|Title||The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Pinard, A, Guey, S, Guo, D, Cecchi, AC, Kharas, N, Wallace, S, Regalado, ES, Hostetler, EM, Sharrief, AZ, Bergametti, F, Kossorotoff, M, Hervé, D, Kraemer, M, Bamshad, MJ, Nickerson, DA, Smith, ER, Tournier-Lasserve, E, Milewicz, DM|
|Date Published||2020 02|
|Keywords||Adult, Cell Cycle Proteins, Cerebrovascular Disorders, Child, Child, Preschool, Developmental Disabilities, DNA Helicases, Exome, Female, Genetic Predisposition to Disease, Humans, Intellectual Disability, Male, Methyltransferases, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Middle Aged, Moyamoya Disease, Mutation, Nuclear Proteins, Transcription Factors, Whole Exome Sequencing|
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.
|Alternate Journal||Genet Med|
|PubMed Central ID||PMC7673309|
|Grant List||U54 HG006493 / HG / NHGRI NIH HHS / United States |
UM1 HG006493 / HG / NHGRI NIH HHS / United States