Novel COL4A1 missense variant in a case of juvenile stroke

Kretz A, Arbeiter M, Strobel J, Blum K, Frischholz B, Rödiger A, Hackstein H, Maihöfner C, Reis A, Vasileiou G, Schwab M (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Journal of Stroke and Cerebrovascular Diseases Elsevier

Book Volume: 34

Article Number: 108463

Journal Issue: 12

DOI: 10.1016/j.jstrokecerebrovasdis.2025.108463

Abstract

Objective: Pathogenic variants in COL4A1 and COL4A2 genes encoding α-chains of type IV collagen in basement membranes of vessels and soft organs are associated with multi-system phenotypes affecting brain, eye, kidney and muscle. To date, several pathogenic germline variants, either de novo or inherited, have been reported, with phenotype descriptions covering a few hundred individuals. Characteristic brain manifestations include cerebral small vessel disease (cSVD), causing microangiopathy with leukoaraiosis, ischemic stroke events, and intracerebral hemorrhages in infancy to adulthood. Here, we report a case with a novel COL4A1 variant, presenting with cSVD at juvenile age. Materials and Methods: A 21-year-old female developed two stroke episodes involving hemiparesis and ocular palsy. Head imaging revealed recurrent supra- and infratentorial ischemic and hemorrhagic brain injuries, subcortical microbleeds and white matter lesions. Porencephalic ventricle dysmorphology was also obvious. Expanded stroke diagnostics included molecular trio-exome sequencing, analyses of mitochondrial DNA and of copy number variants. Results: Diagnostic measures for vascular, cardiac and coagulation disorders did not show pathologies. Genetic analyses revealed a novel, likely pathogenic missense variant in the triple-helical region of COL4A1 not detectable in the patient's parents. Conclusions: We inferred cSVD of monogenic origin, based on a so far undescribed COL4A1 de novo variant. Increased awareness and reporting of COL4A variants can elucidate cryptogenic juvenile stroke and improve patient management in the context of precision medicine.

Authors with CRIS profile

Julian Strobel Department of Transfusion Medicine and Haemostaseology Katalin Blum Institute of Human Genetics Birgit Frischholz Department of Transfusion Medicine and Haemostaseology Holger Hackstein Professur für Transfusionsmedizin und Cell-Engineering André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Georgia Vasileiou Institute of Human Genetics

Involved external institutions

Universitätsklinikum Jena DE Germany (DE) Klinikum Fürth DE Germany (DE)

How to cite

APA:

Kretz, A., Arbeiter, M., Strobel, J., Blum, K., Frischholz, B., Rödiger, A.,... Schwab, M. (2025). Novel COL4A1 missense variant in a case of juvenile stroke. Journal of Stroke and Cerebrovascular Diseases, 34(12). https://doi.org/10.1016/j.jstrokecerebrovasdis.2025.108463

MLA:

Kretz, Alexandra, et al. "Novel COL4A1 missense variant in a case of juvenile stroke." Journal of Stroke and Cerebrovascular Diseases 34.12 (2025).

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