A Systematic Review of Pathogenic COL4A5 Variants and Proteinuria in Women and Girls With X-linked Alport Syndrome

INTRODUCTION: Women and girls with X-linked Alport syndrome have a risk of disease progression that is difficult to predict. This systematic review examined whether proteinuria correlated with genotype and disease severity in this population. METHODS: PubMed and Scopus were searched for manuscripts from the past 20 years with “COL4A5,” “female,” “proteinuria” and related terms. Genotypes and clinical data for women and girls with pathogenic heterozygous COL4A5 variants were extracted. Features were then compared between females with proteinuria or without proteinuria; and genotype-phenotype correlations for age at proteinuria and kidney failure determined. RESULTS: Three-hundred sixty-six women and girls with COL4A5 variants and a median age of 29 years (interquartile range 15–46) were identified. Eighty-eight (24%) had large rearrangements or truncating variants, 63 (17%) had splicing variants, and 215 (59%) had missense changes. In all, 236 (64%) had proteinuria, 56 (16%) had kidney failure, 40 (16%) had a hearing loss, and 15 (7%) had ocular abnormalities. Women and girls with proteinuria were more likely to have large rearrangements or truncating variants (P = 0.005), and less likely to have missense changes (P = 0.0002). Those with proteinuria were also more likely to develop kidney failure (P < 0.0001). Women and girls with truncating, large or splicing variants developed proteinuria earlier than those with missense changes (P = 0.001, P < 0.0001 respectively). Those whose proteinuria was detected before the age of 15 progressed to kidney failure sooner (P < 0.0001). CONCLUSION: Proteinuria correlates with a more severe genotype in women and girls with X-linked Alport syndrome and is an indicator of disease severity and likely progression.