{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:43:56Z","timestamp":1787028236265,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T00:00:00Z","timestamp":1679356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Mutations in COL4A3-A5 cause a spectrum of glomerular disorders, including thin basement membrane nephropathy (TBMN) and Alport syndrome (AS). The wide application of next-generation sequencing (NGS) in the last few years has revealed that mutations in these genes are not limited to these clinical entities. In this study, 176 individuals with a clinical diagnosis of inherited kidney disorders underwent an NGS-based analysis to address the underlying cause; those who changed or perfected the clinical diagnosis after molecular analysis were selected. In 5 out of 83 individuals reaching a molecular diagnosis, the genetic result was unexpected: three individuals showed mutations in collagen type IV genes. These patients showed the following clinical pictures: (1) familial focal segmental glomerulosclerosis; (2) end-stage renal disease (ESRD) diagnosed incidentally in a 49-year-old man, with diffuse cortical calcifications on renal imaging; and (3) dysmorphic and asymmetric kidneys with multiple cysts and signs of tubule\u2013interstitial defects. Genetic analysis revealed rare heterozygote\/compound heterozygote COL4A4-A5 variants. Our study highlights the key role of NGS in the diagnosis of inherited renal disorders and shows the phenotype variability in patients carrying mutations in collagen type IV genes.<\/jats:p>","DOI":"10.3390\/genes14030764","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T07:46:43Z","timestamp":1679471203000},"page":"764","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Next-Generation Sequencing (NGS) Analysis Illustrates the Phenotypic Variability of Collagen Type IV Nephropathies"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0376-2783","authenticated-orcid":false,"given":"Miriam","family":"Zacchia","sequence":"first","affiliation":[{"name":"Department of Medical and Translational Sciences, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Capolongo","sequence":"additional","affiliation":[{"name":"Department of Medical and Translational Sciences, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Del Vecchio Blanco","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5638-0837","authenticated-orcid":false,"given":"Floriana","family":"Secondulfo","sequence":"additional","affiliation":[{"name":"Department of Medical and Translational Sciences, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy"},{"name":"Department of Precision Medicine, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Medical and Translational Sciences, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy"},{"name":"Biogem, Scarl, 83031 Ariano Irpino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Blasio","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa Maria","family":"Pollastro","sequence":"additional","affiliation":[{"name":"Department of Medical and Translational Sciences, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Cervesato","sequence":"additional","affiliation":[{"name":"Department of Medical and Translational Sciences, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9418-125X","authenticated-orcid":false,"given":"Giulio","family":"Piluso","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Gigliotti","sequence":"additional","affiliation":[{"name":"UOC Nefrologia e Dialisi, Ospedale Civile di Eboli \u201cMM.SS. Addolorata\u201d, 84025 Eboli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2479-6018","authenticated-orcid":false,"given":"Annalaura","family":"Torella","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Nigro","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy"},{"name":"Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4048-9392","authenticated-orcid":false,"given":"Alessandra F.","family":"Perna","sequence":"additional","affiliation":[{"name":"Department of Medical and Translational Sciences, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3469-8614","authenticated-orcid":false,"given":"Giovambattista","family":"Capasso","sequence":"additional","affiliation":[{"name":"Biogem, Scarl, 83031 Ariano Irpino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Trepiccione","sequence":"additional","affiliation":[{"name":"Department of Medical and Translational Sciences, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy"},{"name":"Biogem, Scarl, 83031 Ariano Irpino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41581-019-0229-1","article-title":"Type IV Collagen and Diabetic Kidney Disease","volume":"16","author":"Miner","year":"2020","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1007\/s40620-021-01048-4","article-title":"Nephroplex: A Kidney-Focused NGS Panel Highlights the Challenges of PKD1 Sequencing and Identifies a Founder BBS4 Mutation","volume":"34","author":"Zacchia","year":"2021","journal-title":"J. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/S0140-6736(88)90753-2","article-title":"Genetics of Classic Alport\u2019s Syndrome","volume":"2","author":"Flinter","year":"1988","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1046\/j.1523-1755.2003.00234.x","article-title":"Thin Basement Membrane Nephropathy","volume":"64","author":"Savige","year":"2003","journal-title":"Kidney Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.kint.2017.12.018","article-title":"Alport Syndrome: A Unified Classification of Genetic Disorders of Collagen IV \u03b1345: A Position Paper of the Alport Syndrome Classification Working Group","volume":"93","author":"Kashtan","year":"2018","journal-title":"Kidney Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1681\/ASN.2008050507","article-title":"Unified Criteria for Ultrasonographic Diagnosis of ADPKD","volume":"20","author":"Pei","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"143","DOI":"10.2215\/CJN.04230321","article-title":"Guidelines for Genetic Testing and Management of Alport Syndrome","volume":"17","author":"Savige","year":"2022","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1093\/ckj\/sfaa182","article-title":"Urine Concentrating Defect as Presenting Sign of Progressive Renal Failure in Bardet-Biedl Syndrome Patients","volume":"14","author":"Zacchia","year":"2021","journal-title":"Clin. Kidney J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"D840","DOI":"10.1093\/nar\/gkw971","article-title":"The ExAC Browser: Displaying Reference Data Information from over 60 000 Exomes","volume":"45","author":"Karczewski","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_10","unstructured":"Karczewski, K. (2023, March 13). The Genome Aggregation Database (gnomAD). Available online: https:\/\/ibg.colorado.edu\/cdrom2019\/nealeB\/Gnomad\/boulder_190307.pdf."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting Amino Acid Changes That Affect Protein Function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/humu.22225","article-title":"Predicting the Functional, Molecular, and Phenotypic Consequences of Amino Acid Substitutions Using Hidden Markov Models","volume":"34","author":"Shihab","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1002\/prot.20810","article-title":"Prediction of Protein Stability Changes for Single-Site Mutations Using Support Vector Machines","volume":"62","author":"Cheng","year":"2006","journal-title":"Proteins"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1002\/humu.21047","article-title":"Functional Annotations Improve the Predictive Score of Human Disease-Related Mutations in Proteins","volume":"30","author":"Calabrese","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_15","unstructured":"Surhone, L.M., Tennoe, M.T., and Henssonow, S.F. (2010). Uniprot, Betascript Publishing."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1093\/bioinformatics\/btl423","article-title":"Predicting the Insurgence of Human Genetic Diseases Associated to Single Point Protein Mutations with Support Vector Machines and Evolutionary Information","volume":"22","author":"Capriotti","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1093\/bioinformatics\/btw222","article-title":"PANTHER-PSEP: Predicting Disease-Causing Genetic Variants Using Position-Specific Evolutionary Preservation","volume":"32","author":"Tang","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_18","unstructured":"UniProt Consortium (2023). UniProt: The Universal Protein Knowledgebase in 2023. Nucleic Acids Res., 51, D523\u2013D531."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"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","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Esposito, G., Testa, F., Zacchia, M., Crispo, A.A., Di Iorio, V., Capolongo, G., Rinaldi, L., D\u2019Antonio, M., Fioretti, T., and Iadicicco, P. (2017). Genetic Characterization of Italian Patients with Bardet-Biedl Syndrome and Correlation to Ocular, Renal and Audio-Vestibular Phenotype: Identification of Eleven Novel Pathogenic Sequence Variants. BMC Med. Genet., 18.","DOI":"10.1186\/s12881-017-0372-0"},{"key":"ref_21","unstructured":"(2023, March 13). SpliceAI Lookup. Available online: https:\/\/spliceailookup.broadinstitute.org\/."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1038\/s41431-021-00858-1","article-title":"Consensus Statement on Standards and Guidelines for the Molecular Diagnostics of Alport Syndrome: Refining the ACMG Criteria","volume":"29","author":"Savige","year":"2021","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3494","DOI":"10.1074\/jbc.M509333200","article-title":"Collagen XXVIII, a Novel von Willebrand Factor A Domain-Containing Protein with Many Imperfections in the Collagenous Domain","volume":"281","author":"Veit","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/jemt.20564","article-title":"Mammalian Collagen IV","volume":"71","author":"Khoshnoodi","year":"2008","journal-title":"Microsc. Res. Technol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1056\/NEJMra022296","article-title":"Alport\u2019s Syndrome, Goodpasture\u2019s Syndrome, and Type IV Collagen","volume":"348","author":"Hudson","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s00467-018-4121-1","article-title":"Alport Syndrome: Deducing the Mode of Inheritance from the Presence of Haematuria in Family Members","volume":"35","author":"Savige","year":"2020","journal-title":"Pediatr. Nephrol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.kint.2020.02.029","article-title":"Clinical Trial Recommendations for Potential Alport Syndrome Therapies","volume":"97","author":"Weinstock","year":"2020","journal-title":"Kidney Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1038\/ki.2014.305","article-title":"Rare Hereditary COL4A3\/COL4A4 Variants May Be Mistaken for Familial Focal Segmental Glomerulosclerosis","volume":"86","author":"Malone","year":"2014","journal-title":"Kidney Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1038\/ki.2014.326","article-title":"Pathology vs. Molecular Genetics: (re)defining the Spectrum of Alport Syndrome","volume":"86","author":"Miner","year":"2014","journal-title":"Kidney Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2721","DOI":"10.1093\/ndt\/gfp158","article-title":"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","volume":"24","author":"Pierides","year":"2009","journal-title":"Nephrol. Dial. Transplant"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1093\/ckj\/sfu033","article-title":"Multiple Kidney Cysts in Thin Basement Membrane Disease with Proteinuria and Kidney Function Impairment","volume":"7","author":"Sevillano","year":"2014","journal-title":"Clin. Kidney J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.ekir.2019.09.004","article-title":"Collagen IV Gene Mutations in Adults with Bilateral Renal Cysts and CKD","volume":"5","author":"Gulati","year":"2020","journal-title":"Kidney Int. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"D862","DOI":"10.1093\/nar\/gkv1222","article-title":"ClinVar: Public Archive of Interpretations of Clinically Relevant Variants","volume":"44","author":"Landrum","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"37654","DOI":"10.1021\/acsomega.2c04522","article-title":"Computational and Structural Analysis to Assess the Pathogenicity of Bardet-Biedl Syndrome Related Missense Variants Identified in Bardet-Biedl Syndrome 10 Gene (BBS10)","volume":"7","author":"Gupta","year":"2022","journal-title":"ACS Omega"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10638","DOI":"10.1039\/D0SC03003A","article-title":"Rules for the Design of Aza-Glycine Stabilized Triple-Helical Collagen Peptides","volume":"11","author":"Melton","year":"2020","journal-title":"Chem. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1002\/(SICI)1098-1004(1999)13:2<124::AID-HUMU4>3.0.CO;2-Z","article-title":"Detection of Mutations in COL4A5 in Patients with Alport Syndrome","volume":"13","author":"Plant","year":"1999","journal-title":"Hum. Mutat."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1038\/ki.2013.479","article-title":"Milder Clinical Aspects of X-Linked Alport Syndrome in Men Positive for the Collagen IV \u03b15 Chain","volume":"85","author":"Hashimura","year":"2014","journal-title":"Kidney Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/ki.2015.76","article-title":"What Is Nephrocalcinosis?","volume":"88","author":"Shavit","year":"2015","journal-title":"Kidney Int."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Sirangelo, I., Borriello, M., Liccardo, M., Scafuro, M., Russo, P., and Iannuzzi, C. (2021). Hydroxytyrosol Selectively Affects Non-Enzymatic Glycation in Human Insulin and Protects by AGEs Cytotoxicity. Antioxidants, 10.","DOI":"10.3390\/antiox10071127"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13244-019-0826-3","article-title":"CT and MR Imaging of Cystic Renal Lesions","volume":"11","author":"Agnello","year":"2020","journal-title":"Insights Imaging"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1093\/ndt\/gfz121","article-title":"Proteomics and Metabolomics Studies Exploring the Pathophysiology of Renal Dysfunction in Autosomal Dominant Polycystic Kidney Disease and Other Ciliopathies","volume":"35","author":"Zacchia","year":"2020","journal-title":"Nephrol. Dial. Transplant"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1159\/000488096","article-title":"Urine Proteomics Revealed a Significant Correlation Between Urine-Fibronectin Abundance and Estimated-GFR Decline in Patients with Bardet-Biedl Syndrome","volume":"43","author":"Caterino","year":"2018","journal-title":"Kidney Blood Press. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1083\/jcb.130.5.1219","article-title":"Differential Expression of Two Basement Membrane Collagen Genes, COL4A6 and COL4A5, Demonstrated by Immunofluorescence Staining Using Peptide-Specific Monoclonal Antibodies","volume":"130","author":"Ninomiya","year":"1995","journal-title":"J. Cell Biol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/3\/764\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:59:53Z","timestamp":1760122793000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/3\/764"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,21]]},"references-count":43,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["genes14030764"],"URL":"https:\/\/doi.org\/10.3390\/genes14030764","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,21]]}}}