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Objectives Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by pathogenic variants in the NOTCH3 gene. In Finland, the majority of CADASIL patients carry the pathogenic founder variant c.397C>T, (p.Arg133Cys), but the spectrum of other NOTCH3 variants has not been investigated previously. The aim of the study was to investigate the spectrum and prevalence of NOTCH3 variants Finnish CADASIL patients and to examine the clinical features associated with them. Materials and Methods The spectrum of NOTCH3 variants and the clinical features associated with them were retrospectively examined in 294 Finnish CADASIL patients tested during January 1996 to October 2021 in the Medical Genetics laboratory of Department of Genomics of Turku University Hospital, where practically all samples of patients with suspected CADASIL in Finland are investigated. Results The most common NOTCH3 variants in the study cohort were c.397C>T, (p.Arg133Cys) (68%) and c.3206A>G p.(Tyr1069Cys) (18%), but other less common NOTCH3 variants were detected in as many as 14% of the patients. Eight of the detected NOTCH3 variants were novel: c.520T>A,p.(Cys174Ser), c.836A>G,p.(Gln279Arg), c.1369T>G,p.(Cys457Gly), c.1338C>G,p.(Cys446Trp), c.1564T>G,p.(Cys522Gly), c.2848T>G,p.(Cys950Gly), c.6102dup,p.(Gly2035Argfs*60), and c.2410+6C>G. Other NOTCH3 variants than p.Arg133Cys and p.Tyr1069Cys were more often associated with more severe clinical features. Conclusion This study revealed the genetic and clinical spectrum of CADASIL in the Finnish population. Sequencing of the whole NOTCH3 gene performing a gene-panel or exome sequencing is recommended when suspecting CADASIL.

Objectives The genetic background of vascular cognitive impairment (VCI) is poorly understood compared to other dementia disorders. The aim of the study was to investigate the genetic background of VCI in a well-characterized Finnish cohort. Materials & Methods Whole-exome sequencing (WES) was applied in 45 Finnish VCI patients. Copy-number variant (CNV) analysis using a SNP array was performed in 80 VCI patients. This study also examined the prevalence of variants at the miR-29 binding site of COL4A1 in 73 Finnish VCI patients. Results In 40% (18/45) of the cases, WES detected possibly causative variants in genes associated with cerebral small vessel disease (CSVD) or other neurological or stroke-related disorders. These variants included HTRA1:c.847G>A p.(Gly283Arg), TREX1:c.1079A>G, p.(Tyr360Cys), COLGALT1:c.1411C>T, p.(Arg471Trp), PRNP: c.713C>T, p.(Pro238Leu), and MTHFR:c.1061G>C, p.(Gly354Ala). Additionally, screening of variants in the 3 ' UTR of COL4A1 gene in a sub-cohort of 73 VCI patients identified a novel variant c.*36T>A. CNV analysis showed that pathogenic CNVs are uncommon in VCI. Conclusions These data support pathogenic roles of variants in HTRA1, TREX1 and in the 3 ' UTR of COL4A1 in CSVD and VCI, and suggest that vascular pathogenic mechanisms are linked to neurodegeneration, expanding the understanding of the genetic background of VCI.