Table 1. Case-Control Burden Analysis of All Rare Protein-Damage Variants for DIAPH1, ACTA2, and RNF213^a.

Gene	pLI Scoreb	mis_Zc	Yale MMD European Cases		Non-Finnish gnomAD-TOPMed (v2.1.1)		OR (95% CI)	P valued
			Alleles, No.		Alleles, No.
			Alternative	Reference	Alternative	Reference
DIAPH1	0.92	1.65	3	33	1092	146 232	12.17 (2.39-38.89)	2.4 × 10−3
ACTA2	0.93	3.2	1	35	101	147 321	41.67 (1.01-254.7)	.02
RNF213	0	2.3	3	33	2056	145 838	6.45 (1.26-20.58)	.01

Abbreviations: MMD, moyamoya disease; OR, odds ratio.

^a Rare variants (minor allele frequency, ≤5 × 10⁻⁴) protein-damaging mutations compared between 24 MMD cases from Yale Center for Mendelian Genomics and gnomAD-TOPMed controls.

^b pLI is a gene-wide constraint metric that estimates the probability of being intolerant to loss-of-function mutations.

^c mis_Z is a gene-wide constraint metric that estimates the probability of being intolerant to missense mutations.

^d A 2-tailed Fisher exact test was used to evaluate the genetic association by comparing frequencies of rare alleles between Yale Center for Mendelian Genomics MMD European cases and non-Finnish gnomAD (without disease-enriched TOPMed samples) and Simons simplex collection controls. The multiple-testing cutoff was 0.017 (α = .05/3).