Hội chứng Hyper-IgE do một biến thể nội vị đồng hợp mới và khó xác định trong DOCK8

Springer Science and Business Media LLC - Tập 42 - Trang 119-129 - 2021
Stuart G. Tangye1,2,3, Paul E. Gray3,4,5, Bethany A. Pillay1,2, Jin Yan Yap1,3, William A. Figgett1, John Reeves1,2, Sarah K. Kummerfeld1, Jennifer Stoddard6, Gulbu Uzel7, Huie Jing7, Helen C. Su7, Dianne E. Campbell8,9, Anna Sullivan3,10, Leslie Burnett1,2,3,9, Jane Peake3,10, Cindy S. Ma1,2,3
1Garvan Institute of Medical Research, Darlinghurst, Australia
2St Vincent’s Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia
3Clinical Immunogenomics Research Consortium of Australasia (CIRCA), Sydney, Australia
4Department of Immunology and Infectious Diseases, Sydney Children’s Hospital, Sydney, Australia
5School of Women's and Children's Health, UNSW Sydney, Sydney, Australia
6Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, USA
7Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA
8Department of Allergy and Immunology, Children's Hospital at Westmead, Westmead, Australia
9Sydney Medical School, University of Sydney, Sydney, Australia
10Queensland Children’s Hospital and University of Queensland, South Brisbane, Australia

Tóm tắt

Một số đột biến hiếm, đồng hợp làm mất chức năng trong DOCK8 dẫn đến một dạng suy giảm hệ miễn dịch kết hợp điển hình với các nhiễm trùng da nghiêm trọng và tái phát, eczema, dị ứng, và tính nhạy cảm với bệnh ác tính, cũng như suy giảm miễn dịch thể dịch và tế bào và tăng IgE. Sự ra đời của công nghệ giải trình tự thế hệ mới đã cho phép chẩn đoán phân tử nhanh chóng các bệnh di truyền hiếm gặp, bao gồm lỗi bẩm sinh của hệ miễn dịch. Những tiến bộ này đã dẫn đến việc áp dụng các phương pháp điều trị hướng dẫn bởi gen, chẳng hạn như ghép tế bào gốc huyết học cho sự thiếu hụt DOCK8. Tuy nhiên, các biến thể có thể gây bệnh được phát hiện bởi giải trình tự thế hệ mới cần phải được xác thực nghiêm ngặt để chứng minh tính gây bệnh. Ở đây, chúng tôi báo cáo việc chẩn đoán cuối cùng về sự thiếu hụt DOCK8 trong một gia đình có quan hệ huyết thống do một biến thể đồng hợp mới trong nội vị gây ra sự cắt ghép exon sai lệch và dẫn đến mất biểu hiện protein DOCK8. Đáng chú ý, biến thể gây bệnh không được phát hiện trong lần đầu tiên với giải trình tự toàn bộ bộ gen lâm sàng nhưng sau đó đã được xác định và xác thực bằng cách kết hợp phân tích gen nâng cao, phân tích RNA-seq và cytofluorometry. Trường hợp này nhấn mạnh sự cần thiết phải áp dụng các phương pháp xác thực đa chiều để giải quyết dứt điểm các trường hợp di truyền phức tạp phát sinh từ các biến thể ngoài các exon mã hóa protein và các vị trí cắt ghép thông thường.

Từ khóa

#DOCK8 #hội chứng Hyper-IgE #đột biến di truyền #giải trình tự thế hệ mới #thiếu hụt miễn dịch #cắt ghép exon

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