Neglected Mendelian causes of stroke in adult Chinese patients who had an ischaemic stroke or transient ischaemic attack.

Background and purpose: Multiple factors play important roles in the occurrence and prognosis of stroke. However, the roles of monogenic variants in all-cause ischaemic stroke have not been systematically investigated. We aim to identify underdiagnosed monogenic stroke in an adult ischaemic stroke/transient ischaemic attack (TIA) cohort (the Third China National Stroke Registry, CNSR-III).

Methods: Targeted next-generation sequencing for 181 genes associated with stroke was conducted on DNA samples from 10 428 patients recruited through CNSR-III. The genetic and clinical data from electronic health records (EHRs) were reviewed for completion of the diagnostic process. We assessed the percentages of individuals with pathogenic or likely pathogenic (P/LP) variants, and the diagnostic yield of pathogenic variants in known monogenic disease genes with associated phenotypes.

Results: In total, 1953 individuals harboured at least one P/LP variant out of 10 428 patients. Then, 792 (7.6%) individuals (comprising 759 individuals harbouring one P/LP variant in one gene, 29 individuals harbouring two or more P/LP variants in different genes and 4 individuals with two P/LP variants in ABCC6) were predicted to be at risk for one or more monogenic diseases based on the inheritance pattern. Finally, 230 of 792 individuals manifested a clinical phenotype in the EHR data to support the diagnosis of stroke with a monogenic cause. The most diagnosed Mendelian cause of stroke in the cohort was cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. There were no relationships between age or family history and the incidence of first symptomatic monogenic stroke in patients.

Conclusion: The rate of monogenic cause of stroke was 2.2% after reviewing the clinical phenotype. Possible reasons that Mendelian causes of stroke may be missed in adult patients who had an ischaemic stroke/TIA include a late onset of stroke symptoms, combination with common vascular risks and the absence of a prominent family history.