Exon location of glycine substitutions impacts kidney survival in autosomal dominant Alport Syndrome

ABSTRACT Background Unlike X-linked or autosomal recessive Alport syndrome, no clear genotype/phenotype correlation has yet been demonstrated in patients carrying a single variant of COL4A3 or COL4A4. Methods We carried out a multicentre retrospective study to assess the risk factors involved in renal survival in patients presenting a single pathogenic variant on COL4A3 or COL4A4. Results A total of 97 patients presenting a single pathogenic variant of COL4A3 or COL4A4 were included. The prevalence of end-stage kidney disease (ESKD) during follow-up was 28.7% [median age 47.5 years (interquartile range 39.1–55.8). A total of 23 patients carried a ‘severe’ mutation (frameshift, stop gain, extensive deletion, impacting splicing) and 60 patients presented a glycine substitution in a collagenous domain. In patients with glycine missense variants, the location of the mutation in the distal exons was associated with worse renal survival with a more pronounced decline in the estimated glomerular filtration rate compared with variants in proximal exons. Conversely, the presence of a severe mutation did not impact renal survival. Conclusion Our results confirm that autosomal dominant Alport syndrome (ADAS) can lead to ESKD. We demonstrated that a glycine substitution involving the distal exons had a negative impact on renal survival in ADAS patients, probably due to a trimerization defect. This could help improve personalized follow-up in ADAS patients with glycine substitution and could be integrated into a future prognostic score to accurately predict renal outcomes.