A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people
IntroductionRomani people have a high prevalence of kidney failure. This study examined a Romani cohort for pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes that are affected in Alport syndrome (AS), a common cause of genetic kidney disease, characterized by hematuria, proteinuria, end-st...
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmed.2023.1096869/full |
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| author | Pavlina Plevova Pavlina Plevova Jana Indrakova Judy Savige Petra Kuhnova Petra Tvrda Dita Cerna Sarka Hilscherova Monika Kudrejova Daniela Polendova Radka Jaklova Martina Langova Helena Jahnova Jana Lastuvkova Jiri Dusek Josef Gut Marketa Vlckova Pavla Solarova Gabriela Kreckova Eva Kantorova Jana Soukalova Rastislav Slavkovsky Jana Zapletalova Tomas Tichy Dana Thomasova |
| author_facet | Pavlina Plevova Pavlina Plevova Jana Indrakova Judy Savige Petra Kuhnova Petra Tvrda Dita Cerna Sarka Hilscherova Monika Kudrejova Daniela Polendova Radka Jaklova Martina Langova Helena Jahnova Jana Lastuvkova Jiri Dusek Josef Gut Marketa Vlckova Pavla Solarova Gabriela Kreckova Eva Kantorova Jana Soukalova Rastislav Slavkovsky Jana Zapletalova Tomas Tichy Dana Thomasova |
| author_sort | Pavlina Plevova |
| collection | DOAJ |
| description | IntroductionRomani people have a high prevalence of kidney failure. This study examined a Romani cohort for pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes that are affected in Alport syndrome (AS), a common cause of genetic kidney disease, characterized by hematuria, proteinuria, end-stage kidney failure, hearing loss, and eye anomalies.Materials and methodsThe study included 57 Romani from different families with clinical features that suggested AS who underwent next-generation sequencing (NGS) of the COL4A3, COL4A4, and COL4A5 genes, and 83 family members.ResultsIn total, 27 Romani (19%) had autosomal recessive AS caused by a homozygous pathogenic c.1598G>A, p.Gly533Asp variant in COL4A4 (n = 20) or a homozygous c.415G>C, p.Gly139Arg variant in COL4A3 (n = 7). For p.Gly533Asp, 12 (80%) had macroscopic hematuria, 12 (63%) developed end-stage kidney failure at a median age of 22 years, and 13 (67%) had hearing loss. For p.Gly139Arg, none had macroscopic hematuria (p = 0.023), three (50%) had end-stage kidney failure by a median age of 42 years (p = 0.653), and five (83%) had hearing loss (p = 0.367). The p.Gly533Asp variant was associated with a more severe phenotype than p.Gly139Arg, with an earlier age at end-stage kidney failure and more macroscopic hematuria. Microscopic hematuria was very common in heterozygotes with both p.Gly533Asp (91%) and p.Gly139Arg (92%).ConclusionThese two founder variants contribute to the high prevalence of kidney failure in Czech Romani. The estimated population frequency of autosomal recessive AS from these variants and consanguinity by descent is at least 1:11,000 in Czech Romani. This corresponds to a population frequency of autosomal dominant AS from these two variants alone of 1%. Romani with persistent hematuria should be offered genetic testing. |
| first_indexed | 2024-04-10T16:21:36Z |
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| id | doaj.art-a61fd3b445844401ac3d8d045e9d77aa |
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| language | English |
| last_indexed | 2024-04-10T16:21:36Z |
| publishDate | 2023-02-01 |
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| series | Frontiers in Medicine |
| spelling | doaj.art-a61fd3b445844401ac3d8d045e9d77aa2023-02-09T12:36:35ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2023-02-011010.3389/fmed.2023.10968691096869A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani peoplePavlina Plevova0Pavlina Plevova1Jana Indrakova2Judy Savige3Petra Kuhnova4Petra Tvrda5Dita Cerna6Sarka Hilscherova7Monika Kudrejova8Daniela Polendova9Radka Jaklova10Martina Langova11Helena Jahnova12Jana Lastuvkova13Jiri Dusek14Josef Gut15Marketa Vlckova16Pavla Solarova17Gabriela Kreckova18Eva Kantorova19Jana Soukalova20Rastislav Slavkovsky21Jana Zapletalova22Tomas Tichy23Dana Thomasova24Department of Clinical and Molecular Pathology and Medical Genetics, University Hospital Ostrava, Ostrava, CzechiaDepartment of Biomedical Sciences, Faculty of Medicine, University of Ostrava, Ostrava, CzechiaDepartment of Clinical and Molecular Pathology and Medical Genetics, University Hospital Ostrava, Ostrava, CzechiaDepartment of Medicine (Melbourne Health and Northern Health), The University of Melbourne, Royal Melbourne Hospital, Melbourne, AustraliaDepartment of Clinical and Molecular Pathology and Medical Genetics, University Hospital Ostrava, Ostrava, CzechiaDepartment of Clinical and Molecular Pathology and Medical Genetics, University Hospital Ostrava, Ostrava, CzechiaDepartment of Clinical and Molecular Pathology and Medical Genetics, University Hospital Ostrava, Ostrava, CzechiaDepartment of Clinical and Molecular Pathology and Medical Genetics, University Hospital Ostrava, Ostrava, CzechiaDepartment of Clinical and Molecular Pathology and Medical Genetics, University Hospital Ostrava, Ostrava, CzechiaDepartment of Medical Genetics, Faculty of Medicine in Plzeň, Charles University and University Hospital Plzeň, Plzeň, CzechiaDepartment of Medical Genetics, Faculty of Medicine in Plzeň, Charles University and University Hospital Plzeň, Plzeň, CzechiaDepartment of Medical Genetics, Thomayer University Hospital, Prague, CzechiaDepartment of Pediatrics, Third Faculty of Medicine, Charles University and University Hospital Královské Vinohrady, Prague, CzechiaDepartment of Medical Genetics, Krajská zdravotní, a.s., Masaryk Hospital in Ústí nad Labem, Ústí nad Labem, CzechiaDepartment of Pediatrics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, CzechiaDepartment of Pediatrics, Hospital Česká Lípa, Česká Lípa, Czechia0Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia1Department of Medical Genetics, University Hospital Hradec Králové, Hradec Králové, Czechia2Department of Medical Genetics, Gennet, s.r.o., Liberec, Czechia3Department of Medical Genetics, Hospital České Budějovice a.s., České Budějovice, Czechia4Department of Medical Genetics and Genomics, University Hospital Brno, Brno, Czechia5Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia6Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia7Institute of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia0Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, CzechiaIntroductionRomani people have a high prevalence of kidney failure. This study examined a Romani cohort for pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes that are affected in Alport syndrome (AS), a common cause of genetic kidney disease, characterized by hematuria, proteinuria, end-stage kidney failure, hearing loss, and eye anomalies.Materials and methodsThe study included 57 Romani from different families with clinical features that suggested AS who underwent next-generation sequencing (NGS) of the COL4A3, COL4A4, and COL4A5 genes, and 83 family members.ResultsIn total, 27 Romani (19%) had autosomal recessive AS caused by a homozygous pathogenic c.1598G>A, p.Gly533Asp variant in COL4A4 (n = 20) or a homozygous c.415G>C, p.Gly139Arg variant in COL4A3 (n = 7). For p.Gly533Asp, 12 (80%) had macroscopic hematuria, 12 (63%) developed end-stage kidney failure at a median age of 22 years, and 13 (67%) had hearing loss. For p.Gly139Arg, none had macroscopic hematuria (p = 0.023), three (50%) had end-stage kidney failure by a median age of 42 years (p = 0.653), and five (83%) had hearing loss (p = 0.367). The p.Gly533Asp variant was associated with a more severe phenotype than p.Gly139Arg, with an earlier age at end-stage kidney failure and more macroscopic hematuria. Microscopic hematuria was very common in heterozygotes with both p.Gly533Asp (91%) and p.Gly139Arg (92%).ConclusionThese two founder variants contribute to the high prevalence of kidney failure in Czech Romani. The estimated population frequency of autosomal recessive AS from these variants and consanguinity by descent is at least 1:11,000 in Czech Romani. This corresponds to a population frequency of autosomal dominant AS from these two variants alone of 1%. Romani with persistent hematuria should be offered genetic testing.https://www.frontiersin.org/articles/10.3389/fmed.2023.1096869/fullAlport syndromeRomanihematuriaproteinuriaend-stage kidney failurehearing loss |
| spellingShingle | Pavlina Plevova Pavlina Plevova Jana Indrakova Judy Savige Petra Kuhnova Petra Tvrda Dita Cerna Sarka Hilscherova Monika Kudrejova Daniela Polendova Radka Jaklova Martina Langova Helena Jahnova Jana Lastuvkova Jiri Dusek Josef Gut Marketa Vlckova Pavla Solarova Gabriela Kreckova Eva Kantorova Jana Soukalova Rastislav Slavkovsky Jana Zapletalova Tomas Tichy Dana Thomasova A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people Frontiers in Medicine Alport syndrome Romani hematuria proteinuria end-stage kidney failure hearing loss |
| title | A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people |
| title_full | A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people |
| title_fullStr | A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people |
| title_full_unstemmed | A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people |
| title_short | A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people |
| title_sort | founder col4a4 pathogenic variant resulting in autosomal recessive alport syndrome accounts for most genetic kidney failure in romani people |
| topic | Alport syndrome Romani hematuria proteinuria end-stage kidney failure hearing loss |
| url | https://www.frontiersin.org/articles/10.3389/fmed.2023.1096869/full |
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