Skip to main content
Log in

Copy-number variation associated with congenital anomalies of the kidney and urinary tract

Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background

The most common cause of end-stage renal disease in children can be attributed to congenital anomalies of the kidney and urinary tract (CAKUT). Despite this high incidence of disease, the genetic mutations responsible for the majority of CAKUT cases remain unknown.

Methods

To identify novel genomic regions associated with CAKUT, we screened 178 children presenting with the entire spectrum of structural anomalies associated with CAKUT for submicroscopic chromosomal imbalances (deletions or duplications) using single-nucleotide polymorphism (SNP) microarrays.

Results

Copy-number variation (CNV) was detected in 10.1 % (18/178) of the patients; in 6.2 % of the total cohort, novel duplications or deletions of unknown significance were identified, and the remaining 3.9 % harboured CNV of known pathogenicity. CNVs were inherited in 90 % (9/10) of the families tested. In this cohort, patients diagnosed with multicystic dysplastic kidney (30 %) and posterior urethral valves (24 %) had a higher incidence of CNV.

Conclusions

The genes contained in the altered genomic regions represent novel candidates for CAKUT. This study has demonstrated that a significant proportion of patients with CAKUT harbour submicroscopic chromosomal imbalances, warranting screening in clinics for CNV.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Woolf AS, Price KL, Scambler PJ, Winyard PJ (2004) Evolving concepts in human renal dysplasia. J Am Soc Nephrol 15:998–1007

    Article  PubMed  Google Scholar 

  2. Neild GH (2010) Primary renal disease in young adults with renal failure. Nephrol Dial Transplant 25:1025–32

    Article  PubMed  Google Scholar 

  3. Australian and New Zealand Dialysis and Transplant Registry (ANZDATA). (2012) Annual Paediatric Report. http://www.anzdata.org.au/v1/report_2012.html.

  4. North American Paediatric Renal Transplant Cooperative Study (NAPRTCS) (2008) Annual report. The EMMES Corporation, Rockville

    Google Scholar 

  5. Schedl A (2007) Renal abnormalities and their developmental origin. Nat Rev Genet 8:791–802

    Article  CAS  PubMed  Google Scholar 

  6. Sanyanusin P, Schimmenti LA, McNoe LA, Ward TA, Ella M, Pierpont M, Sullivan MJ, Dobyns WB, Eccles MR (1995) Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux. Nat Genet 9:358–364

    Article  CAS  PubMed  Google Scholar 

  7. Abdelhak S, Kalatzis V, Heilig R, Compain S, Samson D, Vincent C, Weil D, Cruaud C, Sahly I, Leibovici M, Bitner-Glindzicz M, Francis M, Lacombe D, Vigneron J, Charachon R, Boven K, Bedbeder P, Van Regemorter N, Weissenbach J, Petit C (1997) A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family. Nat Genet 15:157–64

    Article  CAS  PubMed  Google Scholar 

  8. Airik R, Kispert A (2007) Down the tube of obstructive nephropathies: the importance of tissue interactions during ureter development. Kidney Int 72:1459–67

    Article  CAS  PubMed  Google Scholar 

  9. Yosypiv IV (2012) Congenital anomalies of the kidney and urinary tract: a genetic disorder? Int J Nephrol 2012, article ID 909083 http://dx.doi.org/10.1155/2012/909083

  10. Renkema KY, Winyard PJ, Skovorodkin IN, Levtchenko E, Hindryckx A, Jeanpierre C, Weber S, Salomon R, Antignac C, Vainio S, Schedl A, Schaefer F, Knoers NV, Bongers EM; EUCAKUT consortium (2011) Novel perspectives for investigating congenital anomalies of the kidney and urinary tract (CAKUT). Nephrol Dial Transplant 26:3843–51

    Article  Google Scholar 

  11. Thomas R, Sanna-Cherchi S, Warady BA, Furth SL, Kaskel FJ, Gharavi AG (2011) HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort. Pediatr Nephrol 26:897–903

    Article  PubMed Central  PubMed  Google Scholar 

  12. Saisawat P, Tasic V, Vega-Warner V, Kehinde EO, Günther B, Airik R, Innis JW, Hoskins BE, Hoefele J, Otto EA, Hildebrandt F (2012) Identification of two novel CAKUT-causing genes by massively parallel exon resequencing of candidate genes in patients with unilateral renal agenesis. Kidney Int 81:196–200

    Article  CAS  PubMed  Google Scholar 

  13. Saisawat P, Kohl S, Hilger AC, Hwang D-Y, Gee HY, Dworschak GC, Tasic V, Pennimpede T, Natarajan S, Sperry E, Matassa DS, Stajić N, Bogdanovic R, de Blaauw MCL, Wijers CH, Bartels E, Schmiedeke E, Schmidt D, Märzheuser S, Grasshoff-Derr S, Holland-Cunz S, Ludwig M, Nöthen MM, Draaken M, Brosens E, Heij H, Tibboel D, Herrmann B, Solomon BD, de Klein A, van Rooij IA, Esposito F, Reutter HM, Hildebrandt F (2013) Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association. Kidney Int 85(6):1310–1317

    Article  PubMed Central  PubMed  Google Scholar 

  14. Sanna-Cherchi S, Sampogna RV, Papeta N, Burgess KE, Nees SN, Perry BJ, Choi M, Bodria M, Liu Y, Weng PL, Lozanovski VJ, Verbitsky M, Lugani F, Sterken R, Paragas N, Caridi G, Carrea A, Dagnino M, Materna-Kiryluk A, Santamaria G, Murtas C, Ristoska-Bojkovska N, Izzi C, Kacak N, Bianco B, Giberti S, Gigante M, Piaggio G, Gesualdo L, Kosuljandic Vukic D, Vukojevic K, Saraga-Babic M, Saraga M, Gucev Z, Allegri L, Latos-Bielenska A, Casu D, State M, Scolari F, Ravazzolo R, Kiryluk K, Al-Awqati Q, D’Agati VD, Drummond IA, Tasic V, Lifton RP, Ghiggeri GM, Gharavi AG (2013) Mutations in DSTYK and dominant urinary tract malformations. N Engl J Med 369:621–629

    Article  CAS  PubMed  Google Scholar 

  15. Hwang DY, Dworschak GC, Kohl S, Saisawat P, Vivante A, Hilger AC, Reutter HM, Soliman NA, Bogdanovic R, Kehinde EO, Tasic V, Hildebrandt F (2014) Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract. Kidney Int. doi:10.1038/ki.2013.508

    Google Scholar 

  16. Vivante A, Kohl S, Hwang DY, Dworschak GC, Hildebrandt F (2014) Single-gene causes of congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Pediatr Nephrol. doi:10.1007/s00467-013-2684-4

    PubMed  Google Scholar 

  17. Weber S, Landwehr C, Renkert M, Hoischen A, Wühl E, Denecke J, Radlwimmer B, Haffner D, Schaefer F, Weber RG (2011) Mapping candidate regions and genes for congenital anomalies of the kidneys and urinary tract (CAKUT) by array-based comparative genomic hybridization. Nephrol Dial Transplant 26:136–43

    Article  CAS  PubMed  Google Scholar 

  18. Sanna-Cherchi S, Kiryluk K, Burgess KE, Bodria M, Sampson MG, Hadley D, Nees SN, Verbitsky M, Perry BJ, Sterken R, Lozanovski VJ, Materna-Kiryluk A, Barlassina C, Kini A, Corbani V, Carrea A, Somenzi D, Murtas C, Ristoska-Bojkovska N, Izzi C, Bianco B, Zaniew M, Flogelova H, Weng PL, Kacak N, Giberti S, Gigante M, Arapovic A, Drnasin K, Caridi G, Curioni S, Allegri F, Ammenti A, Ferretti S, Goj V, Bernardo L, Jobanputra V, Chung WK, Lifton RP, Sanders S, State M, Clark LN, Saraga M, Padmanabhan S, Dominiczak AF, Foroud T, Gesualdo L, Gucev Z, Allegri L, Latos-Bielenska A, Cusi D, Scolari F, Tasic V, Hakonarson H, Ghiggeri GM, Gharavi AG (2012) Copy-number disorders are a common cause of congenital kidney malformations. Am J Hum Genet 91:987–97

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Kohl S, Hwang DY, Dworschak GC, Hilger AC, Saisawat P, Vivante A, Stajic N, Bogdanovic R, Reutter HM, Kehinde EO, Tasic V, Hildebrandt F (2014) Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol 25(9):1917–1922

    Article  CAS  PubMed  Google Scholar 

  20. Lindner TH, Njolstad PR, Horikawa Y, Bostad L, Bell GI, Sovik O (1999) A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1beta. Hum Mol Genet 8:2001–8

    Article  CAS  PubMed  Google Scholar 

  21. Donoviel DB, Freed DD, Vogel H, Potter DG, Hawkins E, Barrish JP, Mathur BN, Turner CA, Geske R, Montgomery CA, Starbuck M, Brandt M, Gupta A, Ramirez-Solis R, Zambrowicz BP, Powell DR (2001) Proteinuria and perinatal lethality in mice lacking NEPH1, a novel protein with homology to NEPHRIN. Mol Cell Biol 21:4829–4836

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Matsuo H, Chiba T, Nagamori S, Nakayama A, Domoto H, Phetdee K, Wiriyasermkul P, Kikuchi Y, Oda T, Nishiyama J, Nakamura T, Morimoto Y, Kamakura K, Sakurai Y, Nonoyama S, Kanai Y, Shinomiya N (2008) Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. Am J Hum Genet 83:744–51

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Hodgkinson AD, Søndergaard KL, Yang B, Cross DF, Millward BA, Demaine AG (2001) Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy. Kidney Int 60:211–218

    Article  CAS  PubMed  Google Scholar 

  24. Liu G, Clement LC, Kanwar YS, Avila-Casado C, Chugh SS (2006) ZHX proteins regulate podocyte gene expression during the development of nephrotic syndrome. J Biol Chem 281:39681–92

    Article  CAS  PubMed  Google Scholar 

  25. Radmayr C, Schwentner C, Lunacek A, Karatzas A, Oswald J (2010) Embryology and anatomy of the vesicoureteric junction with special reference to the etiology of vesicoureteral reflux. Ther Adv Urol 1:243–250

    Article  Google Scholar 

  26. Chen F (2009) Genetic and developmental basis for urinary tract obstruction. Pediatr Nephrol 24:1621–1632

    Article  PubMed Central  PubMed  Google Scholar 

  27. Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP (2001) A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413:519–23

    Article  CAS  PubMed  Google Scholar 

  28. MacDermot KD, Bonora E, Sykes N, Coupe AM, Lai CS, Vernes SC, Vargha-Khadem F, McKenzie F, Smith RL, Monaco AP, Fisher SE (2005) Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. Am J Hum Genet 76:1074–80

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Turner SJ, Hildebrand MS, Block S, Damiano J, Fahey M, Reilly S, Bahlo M, Scheffer IE, Morgan AT (2013) Small intragenic deletion in FOXP2 associated with childhood apraxia of speech and dysarthria. Am J Med Genet A 161:2321–6

    Article  CAS  Google Scholar 

  30. Groszer M, Keays DA, Deacon RM, de Bono JP, Prasad-Mulcare S, Gaub S, Baum MG, French CA, Nicod J, Coventry JA, Enard W, Fray M, Brown SD, Nolan PM, Pääbo S, Channon KM, Costa RM, Eilers J, Ehret G, Rawlins JN, Fisher SE (2008) Impaired synaptic plasticity and motor learning in mice with a point mutation implicated in human speech deficits. Curr Biol 18:354–62

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Shu W, Lu MM, Zhang Y, Tucker PW, Zhou D, Morrisey EE (2007) Foxp2 and Foxp1 cooperatively regulate lung and esophagus development. Development 134:1991–2000

    Article  CAS  PubMed  Google Scholar 

  32. Nagamani SC, Erez A, Bader P, Lalani SR, Scott DA, Scaglia F, Plon SE, Tsai C-H, Reimschisel T, Roeder E, Malphrus AD, Eng PA, Hixson PM, Kang SH, Stankiewicz P, Patel A, Cheung SW (2011) Phenotypic manifestations of copy number variation in chromosome 16p13.11. Eur J Hum Genet 19:280–6

    Article  PubMed Central  PubMed  Google Scholar 

  33. Hodges S, Patel B, McLorie AA (2009) Posterior urethral valves. Sci World J 9:1119–1126

    Article  Google Scholar 

  34. Bailey CG, Ryan RM, Thoeng AD, Ng C, King K, Vanslambrouck JM, Auray-Blais C, Vandenberg RJ, Bröer S, Rasko JE (2011) Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. J Clin Invest 121:446–53

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Isidor B, Pichon O, Redon R, Day-Salvatore D, Hamel A, Siwicka KA, Bitner-Glindzicz M, Heymann D, Kjelle’n L, Kraus C, Leroy JG, Mortier GR, Rauch A, Verloes A, David A, Le Caignec C (2010) Mesomelia-Synostoses Syndrome Results from Deletion of SULF1 and SLCO5A1 Genes at 8q13. Am J Hum Genet 87:95–100

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Holst CR, Bou-Reslan H, Gore BB, Wong K, Grant D, Chalasani S, Carano RA, Frantz GD, Tessier-Lavigne M, Bolon B, French DM, Ashkenazi A (2007) Secreted sulfatases Sulf1 and Sulf2 have overlapping yet essential roles in mouse neonatal survival. PLoS One 2:e575

    Article  PubMed Central  PubMed  Google Scholar 

  37. Shprintzen RJ (1994) Velocardiofacial syndrome and DiGeorge sequence. J Med Genet 31:423–424

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Schramm C, Draaken M, Bartelsa E, Boemersc TM, Aretza S, Brockschmidt FF, Nöthena MM, Ludwig M, Reutter H (2011) De novo microduplication at 22q11.21 in a patient with VACTERL association. Eur J Med Gen 54:9–13

    Article  Google Scholar 

  39. Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K (1998) Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome. Mol Cell 1:575–582

    Article  CAS  PubMed  Google Scholar 

  40. Liu G, Kaw B, Kurfis J, Rahmanuddin S, Kanwar YS, Chugh SS (2003) Neph1 and nephrin interaction in the slit diaphragm is an important determinant of glomerular permeability. J Clin Invest 112:209–221

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Shaw N, Bingmei Y, Millward A, Demaine A, Hodgkinson A (2014) AKR1B10 is induced by hyperglycaemia and lipopolysaccharide in patients with diabetic nephropathy. Cell Stress Chaperones 19:281–287

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Li J, Parker B, Martyn C, Natarajan C, Guo J (2013) The PMP22 gene and Its related diseases. Mol Neurobiol 47:673–698

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Bergemann AD, Cole F, Hirschhorn K (2005) The etiology of Wolf-Hirschhorn syndrome. Trends Genet 21:188–95

    Article  CAS  PubMed  Google Scholar 

  44. Bulum B, Ozçakar ZB, Ustüner E, Düşünceli E, Kavaz A, Duman D, Walz K, Fitoz S, Tekin M, Yalçınkaya F (2013) High frequency of kidney and urinary tract anomalies in asymptomatic first-degree relatives of patients with CAKUT. Pediatr Nephrol 28:2143–7

    Article  PubMed  Google Scholar 

  45. Luo C, Yang YF, Yin BL, Chen JL, Huang C, Zhang WZ, Wang J, Zhang H, Yang JF, Tan ZP (2012) Microduplication of 3p25.2 encompassing RAF1 associated with congenital heart disease suggestive of Noonan syndrome. Am J Med Genet 158A:1918–23

    Article  PubMed  Google Scholar 

  46. Faivre L, Gosset P, Cormier-Daire V, Odent S, Amiel J, Giurgea I, Nassogne M-C, Pasquier L, Munnich A, Romana S, Prieur M, Vekemans M, De Blois MC, Turleau C (2002) Overgrowth and trisomy 15q26.1-qter including the IGF1 receptor gene: report of two families and review of the literature. Eur J Hum Genet 10:699–706

    Article  CAS  PubMed  Google Scholar 

  47. Rudnik-Schöneborn S, Schüler HM, Schwanitz G, Hansmann M, Zerres K (1996) Further arguments for non-fortuitous association of Potter sequence with XYY males. Ann Genet 39:43–6

    PubMed  Google Scholar 

  48. Weiss AC, Airik R, Bohnenpoll T, Greulich F, Foik A, Trowe MO, Rudat C, Costantini F, Adams RH, Kispert A (2014) Nephric duct insertion requires EphA4/EphA7 signaling from the pericloacal mesenchyme. Development 141:3420–30

Download references

Acknowledgments

The authors thank the families for their participation in this study, which was supported by a National Health and Medical Research Council Project Grant (APP1021532).

URLs for data presented herein are as follows:

DECIPHER,

https://decipher.sanger.ac.uk/

GUDMAP Genitourinary Database Molecular Anatomy Project,

http://www.gudmap.org/

National Center for Biotechnology Information,

http://www.ncbi.nlm.nih.gov/

Online Mendelian Inheritance in Man (OMIM),

http://www.omim.org/

UCSC Genome Browser Home,

http://www.genome.ucsc.edu

CHOPS, http://cnv.chop.edu/

International Standards for Cytogenomic Arrays (ISCA),

http://www.iscaconsortium.org/

Database of Genomic Variants (DGV)

http://dgv.tcag.ca/dgv/app/home

Funding

National Health and Medical Research Council Project Grant (APP1021532)

Note added in proof

Recently, Epha4 –/–; Epha7 –/–mice have been reported to display hydroureter, megaureter and hydronephrosis, therefore EPHA7 can be considered as a candidate for Case 1 (Table 2) [48].

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Georgina Caruana.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 26 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Caruana, G., Wong, M.N., Walker, A. et al. Copy-number variation associated with congenital anomalies of the kidney and urinary tract. Pediatr Nephrol 30, 487–495 (2015). https://doi.org/10.1007/s00467-014-2962-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-014-2962-9

Keywords

Navigation