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01-06-2014 | Review

DNA variant databases improve test accuracy and phenotype prediction in Alport syndrome

Authors: Judy Savige, Elisabet Ars, Richard G. H. Cotton, David Crockett, Hayat Dagher, Constantinos Deltas, Jie Ding, Frances Flinter, Genevieve Pont-Kingdon, Nizar Smaoui, Roser Torra, Helen Storey, The International Alport Mutation Consortium

Published in: Pediatric Nephrology | Issue 6/2014

Abstract

X-linked Alport syndrome is a form of progressive renal failure caused by pathogenic variants in the COL4A5 gene. More than 700 variants have been described and a further 400 are estimated to be known to individual laboratories but are unpublished. The major genetic testing laboratories for X-linked Alport syndrome worldwide have established a Web-based database for published and unpublished COL4A5 variants (https://grenada.lumc.nl/LOVD2/COL4A/home.php?select_db=COL4A5). This conforms with the recommendations of the Human Variome Project: it uses the Leiden Open Variation Database (LOVD) format, describes variants according to the human reference sequence with standardized nomenclature, indicates likely pathogenicity and associated clinical features, and credits the submitting laboratory. The database includes non-pathogenic and recurrent variants, and is linked to another COL4A5 mutation database and relevant bioinformatics sites. Access is free. Increasing the number of COL4A5 variants in the public domain helps patients, diagnostic laboratories, clinicians, and researchers. The database improves the accuracy and efficiency of genetic testing because its variants are already categorized for pathogenicity. The description of further COL4A5 variants and clinical associations will improve our ability to predict phenotype and our understanding of collagen IV biochemistry. The database for X-linked Alport syndrome represents a model for databases in other inherited renal diseases.

Levy M, Feingold J (2000) Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int 58:925–943PubMedCrossRef

Feingold J, Bois E, Chompret A, Broyer M, Gubler MC, Grunfeld JP (1985) Genetic heterogeneity of Alport syndrome. Kidney Int 27:672–677PubMedCrossRef

Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR, Gerken SC, Gregory MC, Skolnick MH, Atkin CL, Tryggvason K (1990) Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248:1224–1227PubMedCrossRef

Flinter FA, Cameron JS, Chantler C, Houston I, Bobrow M (1988) Genetics of classic Alport’s syndrome. Lancet 2:1005–1007PubMedCrossRef

Gubler M, Levy M, Broyer M, Naizot C, Gonzales G, Perrin D, Habib R (1981) Alport’s syndrome. A report of 58 cases and a review of the literature. Am J Med 70:493–505PubMedCrossRef

Hanson H, Storey H, Pagan J, Flinter F (2011) The value of clinical criteria in identifying patients with X-linked Alport syndrome. Clin J Am Soc Nephrol 6:198–203PubMedCentralPubMedCrossRef

Teekhasaenee C, Nimmanit S, Wutthiphan S, Vareesangthip K, Laohapand T, Malasitr P, Ritch R (1991) Posterior polymorphous dystrophy and Alport syndrome. Ophthalmology 98:1207–1215PubMedCrossRef

Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Verellen C, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schroder C, Sanak M, Krejcova S, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC (2000) X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol 11:649–657PubMed

Tan R, Colville D, Wang YY, Rigby L, Savige J (2010) Alport retinopathy results from “severe” COL4A5 mutations and predicts early renal failure. Clin J Am Soc Nephrol 5:34–38PubMedCentralPubMedCrossRef

10.

Demosthenous P, Voskarides K, Stylianou K, Hadjigavriel M, Arsali M, Patsias C, Georgaki E, Zirogiannis P, Stavrou C, Daphnis E, Pierides A, Deltas C (2011) X-linked Alport syndrome in Hellenic families: Phenotypic heterogeneity and mutations near interruptions of the collagen domain in COL4A5. Clin Genet 81:240–248PubMedCrossRef

11.

Dagher H, Buzza M, Colville D, Jones C, Powell H, Fassett R, Wilson D, Agar J, Savige J (2001) A comparison of the clinical, histopathologic, and ultrastructural phenotypes in carriers of X-linked and autosomal recessive Alport’s syndrome. Am J Kidney Dis 38:1217–1228PubMedCrossRef

12.

Churg J, Sherman RL (1973) Pathologic characteristics of hereditary nephritis. Arch Pathol 95:374–379PubMed

13.

van der Loop FT, Monnens LA, Schroder CH, Lemmink HH, Breuning MH, Timmer ED, Smeets HJ (1999) Identification of COL4A5 defects in Alport’s syndrome by immunohistochemistry of skin. Kidney Int 55:1217–1224PubMedCrossRef

14.

Yoshioka K, Hino S, Takemura T, Maki S, Wieslander J, Takekoshi Y, Makino H, Kagawa M, Sado Y, Kashtan CE (1994) Type IV collagen alpha 5 chain. Normal distribution and abnormalities in X-linked Alport syndrome revealed by monoclonal antibody. Am J Pathol 144:986–996PubMedCentralPubMed

15.

Deltas C, Gale D, Cook T, Voskarides K, Athanasiou Y, Pierides A (2013) C3 glomerulonephritis/CFHR5 nephropathy is an endemic disease in Cyprus: clinical and molecular findings in 21 families. Adv Exp Med Biol 734:189–196CrossRef

16.

Zhou J, Leinonen A, Tryggvason K (1994) Structure of the human type IV collagen COL4A5 gene. J Biol Chem 269:6608–6614PubMed

17.

Bockenhauer D, Medlar AJ, Ashton E, Kleta R, Lench N (2012) Genetic testing in renal disease. Pediatr Nephrol 27:873–883PubMedCrossRef

18.

Bale S, Devisscher M, Van Criekinge W, Rehm HL, Decouttere F, Nussbaum R, Dunnen JT, Willems P (2011) MutaDATABASE: a centralized and standardized DNA variation database. Nat Biotechnol 29:117–118PubMedCrossRef

19.

Hertz JM, Thomassen M, Storey H, Flinter F (2012) Clinical utility gene card for: Alport syndrome. Eur J Hum Genet. doi:10.1038/EJHG.2011.237

20.

Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Dahan K, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schroder C, Sanak M, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC (2003) X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a “European Community Alport Syndrome Concerted Action” study. J Am Soc Nephrol 14:2603–2610PubMedCrossRef

21.

Lemmink HH, Schroder CH, Monnens LA, Smeets HJ (1997) The clinical spectrum of type IV collagen mutations. Hum Mutat 9:477–499PubMedCrossRef

22.

Persikov AV, Pillitteri RJ, Amin P, Schwarze U, Byers PH, Brodsky B (2004) Stability related bias in residues replacing glycines within the collagen triple helix (Gly-Xaa-Yaa) in inherited connective tissue disorders. Hum Mutat 24:330–337PubMedCrossRef

23.

Marini JC, Forlino A, Cabral WA, Barnes AM, San Antonio JD, Milgrom S, Hyland JC, Korkko J, Prockop DJ, De Paepe A, Coucke P, Symoens S, Glorieux FH, Roughley PJ, Lund AM, Kuurila-Svahn K, Hartikka H, Cohn DH, Krakow D, Mottes M, Schwarze U, Chen D, Yang K, Kuslich C, Troendle J, Dalgleish R, Byers PH (2007) Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat 28:209–221PubMedCrossRef

24.

Sweeney SM, Orgel JP, Fertala A, McAuliffe JD, Turner KR, Di Lullo GA, Chen S, Antipova O, Perumal S, Ala-Kokko L, Forlino A, Cabral WA, Barnes AM, Marini JC, San Antonio JD (2008) Candidate cell and matrix interaction domains on the collagen fibril, the predominant protein of vertebrates. J Biol Chem 283:21187–21197PubMedCentralPubMedCrossRef

25.

Harris PC, Rossetti S (2010) Molecular diagnostics for autosomal dominant polycystic kidney disease. Nat Rev Nephrol 6:197–206PubMedCrossRef

26.

Cotton RG (2000) Progress of the HUGO mutation database initiative: a brief introduction to the human mutation MDI special issue. Hum Mutat 15:4–6PubMedCrossRef

27.

Cotton RG, Auerbach AD, Beckmann JS, Blumenfeld OO, Brookes AJ, Brown AF, Carrera P, Cox DW, Gottlieb B, Greenblatt MS, Hilbert P, Lehvaslaiho H, Liang P, Marsh S, Nebert DW, Povey S, Rossetti S, Scriver CR, Summar M, Tolan DR, Verma IC, Vihinen M, den Dunnen JT (2008) Recommendations for locus-specific databases and their curation. Hum Mutat 29:2–5PubMedCentralPubMedCrossRef

28.

Kaput J, Cotton RG, Hardman L, Watson M, Al Aqeel AI, Al-Aama JY, Al-Mulla F, Alonso S, Aretz S, Auerbach AD, Bapat B, Bernstein IT, Bhak J, Bleoo SL, Blocker H, Brenner SE, Burn J, Bustamante M, Calzone R, Cambon-Thomsen A, Cargill M, Carrera P, Cavedon L, Cho YS, Chung YJ, Claustres M, Cutting G, Dalgleish R, den Dunnen JT, Diaz C, Dobrowolski S, dos Santos MR, Ekong R, Flanagan SB, Flicek P, Furukawa Y, Genuardi M, Ghang H, Golubenko MV, Greenblatt MS, Hamosh A, Hancock JM, Hardison R, Harrison TM, Hoffmann R, Horaitis R, Howard HJ, Barash CI, Izagirre N, Jung J, Kojima T, Laradi S, Lee YS, Lee JY, Gil-da-Silva-Lopes VL, Macrae FA, Maglott D, Marafie MJ, Marsh SG, Matsubara Y, Messiaen LM, Moslein G, Netea MG, Norton ML, Oefner PJ, Oetting WS, O’Leary JC, de Ramirez AM, Paalman MH, Parboosingh J, Patrinos GP, Perozzi G, Phillips IR, Povey S, Prasad S, Qi M, Quin DJ, Ramesar RS, Richards CS, Savige J, Scheible DG, Scott RJ, Seminara D, Shephard EA, Sijmons RH, Smith TD, Sobrido MJ, Tanaka T, Tavtigian SV, Taylor GR, Teague J, Topel T, Ullman-Cullere M, Utsunomiya J, van Kranen HJ, Vihinen M, Webb E, Weber TK, Yeager M, Yeom YI, Yim SH, Yoo HS (2009) Planning the Human Variome Project: the Spain report. Hum Mutat 30:496–510PubMedCrossRef

29.

Fokkema IF, den Dunnen JT, Taschner PE (2005) LOVD: easy creation of a locus-specific sequence variation database using an “LSDB-in-a-box” approach. Hum Mutat 26:63–68PubMedCrossRef

30.

Crockett DK, Pont-Kingdon G, Gedge F, Sumner K, Seamons R, Lyon E (2010) The Alport syndrome COL4A5 variant database. Hum Mutat 31:E1652–E1657PubMedCrossRef

31.

Gout AM, Ravine D, Harris PC, Rossetti S, Peters D, Breuning M, Henske EP, Koizumi A, Inoue S, Shimizu Y, Thongnoppakhun W, Yenchitsomanus PT, Deltas C, Sandford R, Torra R, Turco AE, Jeffery S, Fontes M, Somlo S, Furu LM, Smulders YM, Mercier B, Ferec C, Burtey S, Pei Y, Kalaydjieva L, Bogdanova N, McCluskey M, Geon LJ, Wouters CH, Reiterova J, Stekrova J, San Millan JL, Aguiari G, Del Senno L (2007) Analysis of published PKD1 gene sequence variants. Nat Genet 39:427–428PubMedCrossRef

32.

Povey S, Al Aqeel AI, Cambon-Thomsen A, Dalgleish R, den Dunnen JT, Firth HV, Greenblatt MS, Barash CI, Parker M, Patrinos GP, Savige J, Sobrido MJ, Winship I, Cotton RG (2010) Practical guidelines addressing ethical issues pertaining to the curation of human locus-specific variation databases (LSDBs). Hum Mutat 31:1179–1184PubMedCentralPubMedCrossRef

33.

Gross O, Netzer KO, Lambrecht R, Seibold S, Weber M (2002) Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling. Nephrol Dial Transplant 17:1218–1227PubMedCrossRef

34.

Gross O, Beirowski B, Koepke ML, Kuck J, Reiner M, Addicks K, Smyth N, Schulze-Lohoff E, Weber M (2003) Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int 63:438–446PubMedCrossRef

35.

Kashtan CE, Ding J, Gregory M, Gross O, Heidet L, Knebelmann B, Rheault M, Licht C (2013) Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport Syndrome Research Collaborative. Pediatr Nephrol 28:5–11PubMedCentralPubMedCrossRef

36.

Parkin JD, San Antonio JD, Pedchenko V, Hudson B, Jensen ST, Savige J (2011) Mapping structural landmarks, ligand binding sites, and missense mutations to the collagen IV heterotrimers predicts major functional domains, novel interactions, and variation in phenotypes in inherited diseases affecting basement membranes. Hum Mutat 32:127–143PubMedCrossRef

37.

Bergmann C, Senderek J, Kupper F, Schneider F, Dornia C, Windelen E, Eggermann T, Rudnik-Schoneborn S, Kirfel J, Furu L, Onuchic LF, Rossetti S, Harris PC, Somlo S, Guay-Woodford L, Germino GG, Moser M, Buttner R, Zerres K (2004) PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD). Hum Mutat 23:453–463PubMedCrossRef

38.

Gout AM, Martin NC, Brown AF, Ravine D (2007) Polycystic Kidney Disease Mutation Database–a gene variant database for autosomal dominant polycystic kidney disease. Hum Mutat 28:654–659PubMedCrossRef

39.

Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24:349–354PubMedCrossRef

40.

Hildebrandt F, Attanasio M, Otto E (2009) Nephronophthisis: disease mechanisms of a ciliopathy. J Am Soc Nephrol 20:23–35PubMedCentralPubMedCrossRef

41.

Watson MS, Epstein C, Howell RR, Jones MC, Korf BR, McCabe ER, Simpson JL (2008) Developing a national collaborative study system for rare genetic diseases. Genet Med 10:325–329PubMedCrossRef

42.

Pennisi E (2007) Genetics. Working the (gene count) numbers: finally, a firm answer? Science 316:1113PubMedCrossRef

43.

Hildebrandt F (2010) Genetic kidney diseases. Lancet 375:1287–1295PubMedCentralPubMedCrossRef

Title: DNA variant databases improve test accuracy and phenotype prediction in Alport syndrome
Authors: Judy Savige
Elisabet Ars
Richard G. H. Cotton
David Crockett
Hayat Dagher
Constantinos Deltas
Jie Ding
Frances Flinter
Genevieve Pont-Kingdon
Nizar Smaoui
Roser Torra
Helen Storey
The International Alport Mutation Consortium
Publication date: 01-06-2014
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 6/2014
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-013-2486-8

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

DNA variant databases improve test accuracy and phenotype prediction in Alport syndrome

Abstract

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