Cerebrovascular Manifestations in a Family with a Pathogenic COL4A5 Variant

Abstract

Background/Objectives: Pathogenic variants in collagen type 4 α5 chain (COL4A5), responsible for X-linked Alport syndrome, are classically associated with progressive kidney disease, sensorineural hearing impairment, and ocular abnormalities. Cerebrovascular involvement is not considered part of the COL4A5-related phenotype, although rare recent reports suggest it may occur. We describe a family with cerebrovascular events across three generations, segregating in a clear X-linked pattern, and evaluate whether these events could be linked to a pathogenic COL4A5 variant identified in the proband. Methods: We report the clinical, radiological, and genetic findings in a 16-year-old heterozygous female proband, interpreted in the context of her family’s cerebrovascular history. Exome sequencing, chromosomal microarray, and familial segregation analysis were performed. Results: The proband presented with severe migraine, cerebellar microhemorrhage, and poor visualization of the left distal posterior cerebral artery (PCA) branches. Exome sequencing detected the heterozygous COL4A5 pathogenic variant c.1871G>A; p.(Gly624Asp), inherited from her hemizygous father, who has Alport syndrome. The proband’s sister, an obligate carrier of the same variant with a history of migraine, was found to have a small brain aneurysm. In the paternal line, the great-grandmother died of a cerebrovascular event in her early 40 s, the great-aunt had a stroke at around 40, and her son died of a cerebrovascular event at 35; the obligate-carrier grandmother had chronic kidney disease and migraine. Conclusions: This COL4A5 variant is usually associated with late-onset Alport syndrome and variable renal involvement, even in obligate carriers, and has not previously been linked to cerebrovascular disease. In the present family, the X-linked clustering of cerebrovascular events raises the possibility that COL4A5 may contribute to cerebrovascular fragility, with an effect that may extend beyond the kidney. These findings suggest that COL4A5 may be relevant in selected families with unexplained cerebrovascular disease, even when renal manifestations are mild or absent.

The authors' abstract, as published at the source. Journal of Clinical Medicine, 2026 · DOI ↗