Genetic testing can resolve diagnostic confusion in Alport syndrome

Abstract

Alport syndrome (AS) is a familial glomerular disorder resulting from mutations in the genes encoding several members of the type IV collagen protein family. Despite advances in molecular genetics, renal biopsy remains an important initial diagnostic tool. Histological diagnosis is challenging as features may be non-specific, particularly early in the disease course and in females with X-linked disease. We present three families for whom there was difficulty in correctly diagnosing AS or thin basement membrane nephropathy as a result of misinterpretation of non-specific and incomplete histology. We highlight the importance of electron microscopy and immunofluorescence in improving diagnostic yield and also the hazard of interpreting a descriptive histological term as a diagnostic label. Molecular genetic testing allows a definitive diagnosis to be made in index patients and at-risk family members.

Keywords: Alport syndrome; COL4A3; COL4A5; haematuria; molecular genetics.

Fig. 1.

Family structure, genetic analysis and histological features. (A) Pedigree structure of Family 1, 2 and 3. Probands are arrowed. Squares represent males, circles represent females. Affected individuals are shaded. CKD, chronic kidney disease; ESRD, end-stage renal disease. (B) Left, renal biopsy EM image from proband of Family 1 showing thinning of the glomerular basement membrane. Right, renal biopsy under light microscopy (silver stain) of proband from Family 3 revealed only very mild mesangial proliferative changes. (C) Sequence chromatograms of COL4A5 (Family 1 and 2) and COL4A3 (Family 3) in affected patients with wild-type control. Nucleotides are shown and corresponding amino acids are numbered. Sequence variants are arrowed.