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397. Severe clinical phenotype in Alport syndrome due to two COL4A4 exon skipping eventsJerica Pleško, Nika Kojc, Špela Kert, Sara Petrin, Alenka Matjašič, Anamarija Meglič, Andrej Zupan, 2025, other scientific articles Abstract: Alport syndrome (AS) is a genetically heterogeneous disorder caused by mutations in COL4A3, COL4A4, or COL4A5, leading to progressive renal dysfunction. While genetic screening has advanced, many cases remain undiagnosed due to deep intronic splice site variants. We report a male patient diagnosed with autosomal recessive AS, characterized by hematuria, proteinuria, and chronic kidney disease progression. Initial kidney biopsy at age 10 revealed glomerular basement membrane thinning and focal sclerosis, while targeted DNA sequencing failed to detect pathogenic variants. Over 15 years, renal function declined, and a second biopsy showed severe GBM abnormalities with multilamellated structures. Whole-transcriptome sequencing revealed two events of exon skipping, specifically at exons 27 and 38 of the COL4A4 gene, which were verified by exon-specific PCR and Sanger sequencing. Intronic regions analysis revealed two heterozygous variants positioned 78 bp downstream of exon 27 and 8 bp upstream of exon 38, though their role in aberrant splicing remains uncertain. Immunofluorescence analysis confirmed disrupted α3α4α5(IV) heterotrimer assembly. This is the first documented case of dual exon-skipping events in COL4A4, highlighting their contribution to disease severity. Our findings emphasize the need for RNA-based diagnostics and raise questions about potential benefit of exon-skipping therapy in autosomal recessive AS.
Keywords: Alport syndrome, exon skipping, whole transcriptome sequencing, kidney, COL4A4
Published in DiRROS: 24.11.2025; Views: 105; Downloads: 47
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