The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3-5). It identified 'mutational hotspots' (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that 'well-established' functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common 'incidental' findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3-COL4A5 genes remains a challenge.

Alport UK Gloucester UK

Birmingham Children's Hospital Birmingham UK

Bristol Genetics Laboratory Pathology Sciences Southmead Hospital Bristol UK

Bristol Renal Unit Bristol Medical School University of Bristol Bristol UK

Center for Human Genetics University Hospitals and KU Leuven Leuven Belgium

Center of Excellence in Biobanking and Biomedical Research and Molecule Medicine Center University of Cyprus Nicosia Cyprus

Centre for Nephrology and Metabolic Disorders Weisswasser Germany

Centre for Rare Diseases and Clinical Genetics Unit Medical University of Gdansk Gdansk Poland

Clinic of Pediatrics Institute of Clinical Medicine Faculty of Medicine Vilnius University Vilnius Lithuania

Department of Biology School of Medicine University of Zagreb Zagreb Croatia

Department of Clinical Genetics Maastricht University Medical Center Maastricht The Netherlands

Department of Experimental Diagnostic and Specialty Medicine Nephrology Dialysis and Renal Transplant Unit S Orsola Hospital University of Bologna Bologna Italy

Department of Medical Genetics and Department of Biomedical Sciences University Hospital of Ostrava Ostrava Czech Republic

Department of Medicine The University of Melbourne Parkville VIC Australia

Department of Nephrology and Renal Transplantation University Hospitals Leuven Leuven Belgium

Department of Pathology University of Zagreb School of Medicine Dubrava University Hospital Zagreb Croatia

Department of Physiology Radboud Institute for Molecular Life Sciences Radboud University Medical Center Nijmegen The Netherlands

Departments of Genetics and Center for Molecular Medicine University Medical Center Utrecht University Utrecht The Netherlands

Departments of Pathology and Medicine University of Washington Seattle WA USA

Division of Nephrology and Dialysis Bambino Gesù Children's Hospital IRCCS Rome Italy

Division of Nephrology and Dialysis University Hospital of Verona Verona Italy

Division of Nephrology Department of Medicine University of Utah Health Salt Lake City UT USA

Elizabeth Watson South West Genomic Laboratory Hub North Bristol Trust Bristol UK

Fundeni Clinical Institute Pediatric Nephrology Department Bucharest Romania

Health Sciences Centre University of UTAH Salt Lake City UT USA

Inherited Kidney Disorders Fundacio Puigvert Universitat Autonoma de Barcelona Barcelona Spain

Institute de Pathologie et de Genetique ASBL Departement de Biologie Moleculaire Gosselies Belgium

Institute of Biomedical Sciences Faculty of Medicine Vilnius University Vilnius Lithuania

Institute of Human Genetics Technical University of Munich München Germany

Jens Michael Hertz Department of Clinical Genetics Odense University Hospital Odense Denmark

Medical Genetics Unit Department of Clinical and Experimental Biomedical Sciences Mario Serio University of Florence Florence Italy

Medical Genetics Unit Meyer Children's University Hospital Florence Italy

Medical Genetics University of Siena Siena Italy

Molecular Genetics Viapath Laboratories Guy's Hospital London UK

Nephrology Unit and Meyer Children's University Hospital Firenze Italy

Nephrology Unit University of Campania Naples Italy

North East Thames Regional Genetics Laboratory Great Ormond Street Hospital London UK

School of Immunology and Microbial Sciences Faculty of Life Sciences King's College London London UK

Wellcome Centre for Cell Matrix Research Division of Cell Matrix Biology and Regenerative Medicine School of Biological Sciences Faculty of Biology Medicine and Health The University of Manchester Manchester UK

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Zobrazit více v PubMed

Hasstedt SJ, Atkin CL. X-linked inheritance of Alport syndrome: family P revisited. Am J Hum Genet. 1983;35:1241–51. PubMed PMC

Pajari H, Kaariainen H, Muhonen T, Koskimies O. Alport’s syndrome in 78 patients: epidemiological and clinical study. Acta Paediatr. 1996;85:1300–6. doi: 10.1111/j.1651-2227.1996.tb13915.x. PubMed DOI

Groopman EE, Marasa M, Cameron-Christie S, Petrovski S, Kamalakaran S, Povysil G, et al. Diagnostic utility of exome sequencing for kidney disease. N Engl J Med. 2019;380:142–51. doi: 10.1056/NEJMoa1806891. PubMed DOI PMC

Connaughton DM, Hildebrandt F. Personalized medicine in chronic kidney disease by detection of monogenic mutations. Nephrol Dial Transpl. 2020;35:390–7. doi: 10.1093/ndt/gfz028. PubMed DOI PMC

Mencarelli MA, Heidet L, Storey H, van Geel M, Knebelman B, Fallerini C, et al. Evidence of digenic inheritance in Alport syndrome. J Med Genet. 2015;52:163–74. doi: 10.1136/jmedgenet-2014-102822. PubMed DOI

Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY. Thin basement membrane nephropathy. Kidney Int. 2003;64:1169–78. doi: 10.1046/j.1523-1755.2003.00234.x. PubMed DOI

Gubler M, Levy M, Broyer M, Naizot C, Gonzales G, Perrin D, et al. Alport’s syndrome. A report of 58 cases and a review of the literature. Am J Med. 1981;70:493–505. doi: 10.1016/0002-9343(81)90571-4. PubMed DOI

Savige J, Gregory M, Gross O, Kashtan, Ding J, Flinter F. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol. 2013;24:364–75. doi: 10.1681/ASN.2012020148. PubMed DOI

Savige J, Colville D, Rheault M, Gear S, Lennon R, Lagas S, et al. Alport syndrome in women and girls. Clin J Am Soc Nephrol. 2016;11:1713–20. doi: 10.2215/CJN.00580116. PubMed DOI PMC

Savige J, Ariani F, Mari F, Bruttini M, Renieri A, Gross O, et al. Expert consensus guidelines for the genetic diagnosis of Alport syndrome. Pediatr Nephrol. 2019;34:1175–89. doi: 10.1007/s00467-018-3985-4. PubMed DOI

Gast C, Pengelly RJ, Lyon M, Bunyan D, Seaby E, Graham N, et al. Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis. Nephrol Dial Transpl. 2016;31:961–70. doi: 10.1093/ndt/gfv325. PubMed DOI

Malone AF, Phelan PJ, Hall G, Cetincelik U, Homstad A, Alonso A, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014;86:1253–9. doi: 10.1038/ki.2014.305. PubMed DOI PMC

Yao T, Udwan K, John R, Rana A, Haghighi A, Xu L, et al. Integration of genetic testing and pathology for the diagnosis of adults with FSGS. Clin J Am Soc Nephrol. 2019;14:213–23. doi: 10.2215/CJN.08750718. PubMed DOI PMC

Li Y, Groopman E, D’Agati V, Prakash S, Zhang J, Mizerska Waskiak MM, et al. Type IV collagen mutations in IgA nephropathy. Kid Int Rep. 2020;5:1075–8. doi: 10.1016/j.ekir.2020.04.011. PubMed DOI PMC

Sevillano AM, Gutierrez E, Morales E, Hernandez E, Molina M, Gonzales E, et al. Multiple kidney cysts in thin basement membrane disease with proteinuria and kidney function impairment. Clin Kidney J. 2014;7:251–6. doi: 10.1093/ckj/sfu033. PubMed DOI PMC

Gulati A, Sevillano AM, Praga M, Gutierrez E, Alba I, Dahl N, et al. Collagen IV gene mutations in adults with bilateral renal cysts and CKD. Kidney Int Rep. 2020;5:103–8. doi: 10.1016/j.ekir.2019.09.004. PubMed DOI PMC

Pierides A, Voskarides K, Athanasiou Y, Ioannou K, Damianou L, Arsali M, et al. Clinico-pathological correlations in 127 patients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3/COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis. Nephrol Dial Transpl. 2009;24:2721–9. doi: 10.1093/ndt/gfp158. PubMed DOI

Savige J, Storey H, Il Cheong H, Gyung Kang H, Park E, Hilbert P, et al. X-linked and autosomal recessive Alport syndrome: pathogenic variant features and further genotype-phenotype correlations. PLoS ONE. 2016;11:e0161802. doi: 10.1371/journal.pone.0161802. PubMed DOI PMC

Bekheirnia MR, Reed B, Gregory MC, McFann K, Shamshirsaz A, Masoumi A, et al. Genotype-phenotype correlation in X-linked Alport syndrome. J Am Soc Nephrol. 2010;21:876–83. doi: 10.1681/ASN.2009070784. PubMed DOI PMC

Brown EJ, Pollak MR, Barua M. Genetic testing for nephrotic syndrome and FSGS in the era of next-generation sequencing. Kidney Int. 2014;85:1030–8. doi: 10.1038/ki.2014.48. PubMed DOI PMC

Trautmann A, Lipska-Zietkiewicz BS, Schaefer F. Exploring the clinical and genetic spectrum of steroid resistant nephrotic syndrome: the PodoNet Registry. Front Pediatr. 2018;6:200. doi: 10.3389/fped.2018.00200. PubMed DOI PMC

Moriniere V, Dahan K, Hilbert P, Lison M, Lebbah S, Topa A, et al. Improving mutation screening in familial hematuric nephropathies through next generation sequencing. J Am Soc Nephrol. 2014;25:2740–51. doi: 10.1681/ASN.2013080912. PubMed DOI PMC

Marini JC, Reich A, Smith SM. Osteogenesis imperfecta due to mutations in non-collagenous genes: lessons in the biology of bone formation. Curr Opin Pediatr. 2014;26:500–7. doi: 10.1097/MOP.0000000000000117. PubMed DOI PMC

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;17:405–24. doi: 10.1038/gim.2015.30. PubMed DOI PMC

Patel RY, Shah N, Jackson AR, Ghosh R, Pawliczek P, Paithankar S, et al. ClinGen pathogenicity calculator: a configurable system for assessing pathogenicity of genetic variants. Genome Med. 2017;9:3. doi: 10.1186/s13073-016-0391-z. PubMed DOI PMC

Vihinen M. Problems in variation interpretation guidelines and in their implementation in computational tools. Mol Genet Genom Med. 2020;8:e1206. PubMed PMC

Kopanos C, Tsiolkas V, Kouris A, Chapple C, Albarca Aguilera M, Meyer R, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35:1978–80. doi: 10.1093/bioinformatics/bty897. PubMed DOI PMC

Rivera-Munoz EA, Milko LV, Harrison SM, Azzaritis D, Kurtz C, Lee K, et al. ClinGen Variant Curation Expert Panel experiences and standardized processes for disease and gene-level specification of the ACMG/AMP guidelines for sequence variant interpretation. Hum Mutat. 2018;39:1614–22. doi: 10.1002/humu.23645. PubMed DOI PMC

Kalia SS, Adelman K, Bale SJ, Chung W, Eng C, Evans J, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19:249–55. doi: 10.1038/gim.2016.190. PubMed DOI

Antignac C, Knebelmann B, Drouot L, Gros F, Deschenes G, Hors-Cayla M, et al. Deletions in the COL4A5 collagen gene in X-linked Alport syndrome. Characterization of the pathological transcripts in nonrenal cells and correlation with disease expression. J Clin Invest. 1994;93:1195–207. doi: 10.1172/JCI117073. PubMed DOI PMC

Kalluri R, Shield CF, Todd P, Hudston B, Neilson E. Isoform switching of type IV collagen is developmentally arrested in X-linked Alport syndrome leading to increased susceptibility of renal basement membranes to endoproteolysis. J Clin Invest. 1997;99:2470–8. doi: 10.1172/JCI119431. PubMed DOI PMC

Yoshioka K, Hino S, Takemura T, Maki S, Wieslander J, Takekoshi Y, et al. Type IV collagen alpha 5 chain. Normal distribution and abnormalities in X-linked Alport syndrome revealed by monoclonal antibody. Am J Pathol. 1994;144:986–96. PubMed PMC

Biesecker LG, Harrison SM, ClinGen Sequence Variant Interpretation Working Group The ACMG/AMP reputable source criteria for the interpretation of sequence variants. Genet Med. 2018;20:1687–8. doi: 10.1038/gim.2018.42. PubMed DOI PMC

Richards CS, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Response to Biesecker and Harrison. Genet Med. 2018;20:1689–90. doi: 10.1038/gim.2018.43. PubMed DOI

Kashtan CE, Kleppel MM, Gubler MC. Immunohistologic findings in Alport syndrome. Contrib Nephrol. 1996;117:142–53. doi: 10.1159/000424811. PubMed DOI

Gubler MC, Knebelmann B, Beziau A, Broyer M, Pirson Y, Haddoum F, et al. Autosomal recessive Alport syndrome: immunohistochemical study of type IV collagen chain distribution. Kidney Int. 1995;47:1142–7. doi: 10.1038/ki.1995.163. PubMed DOI

Kamura M, Yamamura T, Omachi K, Suico M, Nozu K, Kaseda S, et al. Trimerization and genotype-phenotype correlation of COL4A5 mutants in Alport syndrome. Kidney Int Rep. 2020;5:718–26. doi: 10.1016/j.ekir.2020.01.008. PubMed DOI PMC

Horinouchi T, Nozu K, Yamamura T, Minamakawa S, Omori T, Nakanishi K, et al. Detection of splicing abnormalities and genotype-phenotype correlation in X-linked Alport syndrome. J Am Soc Nephrol. 2018;29:2244–54. doi: 10.1681/ASN.2018030228. PubMed DOI PMC

Wang YF, Ding J, Wang F, Bu D. Effect of glycine substitutions on alpha5(IV) chain structure and structure-phenotype correlations in Alport syndrome. Biochem Biophys Res Commun. 2004;316:1143–9. doi: 10.1016/j.bbrc.2004.02.168. PubMed DOI

Yeo J, Qiu Y, Jung GS, et al. Adverse effects of Alport syndrome-related Gly missense mutations on collagen type IV: Insights from molecular simulations and experiments. Biomaterials. 2020;240:119857. doi: 10.1016/j.biomaterials.2020.119857. PubMed DOI PMC

Wang Y, Zhang H, Ding J. Correlation between mRNA expression level of the mutant COL4A5 gene and phenotypes of XLAS females. Exp Biol Med. 2007;232:638–42. PubMed

Hudson BG, Reeders ST, Tryggvason K. Type IV collagen: structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis. J Biol Chem. 1993;268:26033–6. doi: 10.1016/S0021-9258(19)74270-7. PubMed DOI

Vanacore R, Pedchenko V, Bhave G, Hudson B. Sulphilimine cross-links in Goodpasture’s disease. Clin Exp Immunol. 2011;164:4–6. doi: 10.1111/j.1365-2249.2011.04356.x. PubMed DOI PMC

Zhou J, Hertz JM, Leinonen A, Tryggvason K. Complete amino acid sequence of the human alpha 5 (IV) collagen chain and identification of a single-base mutation in exon 23 converting glycine 521 in the collagenous domain to cysteine in an Alport syndrome patient. J Biol Chem. 1992;267:12475–81. doi: 10.1016/S0021-9258(18)42301-0. PubMed DOI

Vanacore R, Ham AJ, Voehler M, Sanders C, Conrads T, Veenstra T, et al. A sulfilimine bond identified in collagen IV. Science. 2009;325:1230–4. doi: 10.1126/science.1176811. PubMed DOI PMC

Gunwar S, Ballester F, Noelken ME, Sado Y, Ninomiya Y, Hudson B. Glomerular basement membrane. Identification of a novel disulfide-cross-linked network of alpha3, alpha4, and alpha5 chains of type IV collagen and its implications for the pathogenesis of Alport syndrome. J Biol Chem. 1998;273:8767–75. doi: 10.1074/jbc.273.15.8767. PubMed DOI

Beck K, Chan VC, Shenoy N, Kirkpatrick A, Ramshaw J, Brodsky B. Destabilization of osteogenesis imperfecta collagen-like model peptides correlates with the identity of the residue replacing glycine. Proc Natl Acad Sci USA. 2000;97:4273–8. doi: 10.1073/pnas.070050097. PubMed DOI PMC

Yang W, Battineni ML, Brodsky B. Amino acid sequence environment modulates the disruption by osteogenesis imperfecta glycine substitutions in collagen-like peptides. Biochemistry. 1997;36:6930–5. doi: 10.1021/bi970051h. PubMed DOI

Demosthenous P, Voskarides K, Stylianou K, Hadjigavriel M, Arsali M, Patsias C, et al. X-linked Alport syndrome in Hellenic families: phenotypic heterogeneity and mutations near interruptions of the collagen domain in COL4A5. Clin Genet. 2012;81:240–8. doi: 10.1111/j.1399-0004.2011.01647.x. PubMed DOI

Parkin JD, San Antonio JD, Pedchenko V, Hudson B, Jensen S, Savige J. 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. 2011;32:127–43. doi: 10.1002/humu.21401. PubMed DOI PMC

Zurowska AM, Bielska O, Daca-Roszak P, Jankowski M, Szczepanska M, Roszkowska-Bjanid D, et al. Mild X-linked Alport syndrome due to the COL4A5 G624D variant originating in the Middle Ages is predominant in Central/East Europe and causes kidney failure in midlife. Kidney Int. 2020. 10.1016/j.kint.2020.10.040 PubMed

Pierides A, Voskarides K, Kkolou M, Hadjigavriel M. Deltas C. X-linked, COL4A5 hypomorphic Alport mutations such as G624D and P628L may only exhibit thin basement membrane nephropathy with microhematuria and late onset kidney failure. Hippokratia. 2013;17:207–13. PubMed PMC

Macheroux EP, Braunisch MC, Pucci Pegler S, Satanovskij R, Riedhammer K, Gunthner R, et al. The Hypomorphic Variant p.(Gly624Asp) in COL4A5 as a possible cause for an unexpected severe phenotype in a family with X-linked Alport syndrome. Front Pediatr. 2019;7:485. doi: 10.3389/fped.2019.00485. PubMed DOI PMC

Kashtan CE, Ding J, Gregory M, Gross O, Heidet L, Knebelman P, et al. Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport Syndrome Research Collaborative. Pediatr Nephrol. 2013;28:5–11. doi: 10.1007/s00467-012-2138-4. PubMed DOI PMC

Zhang Y, Ding J, Wang S, Zhang H, Zhong H, Liu X, et al. Reassessing the pathogenicity of c.2858G>T(p.(G953V)) in COL4A5 gene: report of 19 Chinese families. Eur J Hum Genet. 2020;28:244–52. doi: 10.1038/s41431-019-0523-1. PubMed DOI PMC

Mariyama M, Leinonen A, Mochizuki T, Tryggvason K, Reeders S. Complete primary structure of the human alpha 3(IV) collagen chain. Coexpression of the alpha 3(IV) and alpha 4(IV) collagen chains in human tissues. J Biol Chem. 1994;269:23013–7. doi: 10.1016/S0021-9258(17)31612-5. PubMed DOI

Leinonen A, Mariyama M, Mochizuki T, Tryggvason K, Reeders S. Complete primary structure of the human type IV collagen alpha 4(IV) chain. Comparison with structure and expression of the other alpha (IV) chains. J Biol Chem. 1994;269:26172–7. doi: 10.1016/S0021-9258(18)47174-8. PubMed DOI

Genetic Etiologies for Chronic Kidney Disease Revealed through Next-Generation Renal Gene Panel