Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece
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 <i>COL4A5</i> (NM_000495.5) gene or recessive variants in the <i>COL4A3</i>/<...
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MDPI AG
2022-11-01
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| author | Despina Hadjipanagi Gregory Papagregoriou Constantina Koutsofti Christiana Polydorou Polichronis Alivanis Aimilios Andrikos Stalo Christodoulidou Manthos Dardamanis Athanasios A. Diamantopoulos Anastasios Fountoglou Eleni Frangou Eleni Georgaki Ioannis Giannikouris Velissarios Gkinis Pavlos C. Goudas Rigas G. Kalaitzidis Nikolaos Kaperonis Georgios Koutroumpas George Makrydimas Grigorios Myserlis Andromachi Mitsioni Christos Paliouras Fotios Papachristou Dorothea Papadopoulou Nikolaos Papagalanis Aikaterini Papagianni Garyfalia Perysinaki Ekaterini Siomou Konstantinos Sombolos Ioannis Tzanakis Georgios V. Vergoulas Nicoletta Printza Constantinos Deltas |
| author_facet | Despina Hadjipanagi Gregory Papagregoriou Constantina Koutsofti Christiana Polydorou Polichronis Alivanis Aimilios Andrikos Stalo Christodoulidou Manthos Dardamanis Athanasios A. Diamantopoulos Anastasios Fountoglou Eleni Frangou Eleni Georgaki Ioannis Giannikouris Velissarios Gkinis Pavlos C. Goudas Rigas G. Kalaitzidis Nikolaos Kaperonis Georgios Koutroumpas George Makrydimas Grigorios Myserlis Andromachi Mitsioni Christos Paliouras Fotios Papachristou Dorothea Papadopoulou Nikolaos Papagalanis Aikaterini Papagianni Garyfalia Perysinaki Ekaterini Siomou Konstantinos Sombolos Ioannis Tzanakis Georgios V. Vergoulas Nicoletta Printza Constantinos Deltas |
| author_sort | Despina Hadjipanagi |
| collection | DOAJ |
| description | 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 <i>COL4A5</i> (NM_000495.5) gene or recessive variants in the <i>COL4A3</i>/<i>COL4A4</i> (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 <i>COL4A5</i> 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 <i>COL4A5</i> 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 <i>COL4A5</i>-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. |
| first_indexed | 2024-03-09T16:30:56Z |
| format | Article |
| id | doaj.art-f527300ea46b4ec994e94ea39117bb45 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T16:30:56Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-f527300ea46b4ec994e94ea39117bb452023-11-24T15:02:43ZengMDPI AGGenes2073-44252022-11-011312220310.3390/genes13122203Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in GreeceDespina Hadjipanagi0Gregory Papagregoriou1Constantina Koutsofti2Christiana Polydorou3Polichronis Alivanis4Aimilios Andrikos5Stalo Christodoulidou6Manthos Dardamanis7Athanasios A. Diamantopoulos8Anastasios Fountoglou9Eleni Frangou10Eleni Georgaki11Ioannis Giannikouris12Velissarios Gkinis13Pavlos C. Goudas14Rigas G. Kalaitzidis15Nikolaos Kaperonis16Georgios Koutroumpas17George Makrydimas18Grigorios Myserlis19Andromachi Mitsioni20Christos Paliouras21Fotios Papachristou22Dorothea Papadopoulou23Nikolaos Papagalanis24Aikaterini Papagianni25Garyfalia Perysinaki26Ekaterini Siomou27Konstantinos Sombolos28Ioannis Tzanakis29Georgios V. Vergoulas30Nicoletta Printza31Constantinos Deltas32biobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, Cyprusbiobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, Cyprusbiobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, Cyprusbiobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, CyprusDepartment of Nephrology, General Hospital of Rhodes, 85133 Rhodes, GreeceDepartment of Nephrology, “Hatzikosta” General Hospital of Ioannina, 45445 Ioannina, GreeceDepartment of Nephrology, “Evangelismos” General Hospital of Athens, 10676 Athens, GreeceDepartment of Nephrology, General Hospital of Preveza, 48100 Preveza, GreeceDepartment of Nephrology, “St. Andrew” General State Hospital, 26332 Patra, GreeceNephroxenia Dialysis Unit, 45221 Ioannina, GreeceDepartment of Nephrology, Limassol General Hospital, SHSO, Limassol 4131, CyprusPediatric Nephrology Unit, “IASO” Children’s Hospital, 15123 Maroussi, GreeceDepartment of Nephrology and Hemodialysis Unit, Mediterraneo Hospital, 16675 Glyfada, GreeceMedifil SA Private Nephrological Center, 12132 Peristeri, GreeceOlympion, Dialysis Center, 27200 Amaliada, GreeceDepartment of Nephrology, University Hospital of Ioannina, 45500 Ioannina, GreeceDepartment of Nephrology, Hellenic Red Cross Hospital “Korgialeneio-Benakeio”, 11526 Athens, GreeceHemodialysis Unit, “Achillopouleion” General Hospital of Volos, 38222 Volos, GreeceDepartment of Obstetrics and Gynecology, University Hospital of Ioannina, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45110 Ioannina, GreeceOrgan Transplantation Unit, “Hippokration” General Hospital of Thessaloniki, Aristotle University of Thessaloniki, 54642 Thessaloniki, GreeceDepartment of Nephrology, “P. & A. Kyriakou” Children’s Hospital, 11527 Athens, GreeceDepartment of Nephrology, General Hospital of Rhodes, 85133 Rhodes, GreecePediatric Nephrology Unit, 1st Department of Pediatrics, “Hippokration” General Hospital of Thessaloniki, Aristotle University of Thessaloniki, 54643 Thessaloniki, GreeceDepartment of Nephrology, “Papageorgiou” General Hospital of Thessaloniki, 56429 Thessaloniki, GreeceDepartment of Nephrology, Hellenic Red Cross Hospital “Korgialeneio-Benakeio”, 11526 Athens, GreeceDepartment of Nephrology, “Hippokration” General Hospital of Thessaloniki, Aristotle University of Thessaloniki, 54643 Thessaloniki, GreeceDivision of Nephrology, General Hospital of Rethymnon, 74100 Rethymno, GreeceDepartment of Pediatrics, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina, 45500 Ioannina, GreeceRenal Unit, “George Papanikolaou” General Hospital of Thessaloniki, 57010 Thessaloniki, GreeceDepartment of Nephrology, General Hospital of Chania “Agios Georgios”, 73300 Chania, GreeceOrgan Transplantation Unit, “Hippokration” General Hospital of Thessaloniki, Aristotle University of Thessaloniki, 54642 Thessaloniki, GreecePediatric Nephrology Unit, 1st Department of Pediatrics, “Hippokration” General Hospital of Thessaloniki, Aristotle University of Thessaloniki, 54643 Thessaloniki, Greecebiobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, CyprusAlport 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 <i>COL4A5</i> (NM_000495.5) gene or recessive variants in the <i>COL4A3</i>/<i>COL4A4</i> (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 <i>COL4A5</i> 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 <i>COL4A5</i> 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 <i>COL4A5</i>-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.https://www.mdpi.com/2073-4425/13/12/2203Alport syndromeglomerular basement membraneCollagen IV<i>COL4A5</i>founder mutationpathogenic variant |
| spellingShingle | Despina Hadjipanagi Gregory Papagregoriou Constantina Koutsofti Christiana Polydorou Polichronis Alivanis Aimilios Andrikos Stalo Christodoulidou Manthos Dardamanis Athanasios A. Diamantopoulos Anastasios Fountoglou Eleni Frangou Eleni Georgaki Ioannis Giannikouris Velissarios Gkinis Pavlos C. Goudas Rigas G. Kalaitzidis Nikolaos Kaperonis Georgios Koutroumpas George Makrydimas Grigorios Myserlis Andromachi Mitsioni Christos Paliouras Fotios Papachristou Dorothea Papadopoulou Nikolaos Papagalanis Aikaterini Papagianni Garyfalia Perysinaki Ekaterini Siomou Konstantinos Sombolos Ioannis Tzanakis Georgios V. Vergoulas Nicoletta Printza Constantinos Deltas Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece Genes Alport syndrome glomerular basement membrane Collagen IV <i>COL4A5</i> founder mutation pathogenic variant |
| title | Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece |
| title_full | Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece |
| title_fullStr | Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece |
| title_full_unstemmed | Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece |
| title_short | Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece |
| title_sort | novel and founder pathogenic variants in x linked alport syndrome families in greece |
| topic | Alport syndrome glomerular basement membrane Collagen IV <i>COL4A5</i> founder mutation pathogenic variant |
| url | https://www.mdpi.com/2073-4425/13/12/2203 |
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