Whole-exome sequencing of Finnish patients with vascular cognitive impairment

Abstract

Cerebral small vessel disease (CSVD) is the most important cause of vascular cognitive impairment (VCI). Most CSVD cases are sporadic but familial monogenic forms of the disorder have also been described. Despite the variants identified, many CSVD cases remain unexplained genetically. We used whole-exome sequencing in an attempt to identify novel gene variants underlying CSVD. A cohort of 35 Finnish patients with suspected CSVD was analyzed. Patients were screened negative for the most common variants affecting function in NOTCH3 in Finland (p.Arg133Cys and p.Arg182Cys). Whole-exome sequencing was performed to search for a genetic cause of CSVD. Our study resulted in the detection of possibly pathogenic variants or variants of unknown significance in genes known to associate with CSVD in six patients, accounting for 17% of cases. Those genes included NOTCH3, HTRA1, COL4A1, and COL4A2. We also identified variants with predicted pathogenic effect in genes associated with other neurological or stroke-related conditions in seven patients, accounting for 20% of cases. This study supports pathogenic roles of variants in COL4A1, COL4A2 and HTRA1 in CSVD and VCI. Our results also suggest that vascular pathogenic mechanisms are linked to neurodegenerative conditions and provide novel insights into the molecular basis of VCI.

Genetic analysis reveals novel variants for vascular cognitive impairment

“…In the present study, we continued the research of the genetics of VCI by studying the second part of the Finnish cohort with well‐characterized clinical features (v. 2.0 cohort) using WES. The present study resulted in identification of several variants possibly affecting function in genes linked to CSVD, stroke, or other neurological conditions, which is in line with our previous study 11 . We also performed CNV analysis using a SNP microarray on all the exome‐sequenced patients (v. 1.0 and v. 2.0 cohorts).…”

“…CNV analysis of 80 VCI patients (v.1.0 and v.2.0 cohorts) identified nine rare autosomal CNVs that were all classified as being of unknown significance (Table 3). Two of the CNVs were detected in patients for whom WES analysis did not reveal any potential cause of disease (patients 236, 289) in our previous study 11 . Three CNVs were detected in patients who had possibly causative variants identified by WES (patients 1029, 1033, and 1039) in this study.…”

“…Two of the CNVs were detected in patients for whom WES analysis did not reveal any potential cause of disease (patients 236, 289) in our previous study. 11 Three CNVs were detected in patients who had possibly causative variants identified by WES (patients 1029, 1033, and 1039) in this study. CNVs classified as likely benign or benign in the analysis are presented in Table S6.…”

“…In the 73 DNA samples extracted from peripheral blood, the miR‐29 microRNA binding site in the 3′UTR of COL4A1 was Sanger sequenced as previously described 11 …”

“…We recently published a whole-exome analysis of Finnish patients with VCI (v.1.0 cohort, n = 35). 11 The aim of the current study was to further investigate the genetic background of familial VCI by performing a similar analysis in the second part of a Finnish VCI patient population (v.2.0 cohort, n = 45) using whole-exome sequencing (WES). Furthermore, CNVs were explored in both datasets, using a genomewide single nucleotide polymorphism (SNP) array.…”