Familial Variability of Disease Progression in Autosomal Dominant Alport Syndrome: Results from SHRAS

Background: Autosomal dominant Alport syndrome (ADAS), caused by heterozygous COL4A3 or COL4A4 pathogenic variants, is characterized by a large variability of disease progression. This study aims to evaluate the intrafamilial variability of disease progression and the relevant predictors in Chinese ADAS patients from the Shanghai Registry of Alport syndrome (SHRAS). Methods: SHRAS, part of the Shanghai Registry of Genetic Kidney Disease, performed collection of clinical, and genetic data of ADAS patients referred from 14 leading tertiary hospitals across China since 2006. In kindreds with ≥ 2 affected individuals, discordant disease progression were evaluated in 2 categories: age at onset of proteinuria and stage 3 chronic kidney disease (CKD). Marked intrafamilial variability was defined as the onset age across 2 categories differed ≥ 20 years in at least 2 patients in one kindred, or in kindred with both pediatric and adult patients, proteinuria or stage 3 CKD developed in at least 1 pediatric patient while the phenotype of adult patient was isolated hematuria. Results: Among 73 kindreds of 311 ADAS patients (118 pediatric and 193 adult patients), 31 kindreds (42.47%) of 72 patients (21 pediatric and 51 adult patients) were deemed as discordant disease progression. Intrafamilial variability was not associated with family size nor genotype (Table 1). Multivariate mixed-effects model revealed concomitant kidney disease and disease onset age as risk factors of variability (Figure 1). Conclusion: In ADAS cohort of SHRAS, marked intrafamilial variability of disease progression was observed. Our findings didn’t reveal a significant genotype influence on intrafamilial variability, which necessitates a more thorough identification of relevant clinical and genotypic factors.