engleski

Clinical and histopathological characteristics of COL4A3 c.2881+1G>A variant causing Alport spectrum disorders in Croatian population

Background & objectives: Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are kidney disorders caused by mutations in COL4A3, COL4A4, or COL4A5 genes that encode polypeptide chains of collagen IV, the major structural component of basement membranes. Methods: We identified 13 patients from 12 unrelated families with a pathohistological diagnosis of AS or TBMN who tested positive for a heterozygous variant COL4A3 c.2881+1G>A on conducted next-generation sequencing (NGS). Subsequently, their family members were recruited for genetic counselling, urinalysis, and blood sampling for targeted NGS. A correlation of clinical and pathohistological data and genealogy study was also performed. Results: Overall, 34 patients (58.8% male) were found positive for heterozygous, disease-causing variant COL4A3 c.2881+1G>A. Haematuria was present in 33 patients (97.1%), while 19 (55.9%) had proteinuria. Follow-up data showed that four more patients developed proteinuria (23 total ; 67.6%) and 6 (17.6%) developed chronic kidney disease, started dialysis or underwent kidney transplantation by the median age of 51 years. There were 6 (17.6%) patients with hearing loss (3 confirmed with audiogram) and 4 (11.8%) with ocular lesions. Among 13 patients who underwent kidney biopsy, 12 had glomeruli available for electron microscopy. Five patients had classic AS morphology and 7 had TBMN (3 of them with focal lamellation). Conclusion: The suspected founder variant COL4A3 c.2881+1G>A is disease-causing. There is variability among these patients not only in clinical presentation but also in pathohistological findings. Interestingly five out 12 heterozygous patients had classic AS morphology on kidney biopsy. It is essential to conduct a detailed analysis of each collagen IV variant to optimize the affected patients’ prognostic and therapeutic approach.

COL4A3 c.2881+1G>A variant ; Alport spectrum disorder

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