# Genotype-phenotype correlations in a Scottish CADASIL cohort and comparison with sporadic small vessel disease

## TL;DR

This study compares how different NOTCH3 gene mutations in CADASIL affect brain disease severity compared to non-genetic small vessel disease.

## Contribution

The study introduces a novel stratification of CADASIL mutations by location and risk tiers to correlate with disease phenotype.

## Key findings

- Proximal CADASIL mutations are associated with more severe white matter hyperintensities and earlier strokes.
- WMH progression is faster in CADASIL compared to sporadic SVD, with proximal mutations showing the highest progression.
- CADASIL patients with proximal mutations have higher lacune counts and lower hypertension rates than those with distal mutations.

## Abstract

CADASIL is a monogenic inherited cerebral small vessel disease (SVD) caused by a mutation affecting the NOTCH3 gene. Mutation location appears to influence disease severity. We investigated the hypothesis that mutation location modifies phenotype by comparing a CADASIL population stratified by mutation site risk with a cohort of older people with sporadic SVD.

We included adults with CADASIL and control group from the XILO-FIST trial. We recorded age at first stroke, white matter hyperintensity (WMH) volume, lacunes, cerebral microbleeds and other clinical biomarkers. We divided the CADASIL cohort into (1) two groups NOTCH3 mutations affecting epidermal growth factor-like repeat (EGFr) domains 1–6 (proximal) and EGFr domains 7–34 (distal); and (2) three groups; low, medium and high-risk based on a proposed three-tiered risk stratification.

The CADASIL cohort included 129 people, 57 (44.2%) male, mean age 47.5 ± 11.7 years. The sporadic SVD cohort included 460 people, 317 (68.9%) male, mean age 65.7 ± 8.7 years. The CADASIL proximal group were imaged at younger age, but fewer had hypertension (14.3% v 38.1%) compared to distal mutations. Lacune count and WMH volume differed between low, medium and high-risk CADASIL mutations, and sporadic SVD. Percentage progression of WMH volume was higher in proximal CADASIL (0.26%), than distal CADASIL (0.14%) which was higher than sporadic SVD (0.05%), p < 0.001.

Proximal CADASIL mutations average more extensive WMH, higher lacune count and experienced first stroke at younger age than those with distal mutations. Both groups showed imaging differences compared to sporadic SVD.

Graphical Abstract