Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene

Kidney Int. 2004 May;65(5):1598-603. doi: 10.1111/j.1523-1755.2004.00560.x.


Background: Alport syndrome is a clinically and genetically heterogeneous nephropathy. The majority of cases are transmitted as an X-linked semidominant condition due to COL4A5 mutations. In this form males are more severely affected than females. Less than 10% of cases are autosomal recessive due to mutation in either COL4A3 or COL4A4. In this rarer form, both males and females are severely affected. Only two cases of autosomal-dominant Alport syndrome have been reported, one due to a COL4A3 mutation and the other due to a COL4A4 mutation. Because of the paucity of the reported families, the natural history of autosomal-dominant Alport syndrome is mostly unknown.

Methods: Four families with likely autosomal-dominant Alport syndrome were investigated. COL4A3 and COL4A4 genes were analyzed by denaturing high-performance liquid chromatography (HPLC). Automated sequencing was performed to identify the underlying mutation.

Results: Two families had a mutation in the COL4A4 gene and two in the COL4A3. Accurate clinical evaluation of family members showed interesting results. Affected individuals (22 persons) had a wide range of phenotypes from end-stage renal disease (ESRD) in the fifth decade to a nonprogressive isolated microhematuria. Finally, three heterozygous individuals (90, 22 and 11 years old, respectively) were completely asymptomatic.

Conclusion: This paper demonstrated that patients affected by autosomal-dominant Alport syndrome have a high clinical variability. Moreover, a reduced penetrance of about 90% (3 of 25) may be considered for the assessment of recurrence risk during genetic counseling of these families.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Autoantigens / genetics*
  • Child
  • Collagen Type IV / genetics*
  • Female
  • Genes, Dominant
  • Humans
  • Kidney / pathology
  • Male
  • Middle Aged
  • Mutation
  • Nephritis, Hereditary / etiology
  • Nephritis, Hereditary / genetics*
  • Nephritis, Hereditary / pathology
  • Pedigree
  • Phenotype


  • Autoantigens
  • COL4A4 protein, human
  • Collagen Type IV
  • type IV collagen alpha3 chain