{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:55:53Z","timestamp":1790394953163,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2017,2,22]],"date-time":"2017-02-22T00:00:00Z","timestamp":1487721600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Telethon Network of Genetic Biobanks","award":["GTB12001"],"award-info":[{"award-number":["GTB12001"]}]},{"name":"Telethon"},{"name":"Italian Ministry of Health","award":["GR-2009-1578914"],"award-info":[{"award-number":["GR-2009-1578914"]}]},{"DOI":"10.13039\/501100003500","name":"University of Padova","doi-asserted-by":"crossref","award":["CPDA140508\/14"],"award-info":[{"award-number":["CPDA140508\/14"]}],"id":[{"id":"10.13039\/501100003500","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2017,7]]},"abstract":"<jats:p>Alport syndrome (<jats:styled-content style=\"fixed-case\">ATS<\/jats:styled-content>) is a genetically heterogeneous nephropathy with considerable phenotypic variability and different transmission patterns, including monogenic (X\u2010linked\/autosomal) and digenic inheritance (DI). Here we present a new series of families with DI and we discuss the consequences for genetic counseling and risk assessment. Out of five families harboring variants in more than one <jats:italic><jats:styled-content style=\"fixed-case\">COL4<\/jats:styled-content><\/jats:italic> gene detected by next generation sequencing (<jats:styled-content style=\"fixed-case\">NGS<\/jats:styled-content>), minigene\u2010splicing assay allowed us to identify four as true digenic. Two families showed <jats:italic><jats:styled-content style=\"fixed-case\">COL4A3<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">A4<\/jats:styled-content><\/jats:italic> mutations <jats:italic>in cis<\/jats:italic>, mimicking an autosomal dominant inheritance with a more severe phenotype and one showed <jats:italic><jats:styled-content style=\"fixed-case\">COL4A3<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">A4<\/jats:styled-content><\/jats:italic> mutations <jats:italic>in trans<\/jats:italic>, mimicking an autosomal recessive inheritance with a less severe phenotype. In a fourth family, a <jats:italic>de novo<\/jats:italic> mutation (<jats:italic><jats:styled-content style=\"fixed-case\">COL4A5<\/jats:styled-content><\/jats:italic>) combined with an inherited mutation (<jats:italic><jats:styled-content style=\"fixed-case\">COL4A3<\/jats:styled-content><\/jats:italic>) triggered a more severe phenotype. A fifth family, predicted digenic on the basis of silico tools, rather showed monogenic X\u2010linked inheritance due to a hypomorphic mutation, in accordance with a milder phenotype. In conclusion, this study highlights the impact of DI in <jats:styled-content style=\"fixed-case\">ATS<\/jats:styled-content> and explains the associated atypical presentations. More complex inheritance should be therefore considered when reviewing prognosis and recurrence risks. On the other side, these findings emphasize the importance to accompany <jats:styled-content style=\"fixed-case\">NGS<\/jats:styled-content> with splicing assays in order to avoid erroneous identification of at risk members.<\/jats:p>","DOI":"10.1111\/cge.12919","type":"journal-article","created":{"date-parts":[[2016,11,8]],"date-time":"2016-11-08T14:51:44Z","timestamp":1478616704000},"page":"34-44","source":"Crossref","is-referenced-by-count":59,"title":["Alport syndrome: impact of digenic inheritance in patients management"],"prefix":"10.1111","volume":"92","author":[{"given":"C.","family":"Fallerini","sequence":"first","affiliation":[{"name":"Medical Genetics University of Siena  Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Baldassarri","sequence":"additional","affiliation":[{"name":"Medical Genetics University of Siena  Siena Italy"},{"name":"Genetica Medica Azienda Ospedaliera Universitaria Senese  Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Trevisson","sequence":"additional","affiliation":[{"name":"Department of Woman and Child Health University of Padova  Padova Italy"},{"name":"Istituto di Ricerca Pediatria, IRP Citt\u00e0 della Speranza  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"Morbidoni","sequence":"additional","affiliation":[{"name":"Department of Woman and Child Health University of Padova  Padova Italy"},{"name":"Istituto di Ricerca Pediatria, IRP Citt\u00e0 della Speranza  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"La Manna","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Second University of Napoli  Napoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Lazzarin","sequence":"additional","affiliation":[{"name":"Nephrology and Dialysis Ospedale San Giacomo Apostolo  Castelfranco Veneto Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Pasini","sequence":"additional","affiliation":[{"name":"Nephrology and Pediatric Dialysis Ospedale S. 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