The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy

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Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger.


Exome sequencing from 39 trios were analyzed.


We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease.


These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.

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We are grateful to the patients and their family members for participating in this study. This study was funded by the Henrietta B. and Frederick H. Bugher Foundation (D.M.M.), the Texas Heart Institute Fibromuscular Dysplasia Project (D.M.M.), INSERM (E.T.-L.), the American Heart Association (18POST34020031; A. P.) and the Fondation pour le Recherche Médicale (S.G.). Exome sequencing was funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute grant HG006493 to D.A.N., M.J.B., and Suzanne Leal. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Correspondence to Dianna M. Milewicz MD, PhD.

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Pinard, A., Guey, S., Guo, D. et al. The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy. Genet Med (2019) doi:10.1038/s41436-019-0639-2

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  • moyamoya angiopathy
  • exome sequencing
  • developmental disorders
  • chromatin remodeling