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.

Improved genetic counseling in Alport syndrome by new variants of COL4A5 gene

“…Once a genetic diagnosis has been made, a screening of symptomatic or at risk‐family members can be performed, as well as offering clinical advantages to these patients (like avoiding unnecessary biopsies). Recent studies have reinforced the important role of genetic diagnosis in AS to have a correct and definitive diagnosis to be made in index patients and at‐risk family members …”

“…Although not 100% sensitive, genetic testing can provide a definitive means of making a diagnosis of AS, and is the most reliable way to distinguish females carriers from heterozygous ones. This event is especially important in women planning to start a family to have a correct genetic counseling for the risk to her offspring, and to have the decision to undergo prenatal testing . For these reasons it is imperative that all collagen IV gene mutations related to AS are reported to the appropriate databases.…”

The expanding phenotypic spectra of kidney diseases: insights from genetic studies

“…For example, patients with Alport syndrome have been misdiagnosed as having MPGN and patients with congenital chloride diarrhoea caused by SLC26A3 mutations have been misdiagnosed as having Bartter syndrome 75,76 . Clinical phenotyping can confirm a molecular diagnosis by revealing additional symptoms such as hearing loss and retinal anomalies in a patient with Alport syndrome, illustrating the importance of 'reverse phenotyping' (REF.…”

“…Clinical phenotyping can confirm a molecular diagnosis by revealing additional symptoms such as hearing loss and retinal anomalies in a patient with Alport syndrome, illustrating the importance of 'reverse phenotyping' (REF. 75). …”

“…In contrast to histopathology, molecular testing requires only venepuncture and has the potential to pinpoint the aetiology of a disease regardless of the disease stage. The advantages of molecular diagnostics are evident in female carriers of Alport syndrome, where the distinction between a heterozygous mutation in the X-linked COL4A5 gene and a heterozygous mutation in COL4A3/4 can have important implications for prenatal counselling 75 . In addition, the type of COL4A mutation can provide prognostic information regarding renal and extrarenal phenotypes and the risk of post-transplantation anti-GBM glomerulonephritis 75,103 , demonstrating that DNA testing can yield a diagnosis and guide prognostic and therapeutic decision-making in patients with nephrogenetic diseases.…”