{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T11:26:20Z","timestamp":1791890780292,"version":"4.3.4"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2024,10,19]],"date-time":"2024-10-19T00:00:00Z","timestamp":1729296000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,10,19]],"date-time":"2024-10-19T00:00:00Z","timestamp":1729296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Hum Genet"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Alport syndrome is a rare genetic kidney disease caused by variants in the <jats:italic>COL4A3\/A4\/A5<\/jats:italic> genes. It\u2019s characterised by progressive kidney failure, though therapies targeting Renin-Angiotensin System can delay its progression. Additionally, extrarenal manifestations may sometimes coexist. Recent advances in genetic analysis and the necessity to better clarify genotype-phenotype correlations in affected patients raises the importance of detecting even cryptic splicing variants, lying in both canonical and non-canonical splice sites variants such as last exonic nucleotide variants. These variants, often, do not cause an amino acid change but alter the snRNP proteins binding. We studied a big Italian family with Alport syndrome showing a clear dominant pattern of transmission with younger family members having only haematuria and older individuals presenting with End-Stage Kidney Failure (ESKF). Kidney biopsy showed the typical disease hallmarks. We deeply mined the data for SNV and CNV through exome sequencing on DNA from both peripheral blood samples and patients\u2019 podocytes-lineage cells. We identified an already reported synonymous variant, c.765G&gt;A (p.(Thr255Thr)), in the last exonic nucleotide of exon 13 of the <jats:italic>COL4A3<\/jats:italic> gene. Employing the patient\u2019s podocytes we demonstrated that this variant results in exon skipping leading to an <jats:italic>in-frame<\/jats:italic> deletion of 28 amino acids without leaky effect. According to the pattern of transmission, to the kidney biopsy and to the exome data analysis we provided further evidence that autosomal dominant Alport syndrome is a well-defined clinical entity. We also confirmed the pathogenicity of the synonymous <jats:italic>COL4A3<\/jats:italic> variant for the first time demonstrating its role in a dominant pattern of transmission.<\/jats:p>","DOI":"10.1038\/s41431-024-01706-8","type":"journal-article","created":{"date-parts":[[2024,10,19]],"date-time":"2024-10-19T00:01:48Z","timestamp":1729296108000},"page":"461-467","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Slowly progressive autosomal dominant Alport Syndrome due to COL4A3 splicing variant"],"prefix":"10.1038","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6419-9456","authenticated-orcid":false,"given":"Sergio","family":"Daga","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5020-8393","authenticated-orcid":false,"given":"Lorenzo","family":"Loberti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Rollo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loredaria","family":"Adamo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga Lorenza","family":"Colavecchio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Brunelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Zguro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio Antonio","family":"Tripodi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Guarnieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Garosi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1728-6397","authenticated-orcid":false,"given":"Romina","family":"D\u2019Aurizio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Ariani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Tita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0846-9220","authenticated-orcid":false,"given":"Alessandra","family":"Renieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6259-6901","authenticated-orcid":false,"given":"Anna Maria","family":"Pinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,19]]},"reference":[{"key":"1706_CR1","first-page":"1192","volume":"58","author":"A Renieri","year":"1996","unstructured":"Renieri A, Bruttini M, Galli L, Zanelli P, Neri T, Rossetti S, et al. 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X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a \u201cEuropean Community Alport Syndrome Concerted Action\u201d study. J Am Soc Nephrol. 2003;14:2603\u201310.","journal-title":"J Am Soc Nephrol"},{"key":"1706_CR4","doi-asserted-by":"publisher","first-page":"1947","DOI":"10.1046\/j.1523-1755.2002.00379.x","volume":"61","author":"I Longo","year":"2002","unstructured":"Longo I, Porcedda P, Mari F, Giachino D, Meloni I, Deplano C, et al. COL4A3\/COL4A4 mutations: from familial haematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int. 2002;61:1947\u201356.","journal-title":"Kidney Int"},{"key":"1706_CR5","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1093\/ndt\/gfi312","volume":"21","author":"I Longo","year":"2006","unstructured":"Longo I, Scala E, Mari F, Caselli R, Pescucci C, Mencarelli MA, et al. 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