Systematic Genetic Assessment in Young Patients With Cryptogenic Stroke: The ES-EASY project.

Background: Up to 15% of strokes occur in young adults, with more cryptogenic cases, raising the possibility of rare causes, such as genetic diseases. Although available in everyday practice, genetic analyses are usually reserved for patients with evocative personal or family history. We aimed to assess the interest of systematic genetic analyses in young adults with cryptogenic stroke and estimate the true frequency of genetic disorders in such patients.

Methods: We conducted a retrospective observational cohort study with additional prospective genetic testing. We screened all patients under 50 admitted to Dijon University Hospital stroke unit between 2018 and 2021. Those already genetically tested during etiological work-up were included in a first cohort (cohort 1). Among the remaining patients, those with unexplained intracerebral hemorrhage or stroke (ie, cryptogenic stroke), or a stroke subtype known to have monogenic forms, were offered exome sequencing to form cohort 2. Monogenic diagnoses were defined by likely pathogenic/pathogenic variants according to American College of Medical Genetics and Genomics criteria.

Results: Among 305 patients with stroke screened, 24 had prior genetic testing (cohort 1) with exome sequencing, genome sequencing, gene panels or targeted gene analyses, leading to a molecular diagnosis in 8 (33%). Of the remaining 281 patients, 71 met eligibility criteria and 35 consented to the study (cohort 2). Exome sequencing identified pathogenic variants in 4 of them (11%). The overall diagnostic yield of genetic tests was 20.3% (12/59 patients tested across both cohorts). In total, monogenic causes explained 3.9% (12/305) of all young stroke cases. Notably, most diagnosed patients (66%) had no family history of stroke. Genetic cardiopathies and conditions conferring increased cardiovascular risk factors accounted for 50% of diagnoses.

Conclusions: Genetic analyses should be considered in all unexplained strokes or in stroke subtypes with known genetic forms (eg, Moya Moya syndrome, cardiopathy, small vessel disease), even without an evocative family history.