Pathology vs. molecular genetics: (re)defining the spectrum of Alport syndrome

Abstract

Malone et al. performed next-generation sequencing on 70 families with focal segmental glomerulosclerosis (FSGS) and discovered that 10% had variants in surprising 'old' genes, COL4A3 and COL4A4, which are involved in Alport syndrome and thin basement membrane nephropathy. These data show that a subset of renal manifestations associated with COL4A3 or COL4A4 variants cannot be distinguished from FSGS by clinical data or histopathology. Thus, a diagnosis of FSGS may sometimes fall within the spectrum of Alport syndrome.

Figure 1

The spectrum of Alport syndrome, from benign familial hematuria at one extreme and early onset ESRD with hearing and eye defects at the other extreme. Other manifestations of COL4A3, COL4A4, and COL4A5 mutations, which can vary even within a family, fall between the extremes in what are likely overlapping positions.