Early Clinical Manifestations and Long-term Renal Outcomes by Genotype in Children with X-Linked Alport Syndrome

Background X-linked Alport syndrome (XLAS) is the most common pediatric genetic kidney disease. The correlation between genotype, phenotype, and prognosis in children remains poorly defined. This study aims to elucidate these relationships. Methods We analyzed associations between genotype and clinical features at onset, including hematuria, proteinuria, and serum creatinine(Scr). Longitudinal data on creatinine and 24-hour urinary protein (24h UP) were assessed to evaluate genotype-prognosis correlations. Results All children presented with hematuria (33.8% microscopic, 13.2% gross, 52.9% with proteinuria). Extrarenal manifestations occurred in 5.9%. Genetic testing revealed missense (67.7%), splicing (13.2%), frameshift (14.7%), and deletion mutations (4.4%). At onset, males had significantly higher proteinuria than females. Among males, frameshift mutations and mutations beyond exon 40 (> EX40) were associated with more severe phenotypes. During follow-up (10.3% lost), gender and mutation type independently predicted proteinuria progression, with faster progression in males and patients with splicing or deletion mutations. Intronic mutations predicted better outcomes. For renal function decline, gender, mutation type, and site were independent risk factors, with faster decline in males, deletion mutations, and > EX40 mutations. Conclusions In XLAS, gender and genotype closely correlate with disease severity at onset and prognosis. Males, frameshift mutations, and > EX40 sites predict severe initial manifestations. Male gender, splicing/deletion mutations, and > EX40 sites are independent risk factors for faster progression, while intronic mutations predict favorable outcomes.