A Phenotype-Based Score to Prioritize RNF213 p.R4810K Genotyping in Isolated Intracranial Steno-Occlusive Disease.

Abstract

Background: Ring finger protein 213 (RNF213) p.R4810K is a genetic susceptibility factor for intracranial arteriopathies. In patients with isolated intracranial arterial steno-occlusive disease (ICAD) without Moyamoya disease (MMD), we developed a phenotype-based triage score to prioritize RNF213 genotyping by enriching the p.R4810K carriage probability.

Methods: We retrospectively analyzed 753 patients with isolated ICAD involving the distal internal carotid artery or middle cerebral artery M1 segment who underwent RNF213 genotyping between January 2010 and November 2022, excluding definite MMD or significant extracranial steno-occlusion. A prespecified score incorporated anterior cerebral artery (ACA) laterality (0/1/2), tandem lesion burden ≥ 3 (0/1), and MMD family history (0/1; weighted ×4). Discrimination, prespecified thresholds (≥ 3 and ≥ 4), and bootstrap-corrected calibration were assessed, with external application in an independent cohort.

Results: RNF213 p.R4810K was identified in 289 patients (38.4%). MMD family history showed the strongest association with carriage (adjusted odds ratio [OR] 8.34, 95% confidence interval [CI]: 4.15-16.77, p < 0.001), followed by tandem burden ≥ 3 (adjusted OR 1.76, 95% CI: 1.15-2.69, p = 0.009) and ACA laterality (adjusted OR 1.74, 95% CI: 1.35-2.23, p < 0.001). The score showed moderate discrimination (internal area under the curve [AUC] 0.720; external AUC 0.708). A cutoff ≥ 3 restricted genotyping to 33.5% of patients while capturing 55.7% of carriers, reducing genotyping workload by 66.5%. A cutoff ≥ 4 increased the positive predictive value to 81.7% with 97.6% specificity.

Conclusions: In clinically selected isolated ICAD, a phenotype-based score incorporating lesion distribution and family history may help prioritize RNF213 genotyping and improve genotyping yield in resource-limited settings.