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

Genet Med. 2020 Feb;22(2):427-431. doi: 10.1038/s41436-019-0639-2. Epub 2019 Sep 2.


Purpose: 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.

Methods: Exome sequencing from 39 trios were analyzed.

Results: 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.

Conclusion: 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.

Keywords: chromatin remodeling; developmental disorders; exome sequencing; moyamoya angiopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Cycle Proteins / genetics
  • Cerebrovascular Disorders / genetics*
  • Cerebrovascular Disorders / metabolism
  • Child
  • Child, Preschool
  • DNA Helicases / genetics
  • Developmental Disabilities / genetics
  • Exome / genetics
  • Exome Sequencing / methods
  • Female
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Intellectual Disability / genetics
  • Male
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
  • Middle Aged
  • Moyamoya Disease / genetics*
  • Mutation / genetics
  • Nuclear Proteins / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • CHD4 protein, human
  • CNOT3 protein, human
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Transcription Factors
  • YY1AP1 protein, human
  • Methyltransferases
  • SETD5 protein, human
  • SMARCAL1 protein, human
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex
  • DNA Helicases