Sex-Based Disparities in Hematuria Recognition and Diagnosis in Alport Syndrome

Background: Early recognition of Alport syndrome can guide management and reduce risk of disease progression. Hematuria is often the first clinical clue, yet delayed recognition is common in females, in which it is often misattributed to urinary tract infections or menstrual cycles. Here we assessed sex-based differences in hematuria documentation and diagnosis in individuals with genetic findings in COL4A3, COL4A4, or COL4A5. Methods: A retrospective analysis of genetic test results from a broad renal gene panel (the Renasight™ test) was performed to identify individuals with (likely) pathogenic COL4A3, COL4A4, or COL4A5 variants (zygosity was not confirmed). Cases with variants of uncertain significance and COL4A5 hemizygous males were excluded. Clinical information including the presence of hematuria (ICD-10 R31) and age of diagnosis (age at time of testing) was obtained from test requisition forms. Chi-square tests compared hematuria prevalence; t-tests assessed diagnosis age. Results: Among 9238 individuals with COL4A3/4/5 variants, 2278 indicated the presence of hematuria. Hematuria prevalence ranged between 24-31% across all genotypes and was similar in male and female patients (p>0.05). Among those with hematuria, males had a significantly younger mean age at diagnosis compared to females for both COL4A3 (33.8 vs 38.7 years, p=0.002) and COL4A4 genotypes (34.6 vs. 39.7 years, p=0.00017). COL4A5 females had the youngest mean age of diagnosis (27.1 years) of all genotypes. Conclusion: Despite similar hematuria prevalences in male and female patients with Alport syndrome, males with COL4A3/4 variants were diagnosed 5–11 years earlier than females, suggesting sex-based disparities in clinical evaluation. These findings support that consideration of molecular testing for Alport syndrome is warranted in female patients with hematuria and could reduce diagnostic delays and improve outcomes, particularly when kidney function is normal and is detected on routine wellness exams or prenatal visits. Funding: Commercial Support - Natera, Inc. Table 1. Characteristics of Hematuria among Individuals with Alport Syndrome - Gene Sex Hematuria Prevalence Mean Age at Testing (with Hematuria, Years COL4A3 Female 25.4% (441/1,734) 38.7 Male 24.3% (335/1,379) 33.8 COL4A4 Female 29.8% (652/2,188) 39.7 Male 28.2% (447/1,584) 34.6 COL4A5 Female 31.0% (403/1,302) 27.1