Heyer CM, Gainullin VG, Smith JM, et al. Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease. Am J Hum Genet. 2018;102:832–44.

    Google Scholar 

  8. 8.

    Clissold RL, Hamilton AJ, Hattersley AT, Ellard S, Bingham C. HNF1B-associated renal and extra-renal disease—an expanding clinical spectrum. Nat Rev Nephrol. 2014;11:102–12.

    Google Scholar 

  9. 9.

    Mallawaarachchi AC, Furlong TJ, Shine J, Harris PC, Cowley MJ. Population data improves variant interpretation in autosomal dominant polycystic kidney disease. Genet Med. 2019;21:1425–34.

  10. 10.

    Gansevoort RT, Arici M, Benzing T, Birn H, Capasso G, Covic A, et al. Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice. Nephrol Dial Transpl. 2016;31:337–48.

    Google Scholar 

  11. 11.

    Cornec-Le Gall E, Audrezet MP, Rousseau A, Hourmant M, Renaudineau E, Charasse C, et al. The PROPKD Score: a New Algorithm to Predict Renal Survival in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol. 2016;27:942–51.

    Google Scholar 

  12. 12.

    Lanktree MB, Iliuta IA, Haghighi A, Song X, Pei Y. Evolving role of genetic testing for the clinical management of autosomal dominant polycystic kidney disease. Nephrol Dial Transpl. 2019;34:1453–60.

    Google Scholar 

  13. 13.

    Rossetti S, Hopp K, Sikkink RA, Sundsbak JL, Lee YK, Kubly V, et al. Identification of Gene Mutations in Autosomal Dominant Polycystic Kidney Disease through Targeted Resequencing. J Am Soc Nephrol. 2012;23:915–33.

    Google Scholar 

  14. 14.

    Bogdanova N, Markoff A, Gerke V, McCluskey M, Horst J, Dworniczak B. Homologues to the First Gene for Autosomal Dominant Polycystic Kidney Disease Are Pseudogenes. Genomics. 2001;74:333–41.

    Google Scholar 

  15. 15.

    Ong ACM, Devuyst O, Knebelmann B, Walz G. Autosomal dominant polycystic kidney disease:the changing face of clinical management. Lancet. 2015;385:1993–2002.

    Google Scholar 

  16. 16.

    Mallawaarachchi AC, Hort Y, Cowley MJ, McCabe MJ, Minoche A, Dinger ME, et al. Whole-genome sequencing overcomes pseudogene homology to diagnose autosomal dominant polycystic kidney disease. Eur J Hum Genet. 2016;24:1584–90.

    Google Scholar 

  17. 17.

    Audrézet M-P, Cornec-Le Gall E, Chen J-M, Redon S, Quere I, Creff J, et al. Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat. 2012;33:1239–50.

    Google Scholar 

  18. 18.

    Trujillano D, Bullich G, Ossowski S, Ballarín J, Torra R, Estivill X, et al. Diagnosis of autosomal dominant polycystic kidney disease using efficient PKD1and PKD2 targeted next-generation sequencing. Mol Genet Genom Med. 2014;2:412–21.

    Google Scholar 

  19. 19.

    Gayevskiy V, Roscioli T, Dinger ME, Cowley MJ. Seave: a comprehensive web platform for storing and interrogating human genomic variation. Bioinformatics. 2019;35:122–5.

    Google Scholar 

  20. 20.

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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;17:405–23.

    Google Scholar 

  21. 21.

    Layer RM, Chiang C, Quinlan AR, Hall IM. LUMPY: a probabilistic framework for structural variant discovery. Genome Biol. 2014;15:1–19.

    Google Scholar 

  22. 22.

    Abyzov A, Urban AE, Snyder M, Gerstein M. CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. Genome Res. 2011;21:974–84.

    Google Scholar 

  23. 23.

    Trost B, Walker S, Wang Z, Thiruvahindrapuram B, MacDonald JR, Sung WWL, et al. A Comprehensive Workflow for Read Depth-Based Identification of Copy-Number Variation from Whole-Genome Sequence Data. Am J Hum Genet. 2018;102:142–55.

    Google Scholar 

  24. 24.

    Gout AM, Martin NC, Brown AF, Ravine D. PKDB: Polycystic Kidney Disease Mutation Database-a gene variant database for autosomal dominant polycystic kidney disease. Hum Mutat. 2007;28:654–9. https://pkdb.mayo.edu/

    Google Scholar 

  25. 25.

    McLaughlin HM, Ceyhan-Birsoy O, Christensen K, Kohane I, Green RC, Rehm HL, et al. A systematic approach to the reporting of medically relevant findings from whole genome sequencing. BMC Med Genet. 2014;15:134–48.

    Google Scholar 

  26. 26.

    Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Supplements. 2013: 1–163.

  27. 27.

    Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, et al. Imaging Classification of Autosomal Dominant Polycystic Kidney Disease: a Simple Model for Selecting Patients for Clinical Trials. J Am Soc Nephrol. 2015;26:160–72.

    Google Scholar 

  28. 28.

    Cornec-Le Gall E, Audrezet MP, Chen JM, Hourmant M, Morin MP, Perrichot R, et al. Type of PKD1 Mutation Influences Renal Outcome in ADPKD. J Am Soc Nephrol. 2013;24:1006–13.

    Google Scholar 

  29. 29.

    Rangan GK, Alexander SI, Campbell KL, Dexter MA, Lee VW, Lopez-Vargas P, et al. KHA-CARI guideline recommendations for the diagnosis and management of autosomal dominant polycystic kidney disease. Nephrology. 2016;21:705–16.

    Google Scholar 

  30. 30.

    De Rechter S, Breysem L, Mekahli D. Is Autosomal Dominant Polycystic Kidney Disease Becoming a Pediatric Disorder? Front Pediatrics. 2017;5:332.

    Google Scholar 

  31. 31.

    Gimpel C, Bergmann C, Bockenhauer D, Breysem L, Cadnapaphornchai MA, Cetiner M, et al. International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people. Nat Rev Nephrol. 2019;15:713–26.

    Google Scholar 

  32. 32.

    National Genomic Test Directory for rare and inherited disease https://www.england.nhs.uk/publication/national-genomic-test-directories/. (Accessed: 2nd February 2020)

  33. 33.

    Ali H, Al-Mulla F, Hussain N, Naim M, Asbeutah AM, AlSahow A, et al. PKD1 Duplicated regions limit clinical Utility of Whole Exome Sequencing for Genetic Diagnosis of Autosomal Dominant Polycystic Kidney Disease. Sci Rep. 2019;9:4141.

    Google Scholar 

  34. 34.

    Bullich G, Domingo-Gallego A, Vargas I, Ruiz P, Lorente-Grandoso L, Furlano M, et al. A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases. Kidney Int. 2018;94:363–71.

    Google Scholar 

  35. 35.

    Bayrak-Toydemir P, McDonald J, Mao R, Phansalkar A, Gedge F, Robles J, et al. Likelihood ratios to assess genetic evidence for clinical significance of uncertain variants: hereditary hemorrhagic telangiectasia as a model. Exp Mol Pathol. 2008;85:45–9.

    Google Scholar 

  36. 36.

    Miller NA, Farrow EG, Gibson M, Willig LK, Twist G, Yoo B, et al. A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases. Genome Med. 2015;7:100–16.

    Google Scholar 

  37. 37.

    Zhou X, Edmonson MN, Wilkinson MR, Patel A, Gang W, Liu Y, et al. Exploring genomic alteration in pediatric cancer using ProteinPaint. Nat Genet. 2016;48:4–6.

    Google Scholar 

Download references

Acknowledgements

This work was supported by the PKD Foundation of Australia, PKD Foundation USA and The Lewis Foundation. ACM was supported by the RACP Jacquot Foundation. The Mayo Translational PKD Center (DK090728) is thanked for Sanger sequencing and exchange of samples and Sravanthi Lavu is thanked for providing data on the validation cohort.

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Correspondence to Amali C. Mallawaarachchi.

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Mallawaarachchi, A.C., Lundie, B., Hort, Y. et al. Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing. Eur J Hum Genet 29, 760–770 (2021). https://doi.org/10.1038/s41431-020-00796-4

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