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A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people
P. Plevova, J. Indrakova, J. Savige, P. Kuhnova, P. Tvrda, D. Cerna, S. Hilscherova, M. Kudrejova, D. Polendova, R. Jaklova, M. Langova, H. Jahnova, J. Lastuvkova, J. Dusek, J. Gut, M. Vlckova, P. Solarova, G. Kreckova, E. Kantorova, J....
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Document type Journal Article
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INTRODUCTION: Romani 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 METHODS: The 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. RESULTS: In 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%). CONCLUSION: These 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.
Department of Biomedical Sciences Faculty of Medicine University of Ostrava Ostrava Czechia
Department of Medical Genetics and Genomics University Hospital Brno Brno Czechia
Department of Medical Genetics Gennet s r o Liberec Czechia
Department of Medical Genetics Hospital České Budějovice a s České Budějovice Czechia
Department of Medical Genetics Thomayer University Hospital Prague Czechia
Department of Medical Genetics University Hospital Hradec Králové Hradec Králové Czechia
Department of Medicine The University of Melbourne Royal Melbourne Hospital Melbourne Australia
Department of Pediatrics Hospital Česká Lípa Česká Lípa Czechia
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- $a Plevova, Pavlina $u Department of Clinical and Molecular Pathology and Medical Genetics, University Hospital Ostrava, Ostrava, Czechia $u Department of Biomedical Sciences, Faculty of Medicine, University of Ostrava, Ostrava, Czechia
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- $a A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people / $c P. Plevova, J. Indrakova, J. Savige, P. Kuhnova, P. Tvrda, D. Cerna, S. Hilscherova, M. Kudrejova, D. Polendova, R. Jaklova, M. Langova, H. Jahnova, J. Lastuvkova, J. Dusek, J. Gut, M. Vlckova, P. Solarova, G. Kreckova, E. Kantorova, J. Soukalova, R. Slavkovsky, J. Zapletalova, T. Tichy, D. Thomasova
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- $a INTRODUCTION: Romani 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 METHODS: The 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. RESULTS: In 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%). CONCLUSION: These 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.
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