Journal Article

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

Kossorotoff, Manoelle, Bamshad, Michael J., Guo, Dongchuan, Kraemer, Markus, Nickerson, Deborah A., Bergametti, Françoise, Hostetler, Ellen M., Regalado, Ellen S., Milewicz, Dianna M., Tournier-Lasserve, Elisabeth, Hervé, Dominique, Guey, Stéphanie, Kharas, Natasha, Pinard, Amélie, Sharrief, Anjail Z., Smith, Edward R., Cecchi, Alana C., Wallace, Stephanie

2020

Overview

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.

• Publisher: Elsevier Inc,Nature Publishing Group US,Elsevier Limited
• Subject: Adult / Atherosclerosis / Autism / Biomedical and Life Sciences / Biomedicine / Brief Communication / Cardiovascular disease / Carotid arteries / Cell Cycle Proteins - genetics / Cerebrovascular disease / Cerebrovascular Disorders - genetics / Cerebrovascular Disorders - metabolism / Child / Child, Preschool / chromatin remodeling / Congenital diseases / Developmental Disabilities - genetics / developmental disorders / DNA Helicases - genetics / Exome - genetics / exome sequencing / Female / Genetic Predisposition to Disease - genetics / Genetics / Genomics / Hospitals / Human Genetics / Humans / Hypertension / Intellectual disabilities / Intellectual Disability - genetics / Laboratory Medicine / Male / Medical schools / Medicine / Methyltransferases - genetics / Methyltransferases - metabolism / Mi-2 Nucleosome Remodeling and Deacetylase Complex - genetics / Mi-2 Nucleosome Remodeling and Deacetylase Complex - metabolism / Middle Aged / moyamoya angiopathy / Moyamoya Disease - genetics / Mutation - genetics / Neurology / Neurosciences / Nuclear Proteins - genetics / Patients / Pediatrics / Smooth muscle / Transcription Factors - genetics / Transcription Factors - metabolism / Veins & arteries / Whole Exome Sequencing - methods