Rare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease

• DOI: 10.1093/brain/awad172
• Publication Date: 2023-05-30T18:02:53Z
• Authors: Amélie Pinard; Wenlei Ye; Stuart M Fraser; Jill A Rosenfeld; Pavel Pichurin; Scott E Hickey; Dongchuan Guo; Alana C Cecchi; Maura L Boerio; Stéphanie Guey; Chaker Aloui; Kwanghyuk Lee; Markus Kraemer; Saleh Omar Alyemni; ; Michael J Bamshad; Deborah A Nickerson; Elisabeth Tournie...; Shozeb Haider; Sheng Chih Jin; Edward R Smith; Kristopher T Kahle; Lily Yeh Jan; Mu He; Dianna M Milewicz
• Keywords: 610; Medical and Health Sciences; genetic heterogeneity; Young Adult; Clinical Research; Chloride Channels; 616; Internal Medicine; Medical Specialties; Medicine and Health Sciences; Genetics; 2.1 Biological and endogenous factors; Humans; Aetiology; University of Washington Center for Mendelian Genomics; Child; stroke genetics; Anoctamin-1; Neurology & Neurosurgery; pathogenesis; Psychology and Cognitive Sciences; Neurosciences; smooth muscle cells; genotype-phenotype; Neoplasm Proteins; Moyamoya Disease

Abstract Moyamoya disease, a cerebrovascular disease leading to strokes in children and young adults, is characterized by progressive occlusion of the distal internal carotid arteries and the formation of collateral vessels. Altered genes play a prominent role in the aetiology of moyamoya disease, but a causative gene is not identified in the majority of cases. Exome sequencing data from 151 individuals from 84 unsolved families were analysed to identify further genes for moyamoya disease, then candidate genes assessed in additional cases (150 probands). Two families had the same rare variant in ANO1, which encodes a calcium-activated chloride channel, anoctamin-1. Haplotype analyses found the families were related, and ANO1 p.Met658Val segregated with moyamoya disease in the family with an LOD score of 3.3. Six additional ANO1 rare variants were identified in moyamoya disease families. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harbouring these gain-of-function ANO1 variants had classic features of moyamoya disease, but also had aneurysm, stenosis and/or occlusion in the posterior circulation. Our studies support that ANO1 gain-of-function pathogenic variants predispose to moyamoya disease and are associated with unique involvement of the posterior circulation.