{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:01:34Z","timestamp":1790737294207,"version":"4.1.0"},"reference-count":74,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T00:00:00Z","timestamp":1669248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CY-Biobank, an EU Horizon 2020 Research and Innovation Programme","award":["857122"],"award-info":[{"award-number":["857122"]}]},{"name":"CY-Biobank, an EU Horizon 2020 Research and Innovation Programme","award":["2016\u20132020\/INTEGRATED\/0918\/0043"],"award-info":[{"award-number":["2016\u20132020\/INTEGRATED\/0918\/0043"]}]},{"name":"Cyprus Research and Innovation Foundation","award":["857122"],"award-info":[{"award-number":["857122"]}]},{"name":"Cyprus Research and Innovation Foundation","award":["2016\u20132020\/INTEGRATED\/0918\/0043"],"award-info":[{"award-number":["2016\u20132020\/INTEGRATED\/0918\/0043"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant pathogenic variants in the X-linked COL4A5 (NM_000495.5) gene or recessive variants in the COL4A3\/COL4A4 (NM_000091.4\/NM_000092.4) genes. The disease manifests in early childhood with persistent microhematuria and can progress to proteinuria and kidney failure in adolescence or early adulthood if left untreated. On biopsy, pathognomonic features include alternate thinning, thickening and lamellation of the glomerular basement membrane (GBM), in the presence of podocyte foot process effacement. Although previous studies indicate a prevalence of AS of about 1\/50,000, a recent publication reported a predicted rate of pathogenic COL4A5 variants of 1\/2320. We herewith present 98 patients (40 M\/58 F) from 26 Greek families. We are selectively presenting the families segregating the X-linked form of AS with pathogenic variants in the COL4A5 gene. We found 21 different pathogenic variants, 12 novel: eight glycine and one proline substitutions in the collagenous domain, one cysteine substitution in the NC1 domain, two premature termination of translation codons, three splicing variants, one 5-bp insertion\/frameshift variant, one indel-frameshift variant and four gross deletions. Notably, patients in six families we describe here and three families we reported previously, carried the COL4A5-p.G624D substitution, a founder defect encountered all over Europe which is hypomorphic with mostly milder symptomatology. Importantly, on several occasions, the correct genetic diagnosis reclassified patients as patients with AS, leading to termination of previous immunosuppressive\/cyclosporine A therapy and a switch to angiotensin converting enzyme inhibitors (ACEi). With the understanding that all 98 patients span a wide range of ages from infancy to late adulthood, 15 patients (11 M\/4 F) reached kidney failure and 11 (10 M\/1 F) received a transplant. The prospects of avoiding lengthy diagnostic investigations and erroneous medications, and the advantage of delaying kidney failure with very early administration of renin-angiotensin-aldosterone system (RAAS) blockade, highlights the importance of timely documentation of AS by genetic diagnosis.<\/jats:p>","DOI":"10.3390\/genes13122203","type":"journal-article","created":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T02:29:23Z","timestamp":1669343363000},"page":"2203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece"],"prefix":"10.3390","volume":"13","author":[{"given":"Despina","family":"Hadjipanagi","sequence":"first","affiliation":[{"name":"biobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, Cyprus"},{"name":"Department of Biological Sciences, University of Cyprus, Nicosia 2109, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2440-9789","authenticated-orcid":false,"given":"Gregory","family":"Papagregoriou","sequence":"additional","affiliation":[{"name":"biobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantina","family":"Koutsofti","sequence":"additional","affiliation":[{"name":"biobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, Cyprus"},{"name":"Department of Biological Sciences, University of Cyprus, Nicosia 2109, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiana","family":"Polydorou","sequence":"additional","affiliation":[{"name":"biobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polichronis","family":"Alivanis","sequence":"additional","affiliation":[{"name":"Department of Nephrology, General Hospital of Rhodes, 85133 Rhodes, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimilios","family":"Andrikos","sequence":"additional","affiliation":[{"name":"Department of Nephrology, \u201cHatzikosta\u201d General Hospital of Ioannina, 45445 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stalo","family":"Christodoulidou","sequence":"additional","affiliation":[{"name":"Department of Nephrology, \u201cEvangelismos\u201d General Hospital of Athens, 10676 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manthos","family":"Dardamanis","sequence":"additional","affiliation":[{"name":"Department of Nephrology, General Hospital of Preveza, 48100 Preveza, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasios A.","family":"Diamantopoulos","sequence":"additional","affiliation":[{"name":"Department of Nephrology, \u201cSt. Andrew\u201d General State Hospital, 26332 Patra, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasios","family":"Fountoglou","sequence":"additional","affiliation":[{"name":"Nephroxenia Dialysis Unit, 45221 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Frangou","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Limassol General Hospital, SHSO, Limassol 4131, Cyprus"},{"name":"Medical School of the University of Nicosia, Engomi, Nicosia 2408, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Georgaki","sequence":"additional","affiliation":[{"name":"Pediatric Nephrology Unit, \u201cIASO\u201d Children\u2019s Hospital, 15123 Maroussi, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3699-2086","authenticated-orcid":false,"given":"Ioannis","family":"Giannikouris","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hemodialysis Unit, Mediterraneo Hospital, 16675 Glyfada, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Velissarios","family":"Gkinis","sequence":"additional","affiliation":[{"name":"Medifil SA Private Nephrological Center, 12132 Peristeri, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavlos C.","family":"Goudas","sequence":"additional","affiliation":[{"name":"Olympion, Dialysis Center, 27200 Amaliada, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7773-7575","authenticated-orcid":false,"given":"Rigas G.","family":"Kalaitzidis","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Hospital of Ioannina, 45500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Kaperonis","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Hellenic Red Cross Hospital \u201cKorgialeneio-Benakeio\u201d, 11526 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Koutroumpas","sequence":"additional","affiliation":[{"name":"Hemodialysis Unit, \u201cAchillopouleion\u201d General Hospital of Volos, 38222 Volos, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Makrydimas","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University Hospital of Ioannina, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grigorios","family":"Myserlis","sequence":"additional","affiliation":[{"name":"Organ Transplantation Unit, \u201cHippokration\u201d General Hospital of Thessaloniki, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andromachi","family":"Mitsioni","sequence":"additional","affiliation":[{"name":"Department of Nephrology, \u201cP. & A. Kyriakou\u201d Children\u2019s Hospital, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Paliouras","sequence":"additional","affiliation":[{"name":"Department of Nephrology, General Hospital of Rhodes, 85133 Rhodes, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fotios","family":"Papachristou","sequence":"additional","affiliation":[{"name":"Pediatric Nephrology Unit, 1st Department of Pediatrics, \u201cHippokration\u201d General Hospital of Thessaloniki, Aristotle University of Thessaloniki, 54643 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothea","family":"Papadopoulou","sequence":"additional","affiliation":[{"name":"Department of Nephrology, \u201cPapageorgiou\u201d General Hospital of Thessaloniki, 56429 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Papagalanis","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Hellenic Red Cross Hospital \u201cKorgialeneio-Benakeio\u201d, 11526 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aikaterini","family":"Papagianni","sequence":"additional","affiliation":[{"name":"Department of Nephrology, \u201cHippokration\u201d General Hospital of Thessaloniki, Aristotle University of Thessaloniki, 54643 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garyfalia","family":"Perysinaki","sequence":"additional","affiliation":[{"name":"Division of Nephrology, General Hospital of Rethymnon, 74100 Rethymno, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterini","family":"Siomou","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina, 45500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Sombolos","sequence":"additional","affiliation":[{"name":"Renal Unit, \u201cGeorge Papanikolaou\u201d General Hospital of Thessaloniki, 57010 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Tzanakis","sequence":"additional","affiliation":[{"name":"Department of Nephrology, General Hospital of Chania \u201cAgios Georgios\u201d, 73300 Chania, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios V.","family":"Vergoulas","sequence":"additional","affiliation":[{"name":"Organ Transplantation Unit, \u201cHippokration\u201d General Hospital of Thessaloniki, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1618-9285","authenticated-orcid":false,"given":"Nicoletta","family":"Printza","sequence":"additional","affiliation":[{"name":"Pediatric Nephrology Unit, 1st Department of Pediatrics, \u201cHippokration\u201d General Hospital of Thessaloniki, Aristotle University of Thessaloniki, 54643 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5549-9169","authenticated-orcid":false,"given":"Constantinos","family":"Deltas","sequence":"additional","affiliation":[{"name":"biobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, Cyprus"},{"name":"School of Medicine, University of Cyprus, Nicosia 2109, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,24]]},"reference":[{"key":"ref_1","unstructured":"Pagon, R.A., Bird, T.D., Dolan, C.R., Stephens, K., and Adam, M.P. 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