The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy |
| |
| Institution: | 1. Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA;2. INSERM UMR-S1161, Génétique et physiopathologie des maladies cérébro-vasculaires, Université Paris Diderot, Sorbonne Paris Cité, Paris, France;;3. Department of Neurobiology and Anatomy, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA;;4. Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA;;5. AP-HP, French Center for Pediatric Stroke and Pediatric Neurology Department, University Hospital Necker-Enfants Malades, Paris, France;6. AP-HP, Service de neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de L’oeil, Groupe Hospitalier Lariboisière Saint Louis, Paris, France;7. Department of Neurology Alfried Krupp-Hospital, Essen and Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany;8. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA;9. Department of Genome Sciences, University of Washington, Seattle, WA, USA;10. Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA;;11. AP-HP, Service de génétique moléculaire neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l’oeil, Groupe Hospitalier Saint-Louis Lariboisière, Paris, France;1. Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA;2. INSERM UMR-S1161, Génétique et physiopathologie des maladies cérébro-vasculaires, Université Paris Diderot, Sorbonne Paris Cité, Paris, France;;3. Department of Neurobiology and Anatomy, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA;;4. Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA;;5. AP-HP, French Center for Pediatric Stroke and Pediatric Neurology Department, University Hospital Necker-Enfants Malades, Paris, France;6. AP-HP, Service de neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de L’oeil, Groupe Hospitalier Lariboisière Saint Louis, Paris, France;7. Department of Neurology Alfried Krupp-Hospital, Essen and Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany;8. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA;9. Department of Genome Sciences, University of Washington, Seattle, WA, USA;10. Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA;;11. AP-HP, Service de génétique moléculaire neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l’oeil, Groupe Hospitalier Saint-Louis Lariboisière, Paris, France |
| |
| Abstract: | PurposeMoyamoya 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.MethodsExome sequencing from 39 trios were analyzed.ResultsWe 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.ConclusionThese 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: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
