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Identification of PKD1 and PKD2 gene variants in a cohort of 125 Asian Indian patients of ADPKD

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) accounts for 2.6% of the patients with chronic kidney disease in India. ADPKD is caused by pathogenic variants in either PKD1 or PKD2 gene. There is no comprehensive genetic data from Indian subcontinent. We aimed to identify the pathogenic variants in the heterogeneous Indian population. PKD1 and PKD2 variants were identified by direct gene sequencing and/or multiplex ligation-dependent probe amplification (MLPA) in 125 unrelated patients of ADPKD. The pathogenic potential of the variants was evaluated computationally and were classified according to ACMG guidelines. Overall 300 variants were observed in PKD1 and PKD2 genes, of which 141 (47%) have been reported previously as benign. The remaining 159 variants were categorized into different classes based on their pathogenicity. Pathogenic variants were observed in 105 (84%) of 125 patients, of which 99 (94.3%) were linked to PKD1 gene and 6 (6.1%) to PKD2 gene. Of 159 variants, 97 were novel variants, of which 43 (44.33%) were pathogenic, and 10 (10.31%) were of uncertain significance. Our data demonstrate the diverse genotypic makeup of single gene disorders in India as compared to the West. These data would be valuable in counseling and further identification of probable donors among the relatives of patients with ADPKD.

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References

  1. 1.

    Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007;369:1287–301.

    PubMed  Article  Google Scholar 

  2. 2.

    Torres VE, Harris PC. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 2009;76:149–68.

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Rajapurkar MM, John GT, Kirpalani AL, Abraham G, Agarwal SK, Almeida AF, et al. What do we know about chronic kidney disease in India: first report of the Indian CKD registry. BMC Nephrol. 2012;13:10.

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Spithoven EM, Kramer A, Meijer E, Orskov B, Wanner C, Caskey F, et al. Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease. Kidney Int. 2014;86:1244–52.

    PubMed  Article  Google Scholar 

  5. 5.

    Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, Millan JLS, et al. The polycystic kidneydisease1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat Genet. 1995;10:151–60.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Watnick TJ, Piontek KB, Cordai TM, Weber H, Gandolph MA, Qian F, et al. An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection. Hum Mol Genet. 1997;6:1473–81.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Hayashi T, Mochizuki T, Reynolds DM, Wu G, Cai Y, Somlo S. Characterization of the exon structure of the polycystic kidney disease 2 gene (PKD2). Genomics. 1997;44:131–6.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Tan Y-C, Blumenfeld J, Rennert H. Autosomal dominant polycystic kidney disease: Genetics, mutations and microRNAs. Biochim Biophys Acta. 2011;1812:1202–12.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Audrézet MP, Cornec-Le Gall E, Chen JM, Redon S, Quéré 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.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Carrera P, Cal S, Magistroni R, Dunnen JT, Rigo F, Stenirri S. et al. Deciphering variability of PKD1 and PKD2 in an Italian cohort of 643 patients with autosomal dominant polycystic kidney disease (ADPKD). Sci Rep. 2016;6:1–13.

    Article  CAS  Google Scholar 

  11. 11.

    Hwang Y-H, Conklin J, Chan W, Roslin NM, Liu J, He N. et al. Refining genotype–phenotype correlation in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2016;27:1861–8.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Rossetti S, Consugar MB, Chapman AB, Torres VE, Guay-Woodford LM, Grantham JJ, et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007;18:2143–60.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Kurashige M, Hanaoka K, Imamura M, Udagawa T, Kawaguchi Y, Hasegawa T, et al. A comprehensive search for mutations in the PKD1 and PKD2 in Japanese subjects with autosomal dominant polycystic kidney disease. Clin Genet. 2015;87:266–72.

  14. 14.

    Barua M, Cil O, Paterson AD, Wang K, He N, Dicks E, et al. Family history of renal disease severity predicts the mutated gene in ADPKD. J Am Soc Nephrol. 2009;20:1833–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Harris PC, Bae KT, Rossetti S, Torres VE, Grantham JJ, Chapman AB, et al. Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2006;17:3013–9.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Ravine D, Gibson RN, Walker RG, Sheffield LJ, Kincaid-Smith P, Danks DM. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet. 1994;343:824–7.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, clasification and stratification. Am J Kidney Dis. 2002;39:1–266. p

    Article  CAS  Google Scholar 

  18. 18.

    Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:55404–55404.

    Google Scholar 

  19. 19.

    Rossetti S, Chauveau D, Walker D, Saggar-Malik A, Winearls CG, Torres VE, et al. A complete mutation screen of the ADPKD genes by DHPLC. Kidney Int. 2002;61:1588–99.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Liu W, Chen M, Wei J, Sun X, Shi Y, He W, et al. Modification of PCR conditions and design of exon-specific primers for the efficient molecular diagnosis of PKD1 mutations. Kidney Blood Press Res. 2014;39:536–45.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Dunnen JT, den, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, Mcgowan-Jordan J, et al. HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat. 2016;37:564–9.

    Article  CAS  Google Scholar 

  22. 22.

    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.

    PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Vikrant S, Parashar A. Autosomal dominant polycystic kidney disease: Study of clinical characteristics in an Indian population. Saudi J Kidney Dis Transpl. 2017;28:115–24.

    PubMed  Article  Google Scholar 

  24. 24.

    Thong KM, Ong ACM. The natural history of autosomal dominant polycystic kidney disease: 30-year experience from a single centre. QJM. 2013;106:639–46.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Romão EA, Moysés Neto M, Teixeira SR, Muglia VF, Vieira-Neto OM, Dantas M. Renal and extrarenal manifestations of autosomal dominant polycystic kidney disease. Braz J Med Biol Res. 2006;39:533–8.

    PubMed  Article  Google Scholar 

  26. 26.

    Chebib FT, Torres VE. Autosomal dominant polycystic kidney disease: core curriculum 2016. Am J Kidney Dis. 2016;67:792–810.

  27. 27.

    Everson GT, Taylor MRG, Doctor RB. Polycystic disease of the liver. Hepatology. 2004;40:774–82.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Gomez PF, Garcia-Cosmes P, Becerra LG, Romo JM. Clinical analysis of a population with autosomal dominant polycystic kidney disease. Nefrologia. 2010;30:87–94.

    PubMed  Google Scholar 

  29. 29.

    Chen D, Ma Y, Wang X, Yu S, Li L, Dai B.et al. Clinical characteristics and disease predictors of a large Chinese cohort of patients with autosomal dominant polycystic kidney disease. PLoS ONE. 2014; 9:e92232.

  30. 30.

    Rabbani MA, Ali SS, Murtaza G, Ahmad B, Maria Q, Siddiqui BK, et al. Clinical presentation and outcome of autosomal dominant polycystic kidney disease in Pakistan: a single center experience. J Pak Med Assoc. 2008;58:305–9.

    PubMed  Google Scholar 

  31. 31.

    Jin M, Xie Y, Chen Z, Liao Y, Li Z, Hu P. System analysis of gene mutations and clinical phenotype in Chinese patients with autosomal-dominant polycystic kidney disease. Scientific Reports. 2016;26:35945.

  32. 32.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Neumann HPH, Jilg C, Bacher J, Nabulsi Z, Malinoc A, Hummel B, et al. Epidemiology of autosomal-dominant polycystic kidney disease: an in-depth clinical study for south-western Germany. Nephrol Dial Transplant. 2013;28:1472–87.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Raj S, Singh RG, Das P. Mutational screening of PKD2 gene in the north Indian polycystic kidney disease patients revealed 28 genetic variations. J Genet. 2017;96:885–93.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Audrézet M-P, Corbiere C, Lebbah S, Morinière V, Broux F, Louillet F, et al. Comprehensive PKD1 and PKD2 mutation analysis in prenatal autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2016;27:722–9.

  36. 36.

    Neumann HPH, Bacher J, Nabulsi Z, Ortiz Brüchle N, Hoffmann MM, Schaeffner E, et al. Adult patients with sporadic polycystic kidney disease: The importance of screening for mutations in the PKD1 and PKD2 genes. Int Urol Nephrol. 2012;44:1753–62.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Yu C, Yang Y, Zou L, Hu Z, Li J, Liu Y, et al. Identification of novel mutations in Chinese Hans with autosomal dominant polycystic kidney disease. BMC Med Genet. 2011;12:164.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Thongnoppakhun W, Limwongse C, Vareesangthip K, Sirinavin C, Bunditworapoom D, Rungroj N, et al. Novel and de novo PKD1 mutations identified by multiple restriction fragment-single strand conformation polymorphism (MRF-SSCP). BMC Med Genet. 2004;5:1–15.

    Article  Google Scholar 

  39. 39.

    Rossetti S, Strmecki L, Gamble V, Burton S, Sneddon V, Peral B, et al. Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications. Am J Hum Genet. 2001;68:46–63.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Rossetti S, Harris PC. Genotype-phenotype correlations in autosomal dominant and autosomal recessive polycystic kidney disease. J Am Soc Nephrol. 2007;18:1374–80.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Vujic M, Heyer CM, Ars E, Hopp K, Markoff A, Orndal C, et al. Incompletely penetrant PKD1 alleles mimic the renal manifestations of ARPKD. J Am Soc Nephrol. 2010;21:1097–102.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Rossetti S, Kubly VJ, Consugar MB, Hopp K, Roy S, Horsley SW, et al. Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney Int. 2009;75:848–55.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Bergmann C, von Bothmer J, Ortiz Brüchle N, Venghaus A, Frank V, Fehrenbach H, et al. Mutations in multiple PKD genes may explain early and severe polycystic kidney disease. J Am Soc Nephrol. 2011;22:2047–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Pei Y, Lan Z, Wang K, Garcia-Gonzalez M, He N, Dicks E, et al. A missense mutation in PKD1 attenuates the severity of renal disease. Kidney Int. 2012;81:412–7.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Lantinga-van Leeuwen IS, Dauwerse JG, Baelde HJ, Leonhard WN, van de Wal A, Ward CJ, et al. Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. Hum Mol Genet. 2004;13:3069–77.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Qian F, Watnick TJ, Onuchic LF, Germino GG. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell. 1996;87:979–87.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Cnossen WR, te Morsche RH, Hoischen A, Gilissen C, Venselaar H, Mehdi S, et al. LRP5 variants may contribute to ADPKD. Eur J Hum Genet. 2016;24:237–42.

  48. 48.

    Fedeles SV, Tian X, Gallagher A-R, Mitobe M, Nishio S, Lee SH, et al. A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat Genet. 2011;43:639–47.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Porath B, Gainullin VG, Cornec-Le Gall E, 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Tan AY, Blumenfeld J, Michaeel A, Donahue S, Bobb W, Parker T, et al. Autosomal dominant polycystic kidney disease caused by somatic and germline mosaicism. Clin Genet. 2015;87:373–7.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Reiterová J, Štekrová J, Merta M, Kotlas J, Elišáková V, Lněnička P, et al. Autosomal dominant polycystic kidney disease in a family with mosaicism and hypomorphic allele. BMC Nephrol. 2013;14:1–6.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank the patients and their families for their cooperation and interest in the study. We would also like to thank all the clinicians for patient referral. The technical assistance of the laboratory staff and Shikha Chandel is gratefully acknowledged. We are also thankful to Indian Council of Medical Research (ICMR), and Ganga Ram Institute of Postgraduate Medical Education and Research (GRIPMER), Sir Ganga Ram Hospital, New Delhi for providing financial aid.

Funding

The study was financially supported by Indian Council of Medical Research (ICMR), New Delhi vide sanction no. IRIS ID 2011-09610. Partial financial support was also provided by Ganga Ram Institute of Postgraduate Medical Education and Research (GRIPMER) (RDB project no: 4.9.14).

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Correspondence to Shewata Pandita or Ishwar Chander Verma.

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Pandita, S., Ramachandran, V., Balakrishnan, P. et al. Identification of PKD1 and PKD2 gene variants in a cohort of 125 Asian Indian patients of ADPKD. J Hum Genet 64, 409–419 (2019). https://doi.org/10.1038/s10038-019-0582-8

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