To assess associations between rare deleterious mutations in CSVD-related genes and clinical/neuroimaging phenotypes in a Chinese CSVD cohort.

Cerebral small vessel disease (CSVD) is a leading cause of stroke and cognitive decline. While NOTCH3 mutations underlie hereditary CSVD and its rare mutation have been implicated in sporadic cases, the role of rare mutations in other CSVD-related genes remains unclear. Our previous imaging genetics studies indicate carriers of rare variants exhibit distinct MRI patterns, suggesting a genetic predisposition with neuroimaging signatures. However, the imaging-clinical correlation remains poorly defined.

A total of 798 CSVD from multiple centers with complete clinical, neuroimaging, and genetic data were included. High-throughput sequencing targeted 11 CSVD-related genes (NOTCH3, HTRA1, COL4A1, COL4A2, CTSA, GAL, TREX1, CTC1, APP, GSN, ADA2). Rare deleterious variants were defined as those with a minor allele frequency <0.01 in four public databases and predicted as damaging by four in silico tools. Group comparisons were conducted between mutation carriers and non-carriers.

Among 798 participants, 207(25.9%) carried ≥1 rare deleterious mutation, primarily in NOTCH3(14.7%) and HTRA1(2.38%). Rare mutation carriers were significantly younger with fewer clinical symptoms. Gene-specific analyses revealed distinct genotype–phenotype patterns: NOTCH3 carriers showed increased white matter hyperintensity (WMH) but less cognitive impairment, urinary/bowel dysfunction, and gait disturbance. COL4A2 carriers had higher hemorrhagic stroke rates, while APP carriers had less bulbar palsy. On the other hand, HTRA1 and GSN carriers had higher WMH, and CTSA carriers had more cerebral microbleeds; yet these carriers demonstrated comparable phenotypic characteristics to non-carriers.

Rare deleterious CSVD-related gene mutations are associated with distinct clinico-radiological phenotypes. We observed a dissociation between more severe neuroimaging burden and milder clinical manifestations in carriers, suggesting an earlier disease stage and a different progression pattern from sporadic CSVD. Neuroimaging is critical for early identification and risk stratification in genetically susceptible individuals.