Clinical kidney journal · 2026
Heterozygous COL4A3/COL4A4 variants: diagnostic trends and clinical kidney outcomes.
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Tanaka Yu, Horinouchi Tomoko, Aoyama Shuhei, Kimura Yuka, Inoki Yuta, Ichikawa Yuta, Ueda Chika, Kitakado Hideaki, Kondo Atsushi, Sakakibara Nana, Nagano China, Yamamura Tomohiko, Ishimori Shingo, Nozu Kandai
Аннотация
BACKGROUND: Heterozygous pathogenic variants in COL4A3 or COL4A4 are relatively common and associated with a broad clinical spectrum. However, nomenclature and risk stratification remain unsettled. We aimed to investigate temporal diagnostic trends and clinical features of haematuria-positive individuals with heterozygous COL4A3/COL4A4 variants in a genetic testing cohort.
METHODS: This retrospective cohort study involved 992 families genetically diagnosed with Alport syndrome at a single centre in Japan between 2006 and 2023. We identified 265 families comprising 299 haematuria-positive individuals with heterozygous pathogenic or likely pathogenic COL4A3/COL4A4 variants. For kidney failure (KF) analysis, 627 individuals, including affected relatives, were evaluated.
RESULTS: At the family level, the proportion of the study group increased from 8.4% of genetically diagnosed Alport syndrome cases during the Sanger sequencing era (2006-2015) to 26.6% during early next-generation sequencing implementation (2015-2019), and 39.1% in the recent period (2020-2023). At genetic diagnosis, 75.3% of individuals had proteinuria and 4.7% had KF. Kaplan-Meier analysis showed that the median ages at first detection of haematuria and proteinuria, and at onset of KF, were 10, 26, and 72 years, respectively.
CONCLUSIONS: Individuals with haematuria and heterozygous COL4A3/COL4A4 variants accounted for an increasing proportion of genetically diagnosed cases of Alport syndrome. Although this referred cohort does not represent all individuals with heterozygous COL4A3/COL4A4 variants, our findings delineate the natural history of haematuria-positive individuals with these variants and may support early diagnosis and risk stratification aimed at preventing progression to KF.
METHODS: This retrospective cohort study involved 992 families genetically diagnosed with Alport syndrome at a single centre in Japan between 2006 and 2023. We identified 265 families comprising 299 haematuria-positive individuals with heterozygous pathogenic or likely pathogenic COL4A3/COL4A4 variants. For kidney failure (KF) analysis, 627 individuals, including affected relatives, were evaluated.
RESULTS: At the family level, the proportion of the study group increased from 8.4% of genetically diagnosed Alport syndrome cases during the Sanger sequencing era (2006-2015) to 26.6% during early next-generation sequencing implementation (2015-2019), and 39.1% in the recent period (2020-2023). At genetic diagnosis, 75.3% of individuals had proteinuria and 4.7% had KF. Kaplan-Meier analysis showed that the median ages at first detection of haematuria and proteinuria, and at onset of KF, were 10, 26, and 72 years, respectively.
CONCLUSIONS: Individuals with haematuria and heterozygous COL4A3/COL4A4 variants accounted for an increasing proportion of genetically diagnosed cases of Alport syndrome. Although this referred cohort does not represent all individuals with heterozygous COL4A3/COL4A4 variants, our findings delineate the natural history of haematuria-positive individuals with these variants and may support early diagnosis and risk stratification aimed at preventing progression to KF.