Clinical features of hearing loss and genotype-phenotype correlations in Alport syndrome caused by COL4A4 or COL4A5 variants.

Alport syndrome (AS) is a genetic disorder characterized by progressive nephritis, hearing loss, and visual impairment. Quantitative analyses of hearing in AS are rare. We conducted a retrospective chart review of clinical features and longitudinal follow-up of patients with AS, including multiple evaluations of pure-tone audiograms in each individual and examination of the relationships between hearing loss and genetic variants. Twelve AS cases from eight Japanese families were studied: one family had an autosomal dominant COL4A4 variant and seven carried X-linked variants in COL4A5; all cases presented with moderate hearing loss. Progression of hearing loss was 0.25, 0.29, 0.57, and 2.60 dB HL/year at 500, 1000, 4000, and 8000 Hz, respectively. During follow-up (1-10 years), all families exhibited mid-frequency hearing loss. Hearing loss onset occurred later than renal symptoms in all patients with COL4A5 variants, and the COL4A4 variant did not cause renal symptoms. Hearing loss severity and age of onset appeared to vary depending on the characteristics of the genetic variants, indicating genotype-phenotype correlations; however, hearing decline was predominantly at high frequencies, regardless of genetic variation. These findings provide valuable insights into genotype-phenotype correlations in AS, particularly regarding hearing loss progression and characteristics.