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

Matija Horaček; Tamara Nikuševa Martić; Petar Šenjug; Marija Šenjug Perica; Maja Oroz; Sania Kuzmac; Dragan Klarić; Merica Glavina Durdov; Marijan Saraga; Danko Milošević; Danica Batinić; Marijana Ćorić; Frane Paić; Danica Galešić Ljubanović

doi:10.17305/bjbms.2022.7567

Authors

Matija Horaček Institute of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia https://orcid.org/0000-0001-7491-3791
Tamara Nikuševa Martić Department of Medical Biology and Genetics, School of Medicine, University of Zagreb, Zagreb, Croatia
Petar Šenjug Department of Nephropatology and Electron Microscopy, Dubrava University Hospital, Zagreb, Croatia
Marija Šenjug Perica Division of Rheumatology, Srebrnjak Children’s Hospital, Zagreb, Croatia
Maja Oroz Department of Gynecology and Obstetrics, Clinical Hospital “Sveti Duh”, Zagreb, Croatia https://orcid.org/0000-0003-0639-7320
Sania Kuzmac Clinical Department of Pathology and Cytology, University Hospital Centre Zagreb, Zagreb, Croatia
Dragan Klarić Department of Nephrology, General Hospital Zadar, Zadar, Croatia https://orcid.org/0000-0002-1484-877X
Merica Glavina Durdov Department of Pathology, University Hospital Split, Split, Croatia
Marijan Saraga Department of Pediatrics, University Hospital Split, Split, Croatia https://orcid.org/0000-0002-6855-163X
Danko Milošević Department of Pediatrics, University Hospital Centre Zagreb, Zagreb, Croatia https://orcid.org/0000-0003-3877-5824
Danica Batinić Pediatric ordination dr. Danica Batinić, Zagreb, Croatia
Marijana Ćorić Institute of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia; Clinical Department of Pathology and Cytology, University Hospital Centre Zagreb, Zagreb, Croatia https://orcid.org/0000-0001-7887-4101
Frane Paić Department of Medical Biology and Genetics, School of Medicine, University of Zagreb, Zagreb, Croatia; Laboratory for Epigenetics and Molecular medicine, School of Medicine Zagreb, Croatia https://orcid.org/0000-0001-9688-8582
Danica Galešić Ljubanović Institute of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia; Department of Nephropatology and Electron Microscopy, Dubrava University Hospital, Zagreb, Croatia https://orcid.org/0000-0002-2850-6316

DOI:

https://doi.org/10.17305/bjbms.2022.7567

Keywords:

Alport syndrome, thin basement membrane nephropathy, proteinuria, collagen type IV, α3 chain of collagen IV, COL4A3 c.2881 1G>A variant, targeted next-generation sequencing

Abstract

Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are part of the spectrum of kidney disorders caused by pathogenic variants in α3, α4, or α5 chains of the collagen type IV, the major structural component of the glomerular basement membrane (GBM). Using targeted next-generation sequencing (NGS), 34 AS/TBMN patients (58.8% male) from 12 unrelated families were found positive for heterozygous c.2881+1G>A variant of the COL4A3gene, that is considered disease-causing. All patients were from the continental or island part of Croatia. Clinical, laboratory, and histopathological data collected from the medical records were analyzed and compared to understand the clinical course and prognosis of the affected patients. At the time of biopsy or first clinical evaluation, the mean age was 31 years (median: 35 years; range: 1 – 72 years). Hematuria was present in 33 patients (97.1%) and 19 (55.9%) patients had proteinuria. There were 6 (17.6%) patients with hearing loss, 4 (11.8%) with ocular lesions, and 11 (32.4%) with hypertension. Twenty-three (67.6%) patients had proteinuria at follow-up, and 5 (14.7%) patients with the median age of 48 years (range: 27-55) progressed to kidney failure, started dialysis, or underwent kidney transplantation. Of the 13 patients who underwent kidney biopsy, 4 (30.8%) developed focal segmental glomerulosclerosis (FSGS), and 8 (66.7%) showed lamellation of the GBM, including all patients with FSGS. It is essential to conduct a detailed analysis of each collagen type IV genetic variant to optimize the prognosis and therapeutic approach for affected patients.