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 Biology and Medical Genetics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czechia

Department of Biomedical Sciences Faculty of Medicine University of Ostrava Ostrava Czechia

Department of Clinical and Molecular Pathology and Medical Genetics University Hospital Ostrava Ostrava Czechia

Department of Medical Biophysics Faculty of Medicine and Dentistry Palacký University Olomouc Olomouc Czechia

Department of Medical Genetics and Genomics University Hospital Brno Brno Czechia

Department of Medical Genetics Faculty of Medicine in Plzeň Charles University and University Hospital Plzeň Plzeň 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 Krajská zdravotní a s Masaryk Hospital in Ústí nad Labem Ústí nad Labem 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 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czechia

Department of Pediatrics 3rd Faculty of Medicine Charles University and University Hospital Královské Vinohrady Prague Czechia

Department of Pediatrics Hospital Česká Lípa Česká Lípa Czechia

Institute of Clinical and Molecular Pathology Faculty of Medicine and Dentistry Palacký University Olomouc Olomouc Czechia

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Olomouc Olomouc Czechia

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