Các episignature metyl hóa DNA đặc hiệu theo miền gen chỉ ra những thực thể phân tử khác nhau của hội chứng ADNP

Springer Science and Business Media LLC - Tập 11 - Trang 1-17 - 2019
Eric G. Bend1,2, Erfan Aref-Eshghi3,4, David B. Everman1, R. Curtis Rogers1, Sara S. Cathey1, Eloise J. Prijoles1, Michael J. Lyons1, Heather Davis1, Katie Clarkson1, Karen W. Gripp5, Dong Li6, Elizabeth Bhoj6, Elaine Zackai7, Paul Mark8, Hakon Hakonarson6, Laurie A. Demmer9, Michael A. Levy3,4, Jennifer Kerkhof3,4, Alan Stuart3,4, David Rodenhiser10, Michael J. Friez1, Roger E. Stevenson1, Charles E. Schwartz1, Bekim Sadikovic3,4
1Greenwood Genetic Center, Greenwood, USA
2PreventionGenetics, Marshfield, USA
3Department of Pathology and Laboratory Medicine, Western University, London, Canada
4Molecular Genetics Laboratory, Victoria Hospital, London Health Sciences Centre, London, Canada
5Al DuPont Hospital for Children, Wilmington, USA
6Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, USA
7Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, USA
8Spectrum Health, Grand Rapids, USA
9Levine Children’s Hospital, Carolinas Medical Center, Charlotte, USA
10Department of Pediatrics, Biochemistry and Oncology, Western University, London, Canada

Tóm tắt

Hội chứng ADNP là một rối loạn Mendelian hiếm gặp, được đặc trưng bởi sự chậm phát triển toàn cầu, khuyết tật trí tuệ và tự kỷ. Hội chứng này do các đột biến cắt đuôi trong gen ADNP gây ra, gen này tham gia vào việc điều chỉnh nhiễm sắc thể. Chúng tôi giả thuyết rằng sự gián đoạn trong việc điều chỉnh nhiễm sắc thể có thể dẫn đến các mẫu metyl hóa DNA cụ thể có thể được sử dụng trong chẩn đoán phân tử hội chứng ADNP. Chúng tôi đã xác định hai episignature metyl hóa DNA genôm đặc trưng và một phần đối lập trong các mẫu máu ngoại vi của 22 bệnh nhân mắc hội chứng ADNP. Episignature “epi-ADNP-1” bao gồm khoảng 6000 CpG chủ yếu là hypomethylated, và episignature “epi-ADNP-2” bao gồm khoảng 1000 CpG chủ yếu là hypermethylated. Hai dấu hiệu này tương quan với vị trí của các đột biến ADNP. Các đột biến epi-ADNP-1 tập trung vào đầu N và đầu C, trong khi các đột biến epi-ADNP-2 nằm ở tín hiệu địa phương hóa hạt nhân. Các episignature này đều giàu gen liên quan đến sự phát triển và chức năng của hệ thần kinh. Một bộ phân loại được đào tạo dựa trên các hồ sơ này cho độ nhạy và độ đặc hiệu cao trong việc phát hiện bệnh nhân có một trong hai episignature. Áp dụng mô hình này cho bảy bệnh nhân có chẩn đoán lâm sàng không rõ ràng cho phép phân loại lại các biến thể gen có ý nghĩa không chắc chắn và chỉ định chẩn đoán mới khi nghi ngờ lâm sàng ban đầu không chính xác. Khi áp dụng cho một nhóm lớn bệnh nhân chưa được giải quyết với sự chậm phát triển (N = 1150), mô hình đã dự đoán ba bệnh nhân chưa được chẩn đoán trước đây có hội chứng ADNP. Kết quả giải trình tự DNA của những đối tượng này, nơi có thể, đã xác định các đột biến gây bệnh trong các miền gen được mô hình dự đoán. Chúng tôi mô tả tình trạng Mendelian đầu tiên với hai episignature đặc trưng do các đột biến trong một gen duy nhất gây ra. Những episignature metyl hóa DNA cực kỳ nhạy và đặc hiệu này cho phép chẩn đoán, sàng lọc và phân loại các biến thể gen trong hội chứng ADNP.

Từ khóa

#hội chứng ADNP #metyl hóa DNA #đột biến gen #chẩn đoán phân tử #chính xác gen

Tài liệu tham khảo

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