Rare Sequence Variation Underlying Suspected Familial Cerebral Small-Vessel Disease

Area of Science:

• Genetics
• Neurology
• Vascular Biology

Background:

• Cerebral small-vessel disease (cSVD) is a primary genetic cause of stroke.
• Many cSVD cases lack identified causative genetic variants despite screening.
• Whole-genome sequencing is used to investigate genetic underpinnings of familial cSVD.

Purpose of the Study:

• To identify known and novel genetic variants associated with familial cerebral small-vessel disease (cSVD).
• To investigate the role of rare variants in noncoding and matrisomal genes in cSVD etiology.

Main Methods:

• Whole-genome sequencing was performed on a cohort of 257 suspected cSVD cases and 13,086 controls.
• Gene-based burden tests and family analysis were employed to identify associated variants.
• Analysis focused on known monogenic cSVD genes and novel variants in noncoding and matrisomal genes.

Main Results:

• Pathogenic variants in known cSVD genes were found in 8.9% of cases.
• 23.6% of unrelated cSVD cases carried predicted deleterious variants in the Genomics England gene panel, but no association was found.
• Potential associations with cSVD were identified in noncoding genes (e.g., RP4-568F9.3, RP3-466I7.1, ZNF209P) and matrisomal genes (e.g., FAM20C, INHA, LAMC1, VWA5B2).

Conclusions:

• While known cSVD genes were present in a subset of cases, they were not consistently associated with the disease.
• Rare variants in noncoding and matrisomal genes may contribute to cSVD development.
• These genes' roles in tissue development and brain endothelial function warrant further investigation.