Clinical and Genetic Features of Autosomal Dominant Alport Syndrome: A Cohort Study

Am J Kidney Dis. 2021 Oct;78(4):560-570.e1. doi: 10.1053/j.ajkd.2021.02.326. Epub 2021 Apr 7.


Rationale & objective: Alport syndrome is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic variants in the gene COL4A3, COL4A4, or COL4A5. The aim of this study was to evaluate the clinical and genetic spectrum of patients with autosomal dominant Alport syndrome (ADAS).

Study design: Retrospective cohort study.

Setting & participants: 82 families (252 patients) with ADAS were studied. Clinical, genetic, laboratory, and pathology data were collected.

Observations: A pathogenic DNA variant in COL4A3 was identified in 107 patients (35 families), whereas 133 harbored a pathogenic variant in COL4A4 (43 families). Digenic/complex inheritance was observed in 12 patients. Overall, the median kidney survival was 67 (95% CI, 58-73) years, without significant differences across sex (P=0.8), causative genes (P=0.6), or type of variant (P=0.9). Microhematuria was the most common kidney manifestation (92.1%), and extrarenal features were rare. Findings on kidney biopsies ranged from normal to focal segmental glomerulosclerosis. The slope of estimated glomerular filtration rate change was-1.46 (-1.66 to-1.26) mL/min/1.73m2 per year for the overall group, with no significant differences between ADAS genes (P=0.2).

Limitations: The relatively small size of this series from a single country, potentially limiting generalizability.

Conclusions: Patients with ADAS have a wide spectrum of clinical presentations, ranging from asymptomatic to kidney failure, a pattern not clearly related to the causative gene or type of variant. The diversity of ADAS phenotypes contributes to its underdiagnosis in clinical practice.

Keywords: Alport syndrome; COL4A3; COL4A4; autosomal-dominant Alport syndrome; familial benign hematuria; familial hematuria; genetic; genotype–phenotype correlation; hearing loss; hereditary kidney disease; inherited kidney disease; thin basement membrane disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Autoantigens / genetics*
  • Cohort Studies
  • Collagen Type IV / genetics*
  • Female
  • Genetic Testing / methods*
  • Genetic Variation / genetics*
  • Humans
  • Male
  • Middle Aged
  • Nephritis, Hereditary / diagnosis*
  • Nephritis, Hereditary / epidemiology
  • Nephritis, Hereditary / genetics*
  • Renal Insufficiency / diagnosis
  • Renal Insufficiency / epidemiology
  • Renal Insufficiency / genetics
  • Retrospective Studies
  • Young Adult


  • Autoantigens
  • Collagen Type IV
  • type IV collagen alpha3 chain