Figure 4.

NOTCH3 ^cys variants in EGFr domains 1–5, 14 and 26 are most frequent in the CADASIL genotype–phenotype data set: associations with disease severity. Five interval plots showing the estimated marginal means, odds ratios or hazard ratios of SVD imaging markers, risk of stroke and disability for the EGFr domains most frequently harbouring NOTCH3^cys variants in the CADASIL genotype–phenotype data set, after correction for cardiovascular risk factors and sex. Only EGFr domains which had high NOTCH3^cys variant counts (≥10 individuals for SVD imaging markers and ≥20 individuals for clinical outcomes) were included in the analyses. Error bars indicate 95% confidence intervals of the group means. (A–D) Of all frequently mutated HR-EGFr domains, EGFr domains 2 and 3 were associated with the highest burden of nWMHv, PSMD, nLV and risk of stroke. There was an evident decrease in the SVD imaging marker loads and risk of stroke in EGFr domain 3 through EGFr domain 5. EGFr domain 26 was associated with as high a burden of SVD imaging markers and risk of stroke as the other HR-EGFr domains. EGFr domain 14, which was the only MR-EGFr domain with a high frequency of NOTCH3^cys variants in CADASIL patients, was associated with the lowest burden of SVD imaging markers and risk of stroke. (E) There were no significant differences in disability. Further details including statistically significant differences in the burden of SVD imaging markers and risk of stroke between EGFr domains are shown in Supplementary Tables 5 and 6.