Genetic analysis reveals novel variants for vascular cognitive impairment

Abstract

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.

TREX1 p.A129fs and p.Y305C variants in a large multi-ethnic cohort of CADASIL-like unrelated patients

“…p.Ala129fs locates in the conserved catalytic domain, harbouring different loss of function (LoF) mutations leading to Aicardi-Goutières-Syndrome (AGS) or systemic lupus erythematosus (SLE). p.Tyr305Cys maps to the C-Terminal domain of the protein, where frameshift mutations are causative for RVCL and has been already reported in a 2 early-onset CADASILlike patients from Nederland and Finland displaying overlapping features like progressive cognitive impairment to dementia, lacunar infarcts con uent and mild to severe retinopathy 15,19 as well as distinctive signs such as migraine without aura, cerebral amyloid angiopathy and microhemorrhages 19 .…”

“…This domain of the protein is known to harbour loss of function mutations causative for RVCL 2 . This variant is very rare (MAF 1.4e-04) and clusters in a very well conserved domain among different species (Fig2C, Table p.Tyr305Cys has already been described as causative for CADASIL-like disease in 2 patients: a 53-year old Dutch patient who displayed presenile dementia, basal ganglia and pontine lacunar infarcts and bilateral con uent white matter lesions 15 and a 39-year old Finnish patient presenting migrane without aura, severe and pervasive cognitive impairment, hypertensive retinopathy and severe amyloid angiopathy and whose MRI scans displayed lacunar infarcts and several microhaemorrhages 19 .…”

“…Ninety-six patients (53.3%) were from the USA (NINDS Repository), 34 (18.9%) from Portugal, 33 (18.3%) from Finland, 15 (8.3%) from Serbia and 2 (1.1%) from Turkey. Part of the Finnish cohort has been already described in a previous genetic screening focused on Mendelian genes causative for vascular dementia 19 . The mean age at disease onset was 52 years (SD=10.9) and 76 cases (42.2%) had a positive family history.…”

TREX1 p.A129fs and p.Y305C variants in a large multi-ethnic cohort of CADASIL-like unrelated patients

“…1 C, Table 3 ). Importantly, p.Tyr305Cys has already been described as causative for CADASIL-like disease in 2 patients: a 53-year old Dutch patient who displayed presenile dementia, basal ganglia and pontine lacunar infarcts and bilateral confluent white matter lesions ( Pelzer et al, 2013 ) and a 39-year old Finnish patient presenting migrane without aura, severe and pervasive cognitive impairment, hypertensive retinopathy and severe amyloid angiopathy and whose MRI scans displayed lacunar infarcts and several microhemorrhages ( Mönkäre et al, 2022 ).…”

“…The US cohort has been already described in a previous genetic screening of APP and A ẞ metabolism genes ( Blumenau et al, 2020 ) and part of the Finnish cohort has been already included in a previous genetic screening focused on Mendelian genes causative for vascular dementia ( Mönkäre et al, 2022 ). The mean age at disease onset was 52 years (SD = 10.9) and 76 cases (42.2%) had a positive family history.…”