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

Amélie PinardWenlei YeStuart M FraserJill Anne RosenfeldPavel PichurinScott E HickeyDongchuan GuoAlana C CecchiMaura L BoerioStéphanie GueyChaker AlouiKwanghyuk LeeMarkus KraemerSaleh Omar Alyemninull nullMichael J BamshadDeborah A NickersonElisabeth Tournier-LasserveShozeb M HaiderSheng Chih JinEdward R SmithKristopher T KahleLily Yeh JanMu HeDianna M Milewicz
Published in: Brain : a journal of neurology (2023)
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 etiology 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 analyzed 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 harboring these gain-of-function ANO1 variants had classic features of MMD, 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.
Keyphrases
  • copy number
  • middle cerebral artery
  • young adults
  • genome wide
  • machine learning
  • chronic kidney disease
  • dna methylation
  • transcription factor
  • single cell
  • tyrosine kinase
  • prognostic factors
  • artificial intelligence