An Elusive Diagnosis of Autosomal Dominant Alport Syndrome: Genomic Sequencing Is a Game Changer.

Abstract

We report the case of a 55-year-old woman with chronic asymptomatic hematuria and a longstanding diagnosis of thin basement membrane disease, presenting with worsening hypertension and a significant degree of proteinuria progressing to chronic kidney disease. Genetic sequencing identified a heterozygous pathogenic variant in the COL4A4 gene (c.1321_1369+3del), a 52-base pair deletion that disrupts normal ribonucleic acid (RNA) splicing in the exon 20/intron 20 junction. In silico analysis predicted the complete loss of the canonical splice site, leading to improper splicing and the dysfunction of the α4 chain of type-IV collagen. Genetic testing in the family confirmed the presence of the same variant in two additional generations. To our knowledge, this is the first reported family in which the c.1321_1369+3del mutation is the sole cause of autosomal dominant Alport syndrome.