Comparative phenotypic spectrum of the NOTCH3 p.R75P variant and cysteine-altering mutations: A systematic review and meta-analysis

Abstract

The Notch receptor 3 gene (NOTCH3) p.R75P variant, a cysteine-sparing missense substitution, has been frequently reported in East Asian patients with cerebral small vessel disease resembling cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). While classical NOTCH3 mutations involve cysteine alterations, emerging evidence suggests phenotypic overlap between p.R75P and cysteine-altering variants. The aim of this review is to compare the clinical and imaging features of p.R75P with those of cysteine-altering NOTCH3 mutations. Following PRISMA 2020 guidelines, a comprehensive search was conducted up to September 2025 and in August 2026. Meta-analyses were performed using random-effects models to calculate odds ratios (ORs) with 95% confidence intervals (CIs). In addition, genetic and pathological evidence was described narratively. Nineteen studies involving 150 p.R75P carriers were included. Clinical manifestations, including stroke, symptomatic intracerebral hemorrhage (ICH), cognitive impairment, psychiatric disorders, and migraine, were comparable between NOTCH3 p.R75P and cysteine-altering variants. Neuroradiological features were also largely similar, including white matter hyperintensities (WMH) involving the anterior temporal lobe (ATL) and external capsule (EC), as well as cerebral microbleeds (CMBs). In subgroup analyses, p.R75P was associated with a significantly higher prevalence of migraine compared with the R544C variant (OR: 2.98; 95%CI: 1.12–7.94; I²=0.0%) and substantially lower ATL involvement reported than cysteine-altering mutations (OR: 0.01; 95%CI: 0.00–0.05; I²=0.0%). However, these subgroup findings were based on limited and selectively reported datasets and should therefore be interpreted cautiously. The NOTCH3 p.R75P variant demonstrates substantial clinical and imaging overlap with cysteine-altering mutations, supporting its potential pathogenic relevance in CADASIL-type arteriopathy, particularly in East Asian populations. Further multicenter, genotype-confirmed, and mechanistic studies are warranted to validate these findings, clarify underlying mechanisms, and inform diagnostic and counseling strategies across diverse populations.