Amélie Pinard1, Stéphanie Guey2, Elisabeth Tournier-Lasserve2,3, Dianna M Milewicz4, Dongchuan Guo1, Alana C Cecchi1, Natasha Kharas5, Stephanie Wallace1, Ellen S Regalado1, Ellen M Hostetler1, Anjail Z Sharrief6, Françoise Bergametti2, Manoelle Kossorotoff7, Dominique Hervé8, Markus Kraemer9, Michael J Bamshad10,11, Deborah A Nickerson11, Edward R Smith12. 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. AP-HP, Service de génétique moléculaire neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'œil, Groupe Hospitalier Saint-Louis Lariboisière, Paris, France. 4. Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA. Dianna.M.Milewicz@uth.tmc.edu. 5. Department of Neurobiology and Anatomy, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA. 6. Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA. 7. AP-HP, French Center for Pediatric Stroke and Pediatric Neurology Department, University Hospital Necker-Enfants Malades, Paris, France. 8. AP-HP, Service de neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de L'œil, Groupe Hospitalier Lariboisière Saint Louis, Paris, France. 9. Department of Neurology Alfried Krupp-Hospital, Essen and Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany. 10. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA. 11. Department of Genome Sciences, University of Washington, Seattle, WA, USA. 12. Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Abstract
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.
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.
Authors: Peter B Sporns; Heather J Fullerton; Sarah Lee; Helen Kim; Warren D Lo; Mark T Mackay; Moritz Wildgruber Journal: Nat Rev Dis Primers Date: 2022-02-24 Impact factor: 52.329
Authors: Amélie Pinard; Maximillian D J Fiander; Alana C Cecchi; Andrea L Rideout; Mohamed Azouz; Stuart M Fraser; P Daniel McNeely; Simon Walling; Sarah C Novara; Anna C E Hurst; Dongchuan Guo; Sandhya Parkash; Michael J Bamshad; Deborah A Nickerson; Anthony M Vandersteen; Dianna M Milewicz Journal: Neurology Date: 2021-02-10 Impact factor: 9.910
Authors: Adam J Kundishora; Samuel T Peters; Amélie Pinard; Daniel Duran; Shreyas Panchagnula; Tanyeri Barak; Danielle F Miyagishima; Weilai Dong; Hannah Smith; Jack Ocken; Ashley Dunbar; Carol Nelson-Williams; Shozeb Haider; Rebecca L Walker; Boyang Li; Hongyu Zhao; Dean Thumkeo; Arnaud Marlier; Phan Q Duy; Nicholas S Diab; Benjamin C Reeves; Stephanie M Robert; Nanthiya Sujijantarat; Amber N Stratman; Yi-Hsien Chen; Shujuan Zhao; Isabelle Roszko; Qiongshi Lu; Bo Zhang; Shrikant Mane; Christopher Castaldi; Francesc López-Giráldez; James R Knight; Michael J Bamshad; Deborah A Nickerson; Daniel H Geschwind; Shih-Shan Lang Chen; Phillip B Storm; Michael L Diluna; Charles C Matouk; Darren B Orbach; Seth L Alper; Edward R Smith; Richard P Lifton; Murat Gunel; Dianna M Milewicz; Sheng Chih Jin; Kristopher T Kahle Journal: JAMA Neurol Date: 2021-08-01 Impact factor: 29.907
Authors: R Mertens; M Graupera; H Gerhardt; A Bersano; E Tournier-Lasserve; M A Mensah; S Mundlos; P Vajkoczy Journal: Transl Stroke Res Date: 2021-09-16 Impact factor: 6.829
Authors: Iana Meitlis; Eric J Allenspach; Bradly M Bauman; Isabelle Q Phan; Gina Dabbah; Erica G Schmitt; Nathan D Camp; Troy R Torgerson; Deborah A Nickerson; Michael J Bamshad; David Hagin; Christopher R Luthers; Jeffrey R Stinson; Jessica Gray; Ingrid Lundgren; Joseph A Church; Manish J Butte; Mike B Jordan; Seema S Aceves; Daniella M Schwartz; Joshua D Milner; Susan Schuval; Suzanne Skoda-Smith; Megan A Cooper; Lea M Starita; David J Rawlings; Andrew L Snow; Richard G James Journal: Am J Hum Genet Date: 2020-11-16 Impact factor: 11.043