Heterozygous Pathogenic COL4A3 and COL4A4 Variants (Autosomal Dominant Alport Syndrome) Are Common, and Not Typically Associated With End-Stage Kidney Failure, Hearing Loss, or Ocular Abnormalities

The term “autosomal dominant (AD) Alport syndrome” is often used to describe the condition associated with heterozygous pathogenic COL4A3 or COL4A4 variants and has largely replaced “thin basement membrane nephropathy (TBMN).” AD Alport syndrome implies that affected individuals develop end-stage kidney failure (ESKF) as well as the typical Alport hearing loss and ocular abnormalities, but these features have been considered rare with TBMN. Recent studies suggest that ESKF occurs in 14% to 30% of those with heterozygous pathogenic COL4A3 or COL4A4 variants but confirm that the hearing loss and ocular defects occur uncommonly if at all. Uncertainty over the risk of ESKF has persisted. However all the cited studies of heterozygous pathogenic COL4A3 or COL4A4 variants and kidney failure are from hospital-based patients and thus biased toward more severe disease. Multiple unselected cohorts with ESKF have found heterozygous pathogenic variants in COL4A3 and COL4A4 occur about as often as COL4A5 variants, which suggests that AD Alport syndrome causes ESKF as often as X-linked (XL) disease. In the normal population, heterozygous pathogenic COL4A3 and COL4A4 variants are present 20 times more often than COL4A5 variants. Therefore, AD Alport syndrome is complicated by ESKF 20 times less often than XL disease and occurs in fewer than 3% of those with pathogenic COL4A3 or COL4A4 variants by the age of 60. Nevertheless, individuals with heterozygous pathogenic COL4A3 or COL4A4 variants referred to a hospital are still more likely to develop impaired kidney function than those who remain at home undiagnosed.