Genetic mechanisms for stroke in young adults. A clinical perspective

Abstract: A range of cardiovascular risk factors associated with stroke are known, but they do not explain all cases of stroke. Genetic factors can be responsible for certain forms of stroke, and are further investigated in this thesis. The aims of this thesis were to study the occurrence of familial clustering of stroke, compile known stroke-associated genetic conditions for diagnostic and research genetic testing, and examine patients and families with apparently hereditary forms of stroke, focusing on patients who developed stroke at younger age.Based on data from Lund Stroke Register (LSR), patients with a first stroke episode before age 56 years were investigated regarding familial history for stroke and familial clustering of stroke compatible with possible monogenic disease (Paper I). The Online Mendelian Inheritance in Man (OMIM) database was used to systematically compile known stroke related genes, and for all these genes the clinical type of stroke was retrieved from original literature. Stroke gene panels for new generation sequencing were created (Paper II), and were applied to investigate 23 stroke families for known genetic causes of stroke (Papers III and IV). Detailed genetic investigations of larger families with seemingly hereditary stroke by whole exome sequencing (WES), whole genome sequencing (WGS) and conventional Sanger sequencing (Sg) were performed. Pathology of brain and skin vessels was analyzed.Paper I: Ten percent of 4,103 LSR patients were younger than 56 years. Of these, 47% (159 probands) reported a positive family history for stroke. Results revealed that 18% of the patients who were under 56 years at their first stroke episode, and with a positive familial history of stroke, did not have any of the usual vascular risk factors.Paper II: Stroke gene panels for use in clinical diagnostics and for research purposes were compiled. A total of 214 genes documented in OMIM were identified. One hundred-twenty genes were associated with clinically documented episodes of stroke (stroke gene panel 1). Sixty-two additional genes related to stroke, but without a reported case of a stroke episode in humans, were compiled for stroke gene panel 2. We included in stroke gene panel 3 stroke-related genes previously detected by genome-wide association studies. Clinical descriptions for the phenotypes associated with each gene were collected, to facilitate correct interpretation of the ample data generated by new generation sequencing analyses.Papers III and IV: WES of 23 probands and validation by Sg in affected and unaffected relatives identified pathogenic or possibly pathogenic genetic variants in 6 of the families, but the pathogenicity of only one was proven beyond doubt. For two larger families with embolic stroke of undetermined source at before 46 years of age and without any suspected variation in known stroke genes, we identified variants in genes not previously associated with stroke; GPR142 for one of the families and in PTPRN2, LRRC1, SLC7A10, IKBKB, and OXGR1 for the other family. In one large kindred with a novel entity with autosomal dominant small vessel disease, stroke, and tremor, a variant in the MAP3K6 gene was identified. Also this gene had not previously been associated with stroke. Pathology showed abnormalities in blood vessels of the brain and the skin and we suggest a pathomechanism involving vascular endothelial growth factor, based on what presently is known about the function of MAP3K6.WES of stroke patients 55 years or younger has presently a low diagnostic yield, but remains a practical method for clinical diagnostics of known stroke related disease. In research, whole exome or genome sequencing analyses of families may identify novel disease genes and new mechanisms for stroke.