Genetic analysis reveals novel variants for vascular cognitive impairment

Area of Science:

• Neurogenetics
• Vascular Neurology

Background:

• The genetic underpinnings of vascular cognitive impairment (VCI) remain largely unexplored compared to other dementia types.
• Understanding VCI genetics is crucial for developing targeted diagnostic and therapeutic strategies.

Purpose of the Study:

• To investigate the genetic basis of VCI in a well-characterized Finnish population.
• To identify specific genes and variants associated with the development of VCI.

Main Methods:

• Whole-exome sequencing (WES) was performed on 45 Finnish VCI patients.
• Copy-number variant (CNV) analysis was conducted using SNP arrays in 80 VCI patients.
• Prevalence of variants in the miR-29 binding site of COL4A1 was assessed in 73 VCI patients.

Main Results:

• WES identified potentially causative variants in genes linked to cerebral small vessel disease (CSVD) and stroke in 40% of patients.
• Notable variants include HTRA1, TREX1, COLGALT1, PRNP, and MTHFR.
• A novel variant in the 3'UTR of COL4A1 was discovered, while pathogenic CNVs were found to be infrequent in VCI.

Conclusions:

• Variants in HTRA1, TREX1, and COL4A1's 3'UTR show pathogenic roles in CSVD and VCI.
• These findings suggest a link between vascular mechanisms and neurodegeneration in VCI.
• The study expands the comprehension of the genetic architecture underlying VCI.