Novel COL4A1 missense variant in a case of juvenile stroke

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.

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.

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.

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.