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Introduction: Moyamoya disease (MMD) is a cerebrovascular disease often causing pediatric onset strokes and characterized by progressive bilateral occlusion of the distal internal carotid arteries and formation of a compensatory network of collateral vessels. Several genes harbor variants that increase the risk for MMD, but the majority of cases of European descent does not have an identified genetic cause.

Hypothesis: MMD is associated with significant genetic heterogeneity, i.e., many genes in the human genome can be altered to predispose to this condition.

Methods: To identify novel genes for MMD, exome sequencing was performed on DNA from 145 individuals from 80 families with one or more affected members. Bioinformatics filtering included a CADD (GRCh37-v1.4) score > 20 and a minor allele frequency < 0.0001 in gnomAD (v2.1.1 controls). For a subset of ANO1 mutant alleles, we characterized the …