Expert consensus guidelines for the genetic diagnosis of Alport syndrome

Abstract

Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability.

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References

  1. 1.

    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 70:493–505

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Habib R, Gubler MC, Hinglais N, Noel LH, Droz D, Levy M, Mahieu P, Foidart JM, Perrin D, Bois E, Grunfeld JP (1982) Alport’s syndrome: experience at Hopital Necker. Kidney Int Suppl 11:S20–S28

    CAS  PubMed  Google Scholar 

  3. 3.

    Grunfeld JP, Joly D (1997) Hereditary kidney diseases in adults. Rev Prat 47:1566–1569

    CAS  PubMed  Google Scholar 

  4. 4.

    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 248:1224–1227

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Mochizuki T, Lemmink HH, Mariyama M, Antignac C, Gubler MC, Pirson Y, Verellen-Dumoulin C, Chan B, Schroder CH, Smeets HJ, Reeders ST (1994) Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome. Nat Genet 8:77–81

    Article  CAS  PubMed  Google Scholar 

  6. 6.

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

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F (2013) Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol 24:364–375

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    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 14:2603–2610

    Article  PubMed  Google Scholar 

  9. 9.

    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 11:649–657

    CAS  PubMed  Google Scholar 

  10. 10.

    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 17:1218–1227

    Article  PubMed  Google Scholar 

  11. 11.

    Savige J, Storey H, Il Cheong H, Gyung Kang H, Park E, Hilbert P, Persikov A, Torres-Fernandez C, Ars E, Torra R, Hertz JM, Thomassen M, Shagam L, Wang D, Wang Y, Flinter F, Nagel M (2016) X-linked and autosomal recessive Alport syndrome: pathogenic variant features and further genotype-phenotype correlations. PLoS One 11:e0161802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Zhou J, Mochizuki T, Smeets H, Antignac C, Laurila P, de Paepe A, Tryggvason K, Reeders ST (1993) Deletion of the paired alpha 5(IV) and alpha 6(IV) collagen genes in inherited smooth muscle tumors. Science 261:1167–1169

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Kashtan CE, Butkowski RJ, Kleppel MM, First MR, Michael AF (1990) Posttransplant anti-glomerular basement membrane nephritis in related males with Alport syndrome. J Lab Clin Med 116:508–515

    CAS  PubMed  Google Scholar 

  14. 14.

    Ding J, Zhou J, Tryggvason K, Kashtan CE (1994) COL4A5 deletions in three patients with Alport syndrome and posttransplant antiglomerular basement membrane nephritis. J Am Soc Nephrol 5:161–168

    CAS  PubMed  Google Scholar 

  15. 15.

    Deltas C, Pierides A, Voskarides K (2013) Molecular genetics of familial hematuric diseases. Nephrol Dial Transplant 28:2946–2960

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Fallerini C, Dosa L, Tita R, Del Prete D, Feriozzi S, Gai G, Clementi M, La Manna A, Miglietti N, Mancini R, Mandrile G, Ghiggeri GM, Piaggio G, Brancati F, Diano L, Frate E, Pinciaroli AR, Giani M, Castorina P, Bresin E, Giachino D, De Marchi M, Mari F, Bruttini M, Renieri A, Ariani F (2014) Unbiased next generation sequencing analysis confirms the existence of autosomal dominant Alport syndrome in a relevant fraction of cases. Clin Genet 86:252–257

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Fallerini C, Baldassarri M, Trevisson E, Morbidoni V, La Manna A, Lazzarin R, Pasini A, Barbano G, Pinciaroli AR, Garosi G, Frullanti E, Pinto AM, Mencarelli MA, Mari F, Renieri A, Ariani F (2017) Alport syndrome: impact of digenic inheritance in patients management. Clin Genet 92:34–44

  18. 18.

    Mencarelli MA, Heidet L, Storey H, van Geel M, Knebelmann B, Fallerini C, Miglietti N, Antonucci MF, Cetta F, Sayer JA, van den Wijngaard A, Yau S, Mari F, Bruttini M, Ariani F, Dahan K, Smeets B, Antignac C, Flinter F, Renieri A (2015) Evidence of digenic inheritance in Alport syndrome. J Med Genet 52:163–174

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Voskarides K, Stefanou C, Pieri M, Demosthenous P, Felekkis K, Arsali M, Athanasiou Y, Xydakis D, Stylianou K, Daphnis E, Goulielmos G, Loizou P, Savige J, Hohne M, Volker LA, Benzing T, Maxwell PH, Gale DP, Gorski M, Boger C, Kollerits B, Kronenberg F, Paulweber B, Zavros M, Pierides A, Deltas C (2017) A functional variant in NEPH3 gene confers high risk of renal failure in primary hematuric glomerulopathies. Evidence for predisposition to microalbuminuria in the general population. PLoS One 12:e0174274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Savige J, Colville D, Rheault M, Gear S, Lennon R, Lagas S, Finlay M, Flinter F (2016) Alport syndrome in women and girls. Clin J Am Soc Nephrol 11:1713–1720

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Wang YY, Rana K, Tonna S, Lin T, Sin L, Savige J (2004) COL4A3 mutations and their clinical consequences in thin basement membrane nephropathy (TBMN). Kidney Int 65:786–790

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    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 6:198–203

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Gast C, Pengelly RJ, Lyon M, Bunyan DJ, Seaby EG, Graham N, Venkat-Raman G, Ennis S (2016) Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis. Nephrol Dial Transplant 31:961–970

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Voskarides K, Damianou L, Neocleous V, Zouvani I, Christodoulidou S, Hadjiconstantinou V, Ioannou K, Athanasiou Y, Patsias C, Alexopoulos E, Pierides A, Kyriacou K, Deltas C (2007) COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy. J Am Soc Nephrol 18:3004–3016

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY (2003) Thin basement membrane nephropathy. Kidney Int 64:1169–1178

    Article  PubMed  Google Scholar 

  26. 26.

    Usui T, Ichibe M, Hasegawa S, Miki A, Baba E, Tanimoto N, Abe H (2004) Symmetrical reduced retinal thickness in a patient with Alport syndrome. Retina 24:977–979

    Article  PubMed  Google Scholar 

  27. 27.

    Savige J, Sheth S, Leys A, Nicholson A, Mack HG, Colville D (2015) Ocular features in Alport syndrome: pathogenesis and clinical significance. Clin J Am Soc Nephrol 10:703–709

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Ahmed F, Kamae KK, Jones DJ, Deangelis MM, Hageman GS, Gregory MC, Bernstein PS (2013) Temporal macular thinning associated with X-linked Alport syndrome. JAMA Ophthalmol 131:777–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Kashtan CE (1999) Alport syndrome: is diagnosis only skin-deep? Kidney Int 55:1575–1576

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    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 144:986–996

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    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 5:34–38

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    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 24:330–337

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Rheault MN, Kren SM, Hartich LA, Wall M, Thomas W, Mesa HA, Avner P, Lees GE, Kashtan CE, Segal Y (2010) X-inactivation modifies disease severity in female carriers of murine X-linked Alport syndrome. Nephrol Dial Transplant 25:764–769

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Storey H, Savige J, Sivakumar V, Abbs S, Flinter FA (2013) COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome. J Am Soc Nephrol 24:1945–1954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Murray LS, Lu Y, Taggart A, Van Regemorter N, Vilain C, Abramowicz M, Kadler KE, Van Agtmael T (2014) Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke. Hum Mol Genet 23:283–292

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Bateman JF, Freddi S, Nattrass G, Savarirayan R (2003) Tissue-specific RNA surveillance? Nonsense-mediated mRNA decay causes collagen X haploinsufficiency in Schmid metaphyseal chondrodysplasia cartilage. Hum Mol Genet 12:217–225

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Barker DF, Pruchno CJ, Jiang X, Atkin CL, Stone EM, Denison JC, Fain PR, Gregory MC (1996) A mutation causing Alport syndrome with tardive hearing loss is common in the western United States. Am J Hum Genet 58:1157–1165

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Voskarides K, Patsias C, Pierides A, Deltas C (2008) COL4A3 founder mutations in Greek-Cypriot families with thin basement membrane nephropathy and focal segmental glomerulosclerosis dating from around 18th century. Genet Test 12:273–278

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Slajpah M, Gorinsek B, Berginc G, Vizjak A, Ferluga D, Hvala A, Meglic A, Jaksa I, Furlan P, Gregoric A, Kaplan-Pavlovcic S, Ravnik-Glavac M, Glavac D (2007) Sixteen novel mutations identified in COL4A3, COL4A4, and COL4A5 genes in Slovenian families with Alport syndrome and benign familial hematuria. Kidney Int 71:1287–1295

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    Miner JH, Baigent C, Flinter F, Gross O, Judge P, Kashtan CE, Lagas S, Savige J, Blatt D, Ding J, Gale DP, Midgley JP, Povey S, Prunotto M, Renault D, Skelding J, Turner AN, Gear S (2014) The 2014 International workshop on Alport syndrome. Kidney Int 86:679–684

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Moriniere V, Dahan K, Hilbert P, Lison M, Lebbah S, Topa A, Bole-Feysot C, Pruvost S, Nitschke P, Plaisier E, Knebelmann B, Macher MA, Noel LH, Gubler MC, Antignac C, Heidet L (2014) Improving mutation screening in familial hematuric nephropathies through next generation sequencing. J Am Soc Nephrol 25:2740–2751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Hertz JM, Thomassen M, Storey H, Flinter F (2015) Clinical utility gene card for: Alport syndrome - update 2014. Eur J Hum Genet 23 (9)

  43. 43.

    Baleato RM, Guthrie PL, Gubler MC, Ashman LK, Roselli S (2008) Deletion of CD151 results in a strain-dependent glomerular disease due to severe alterations of the glomerular basement membrane. Am J Pathol 173:927–937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Kovacs G, Kalmar T, Endreffy E, Ondrik Z, Ivanyi B, Rikker C, Haszon I, Turi S, Sinko M, Bereczki C, Maroti Z (2016) Efficient targeted next generation sequencing-based workflow for differential diagnosis of Alport-related disorders. PLoS One 11:e0149241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Artuso R, Fallerini C, Dosa L, Scionti F, Clementi M, Garosi G, Massella L, Epistolato MC, Mancini R, Mari F, Longo I, Ariani F, Renieri A, Bruttini M (2012) Advances in Alport syndrome diagnosis using next-generation sequencing. Eur J Hum Genet 20:50–57

    Article  CAS  PubMed  Google Scholar 

  46. 46.

    King K, Flinter FA, Nihalani V, Green PM (2002) Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome. Hum Genet 111:548–554

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    Nakazato H, Hattori S, Ushijima T, Matsuura T, Koitabashi Y, Takada T, Yoshioka K, Endo F, Matsuda I (1994) Mutations in the COL4A5 gene in Alport syndrome: a possible mutation in primordial germ cells. Kidney Int 46:1307–1314

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    Hertz JM, Thomassen M, Storey H, Flinter F (2012) Clinical utility gene card for: Alport syndrome. Eur J Hum Genet 20 (6)

  49. 49.

    King K, Flinter FA, Green PM (2006) A two-tier approach to mutation detection in the COL4A5 gene for Alport syndrome. Hum Mutat 27:1061

    Article  PubMed  Google Scholar 

  50. 50.

    Tazon-Vega B, Ars E, Burset M, Santin S, Ruiz P, Fernandez-Llama P, Ballarin J, Torra R (2007) Genetic testing for X-linked Alport syndrome by direct sequencing of COL4A5 cDNA from hair root RNA samples. Am J Kidney Dis 50:257 e251–214

  51. 51.

    Zhang H, Ding J, Wang F, Zhao D (2011) Mutation detection of COL4An gene based on mRNA of peripheral blood lymphocytes and prenatal diagnosis of Alport syndrome in China. Nephrology (Carlton) 16:377–380

    Article  CAS  Google Scholar 

  52. 52.

    Bonnet C, Krieger S, Vezain M, Rousselin A, Tournier I, Martins A, Berthet P, Chevrier A, Dugast C, Layet V, Rossi A, Lidereau R, Frebourg T, Hardouin A, Tosi M (2008) Screening BRCA1 and BRCA2 unclassified variants for splicing mutations using reverse transcription PCR on patient RNA and an ex vivo assay based on a splicing reporter minigene. J Med Genet 45:438–446

    Article  CAS  PubMed  Google Scholar 

  53. 53.

    Sharma N, Sosnay PR, Ramalho AS, Douville C, Franca A, Gottschalk LB, Park J, Lee M, Vecchio-Pagan B, Raraigh KS, Amaral MD, Karchin R, Cutting GR (2014) Experimental assessment of splicing variants using expression minigenes and comparison with in silico predictions. Hum Mutat 35:1249–1259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Tournier I, Vezain M, Martins A, Charbonnier F, Baert-Desurmont S, Olschwang S, Wang Q, Buisine MP, Soret J, Tazi J, Frebourg T, Tosi M (2008) A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. Hum Mutat 29:1412–1424

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Malone AF, Funk SD, Alhamad T, Miner JH (2017) Functional assessment of a novel COL4A5 splice region variant and immunostaining of plucked hair follicles as an alternative method of diagnosis in X-linked Alport syndrome. Pediatr Nephrol 32:997–1003

    Article  PubMed  Google Scholar 

  56. 56.

    Plant KE, Boye E, Green PM, Vetrie D, Flinter FA (2000) Somatic mosaicism associated with a mild Alport syndrome phenotype. J Med Genet 37:238–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Bruttini M, Vitelli F, Meloni I, Rizzari G, Volpe MD, Mazzucco G, Marchi MD, Renieri A (2000) Mosaicism in Alport syndrome with genetic counselling. J Med Genet 37:717–719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Krol RP, Nozu K, Nakanishi K, Iijima K, Takeshima Y, Fu XJ, Nozu Y, Kaito H, Kanda K, Matsuo M, Yoshikawa N (2008) Somatic mosaicism for a mutation of the COL4A5 gene is a cause of mild phenotype male Alport syndrome. Nephrol Dial Transplant 23:2525–2530

    Article  CAS  PubMed  Google Scholar 

  59. 59.

    Beicht S, Strobl-Wildemann G, Rath S, Wachter O, Alberer M, Kaminsky E, Weber LT, Hinrichsen T, Klein HG, Hoefele J (2013) Next generation sequencing as a useful tool in the diagnostics of mosaicism in Alport syndrome. Gene 526:474–477

    Article  CAS  PubMed  Google Scholar 

  60. 60.

    Fu XJ, Nozu K, Kaito H, Ninchoji T, Morisada N, Nakanishi K, Yoshikawa N, Ohtsubo H, Matsunoshita N, Kamiyoshi N, Matsumura C, Takagi N, Maekawa K, Taniguchi-Ikeda M, Iijima K (2016) Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome. Eur J Hum Genet 24:387–391

    Article  CAS  PubMed  Google Scholar 

  61. 61.

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL (2015) 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 17:405–424

    Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Wallis Y, Payne S, McAnulty C, Bodmer D, Sistermans E, Robertson K, Moore D, Abbs S, Deans Z, Deverau A (2013) Practice guidelines for the evaluation of pathogenicity and reporting of sequence variants in clinical molecular genetics, Association for Clinical Genetic Science, UK, http://www.acgs.uk.com/

  63. 63.

    MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, Adams DR, Altman RB, Antonarakis SE, Ashley EA, Barrett JC, Biesecker LG, Conrad DF, Cooper GM, Cox NJ, Daly MJ, Gerstein MB, Goldstein DB, Hirschhorn JN, Leal SM, Pennacchio LA, Stamatoyannopoulos JA, Sunyaev SR, Valle D, Voight BF, Winckler W, Gunter C (2014) Guidelines for investigating causality of sequence variants in human disease. Nature 508:469–476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    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 32:127–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Malone AF, Funk SD, Alhamad T, Miner JH (2016) Functional assessment of a novel COL4A5 splice region variant and immunostaining of plucked hair follicles as an alternative method of diagnosis in X-linked Alport syndrome. Pediatr Nephrol 32:997–1003

    Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Marcocci E, Uliana V, Bruttini M, Artuso R, Silengo MC, Zerial M, Bergesio F, Amoroso A, Savoldi S, Pennesi M, Giachino D, Rombola G, Fogazzi GB, Rosatelli C, Martinhago CD, Carmellini M, Mancini R, Di Costanzo G, Longo I, Renieri A, Mari F (2009) Autosomal dominant Alport syndrome: molecular analysis of the COL4A4 gene and clinical outcome. Nephrol Dial Transplant 24:1464–1471

    Article  CAS  PubMed  Google Scholar 

  67. 67.

    Rosado C, Bueno E, Felipe C, Valverde S, Gonzalez-Sarmiento R (2015) Study of the true clinical progression of autosomal dominant Alport syndrome in a European population. Kidney Blood Press Res 40:435–442

    Article  PubMed  Google Scholar 

  68. 68.

    Temme J, Peters F, Lange K, Pirson Y, Heidet L, Torra R, Grunfeld JP, Weber M, Licht C, Muller GA, Gross O (2012) Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations. Kidney Int 81:779–783

    Article  CAS  PubMed  Google Scholar 

  69. 69.

    Stefanou C, Pieri M, Savva I, Georgiou G, Pierides A, Voskarides K, Deltas C (2015) Co-inheritance of functional Podocin variants with heterozygous collagen IV mutations predisposes to renal failure. Nephron 130:200–212

    Article  CAS  PubMed  Google Scholar 

  70. 70.

    Mohammad M, Nanra R, Colville D, Trevillian P, Wang Y, Storey H, Flinter F, Savige J (2014) A female with X-linked Alport syndrome and compound heterozygous COL4A5 mutations. Pediatr Nephrol 29:481–485

    Article  PubMed  Google Scholar 

  71. 71.

    Lennon R, Stuart HM, Bierzynska A, Randles MJ, Kerr B, Hillman KA, Batra G, Campbell J, Storey H, Flinter FA, Koziell A, Welsh GI, Saleem MA, Webb NJ, Woolf AS (2015) Coinheritance of COL4A5 and MYO1E mutations accentuate the severity of kidney disease. Pediatr Nephrol 30:1459–1465

    Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Tonna S, Wang YY, Wilson D, Rigby L, Tabone T, Cotton R, Savige J (2008) The R229Q mutation in NPHS2 may predispose to proteinuria in thin-basement-membrane nephropathy. Pediatr Nephrol 23:2201–2207

    Article  PubMed  Google Scholar 

  73. 73.

    Bullich G, Trujillano D, Santin S, Ossowski S, Mendizabal S, Fraga G, Madrid A, Ariceta G, Ballarin J, Torra R, Estivill X, Ars E (2015) Targeted next-generation sequencing in steroid-resistant nephrotic syndrome: mutations in multiple glomerular genes may influence disease severity. Eur J Hum Genet 23:1192–1199

    Article  CAS  PubMed  Google Scholar 

  74. 74.

    Tsukaguchi H, Sudhakar A, Le TC, Nguyen T, Yao J, Schwimmer JA, Schachter AD, Poch E, Abreu PF, Appel GB, Pereira AB, Kalluri R, Pollak MR (2002) NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele. J Clin Invest 110:1659–1666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Savige J, Amos L, Ierino F, Mack HG, Symons RC, Hughes P, Nicholls K, Colville D (2016) Retinal disease in the C3 glomerulopathies and the risk of impaired vision. Ophthalmic Genet 37:369–376

    Article  CAS  PubMed  Google Scholar 

  76. 76.

    Gale DP, de Jorge EG, Cook HT, Martinez-Barricarte R, Hadjisavvas A, McLean AG, Pusey CD, Pierides A, Kyriacou K, Athanasiou Y, Voskarides K, Deltas C, Palmer A, Fremeaux-Bacchi V, de Cordoba SR, Maxwell PH, Pickering MC (2010) Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet 376:794–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Heath KE, Campos-Barros A, Toren A, Rozenfeld-Granot G, Carlsson LE, Savige J, Denison JC, Gregory MC, White JG, Barker DF, Greinacher A, Epstein CJ, Glucksman MJ, Martignetti JA (2001) Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: may-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes. Am J Hum Genet 69:1033–1045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Castelletti F, Donadelli R, Banterla F, Hildebrandt F, Zipfel PF, Bresin E, Otto E, Skerka C, Renieri A, Todeschini M, Caprioli J, Caruso RM, Artuso R, Remuzzi G, Noris M (2008) Mutations in FN1 cause glomerulopathy with fibronectin deposits. Proc Natl Acad Sci U S A 105:2538–2543

    Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, Marro B, Desmettre T, Cohen SY, Roullet E, Dracon M, Fardeau M, Van Agtmael T, Kerjaschki D, Antignac C, Ronco P (2007) COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. N Engl J Med 357:2687–2695

    Article  CAS  PubMed  Google Scholar 

  80. 80.

    Scolari F, Amoroso A, Savoldi S, Mazzola G, Prati E, Valzorio B, Viola BF, Nicola B, Movilli E, Sandrini M, Campanini M, Maiorca R (1999) Familial clustering of IgA nephropathy: further evidence in an Italian population. Am J Kidney Dis 33:857–865

    Article  CAS  PubMed  Google Scholar 

  81. 81.

    Milillo A, La Carpia F, Costanzi S, D'Urbano V, Martini M, Lanuti P, Vischini G, Larocca LM, Marchisio M, Miscia S, Amoroso A, Gurrieri F, Sangiorgi E (2015) A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy. Eur J Hum Genet 23:1673–1678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Heidet L, Bongers EM, Sich M, Zhang SY, Loirat C, Meyrier A, Broyer M, Landthaler G, Faller B, Sado Y, Knoers NV, Gubler MC (2003) In vivo expression of putative LMX1B targets in nail-patella syndrome kidneys. Am J Pathol 163:145–155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Morello R, Zhou G, Dreyer SD, Harvey SJ, Ninomiya Y, Thorner PS, Miner JH, Cole W, Winterpacht A, Zabel B, Oberg KC, Lee B (2001) Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome. Nat Genet 27:205–208

    Article  CAS  PubMed  Google Scholar 

  84. 84.

    Savige J, Dalgleish R, Cotton RG, den Dunnen JT, Macrae F, Povey S (2015) The Human Variome Project: ensuring the quality of DNA variant databases in inherited renal disease. Pediatr Nephrol 30:1893–1901

    Article  PubMed  Google Scholar 

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Correspondence to Judy Savige.

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The following guidelines were developed by an international group of expert adult and paediatric physicians, geneticists and researchers who work on Alport syndrome, and met for discussion at the Second Alport syndrome meeting in Gottingen, Germany in 2015 and at Glagow, UK in 2017. The guidelines have been further refined until a consensus was reached after a year of email discussions. These guidelines are complementary to the ‘Expert guidelines on the diagnosis and management of Alport syndrome and thin basement membrane nephropathy’ (JASN 2013).

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Savige, J., Ariani, F., Mari, F. et al. Expert consensus guidelines for the genetic diagnosis of Alport syndrome. Pediatr Nephrol 34, 1175–1189 (2019). https://doi.org/10.1007/s00467-018-3985-4

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Keywords

  • Alport syndrome
  • Collagen IV genes
  • Next generation sequencing
  • Pathogenic variants