Các biến thể mã hóa và không mã hóa trong EBF3 liên quan đến HADDS và tự kỷ đơn giản

Springer Science and Business Media LLC - 2021
Evin M. Padhi1, Tristan J. Hayeck2, Cheng Zhang3, Sumantra Chatterjee4, Brandon J. Mannion5, Marta Byrska-Bishop6, Marjolaine Willems7, Lucile Pinson7, Sylvia Redon8, Caroline Bénech8, Kévin Uguen8, Séverine Audebert‐Bellanger9, Cédric Le Maréchal8, Claude Férec8, Stéphanie Efthymiou10, Fatima Rahman11, Shazia Maqbool10, Reza Maroofian10, Henry Houlden10, Rajeeva Musunuri6, Giuseppe Narzisi6, Avinash Abhyankar6, Riana D. Hunter5, Jennifer A. Akiyama5, Lauren E. Fries4, Jeffrey K. Ng1, Elvisa Mehinovic1, Nicholas Stong12, Andrew S. Allen13, Diane E. Dickel5, Raphael Bernier14, David U. Gorkin15, L Pennacchio16, Michael C. Zody6, Tychele N. Turner1
1Department of Genetics, Washington University School of Medicine, 4523 Clayton Avenue, Campus Box 8232, St. Louis, MO, 63110, USA
2Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
3Center for Epigenomics, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093, USA
4Center for Human Genetics and Genomics, NYU School of Medicine, New York, NY, 10016, USA
5Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
6New York Genome Center, New York, NY 10013, USA
7University of Montpellier, département de Génétique, maladies rares médecine personnalisée, U 1298, CHU Montpellier, University of Montpellier, Montpellier, France
8CHU Brest, Inserm, Univ Brest, EFS,UMR 1078, GGB, F-29200, Brest, France
9Service de Génétique Médicale, CHRU de Brest, Brest, France
10Department of Neuromuscular disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
11Development and Behavioral Pediatrics Department, Institute of Child Health and Children Hospital, Lahore, Pakistan
12Institute for Genomic Medicine, Columbia University, New York, NY, 10027, USA
13Center for Statistical Genetics and Genomics, Duke University, Durham, NC, 27708, USA
14Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA
15Department of Biology, Emory University, Atlanta, GA 30322, USA
16U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA

Tóm tắt

Tóm tắt Nền tảng Nghiên cứu trước đây về tự kỷ và các rối loạn phát triển thần kinh (NDDs) đã chỉ ra rằng các biến thể de novo mã hóa protein (DNVs) trong các gen cụ thể có một đóng góp quan trọng. Vai trò của các biến thể không mã hóa de novo đã được quan sát như là một sự gia tăng tổng thể của gánh nặng gen nhưng vẫn chưa được xác định đến các yếu tố chức năng riêng lẻ. Trong nghiên cứu này, chúng tôi đã đánh giá dữ liệu giải trình tự toàn bộ gen ở 2671 gia đình có người tự kỷ (tập hợp khám phá gồm 516 gia đình, tập hợp tái lập gồm 2155 gia đình). Chúng tôi tập trung vào các DNVs trong các enhancer có hoạt động in vivo được xác định trong não và đã xác định được một lượng dư thừa của các DNV trong một enhancer được gọi là hs737. Kết quả Chúng tôi đã điều chỉnh mô hình thống kê fitDNM để làm việc trong các vùng không mã hóa và thử nghiệm các enhancer cho sự dư thừa của các DNV trong các gia đình có người tự kỷ. Chúng tôi chỉ phát hiện được một enhancer (hs737) có ý nghĩa danh nghĩa trong tập hợp khám phá (p = 0.0172), tái lập (p = 2.5 × 10−3), và tập hợp kết hợp (p = 1.1 × 10−4). Mỗi cá thể có một DNV trong hs737 đều có những kiểu hình chung bao gồm là nam giới, chức năng nhận thức nguyên vẹn và giảm trương lực cơ hoặc chậm phát triển vận động. Đánh giá in vitro của chúng tôi về các DNV cho thấy tất cả chúng đều làm giảm hoạt động của enhancer trong một dòng tế bào thần kinh. Qua phân tích epigenome, chúng tôi phát hiện rằng hs737 là đặc hiệu cho não và nhắm đến gen yếu tố phiên mã EBF3 trong não thai nhi của con người. EBF3 có ý nghĩa toàn bộ gen đối với các DNVs mã hóa trong NDDs (missense p = 8.12 × 10−35, mất chức năng p = 2.26 × 10−13) và được biểu hiện rộng rãi trong cơ thể. Qua việc xác định các promoter được gắn bởi EBF3 trong các tế bào thần kinh, chúng tôi đã thấy sự gia tăng kết nối với các gen NDD (p = 7.43 × 10−6, OR = 1.87) tham gia vào việc điều chỉnh gen. Các cá thể có DNV mã hóa có mức độ nghiêm trọng về kiểu hình lớn hơn (giảm trương lực cơ, loạn vận động, và hội chứng chậm phát triển [HADDS]) so với những cá thể có DNV không mã hóa mà cũng có tự kỷ và giảm trương lực cơ. Kết luận Trong nghiên cứu này, chúng tôi xác định các DNV trong enhancer hs737 ở các cá thể có tự kỷ. Qua nhiều phương pháp, chúng tôi thấy hs737 nhắm đến gen EBF3 có ý nghĩa toàn bộ gen trong NDDs. Bằng việc đánh giá các biến thể không mã hóa và các gen mà chúng ảnh hưởng, chúng tôi bắt đầu hiểu rõ hơn tác động của chúng đối với các mạng lưới điều chỉnh gen trong NDDs.

Từ khóa


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