Giải trình tự toàn bộ exon trong ba gia đình có trường hợp bệnh sarcoidosis ở trẻ em

BMC Medical Genomics - Tập 11 - Trang 1-19 - 2018
Alain Calender1,2, Pierre Antoine Rollat Farnier3, Adrien Buisson1, Stéphane Pinson1, Abderrazzaq Bentaher2, Serge Lebecque4, Harriet Corvol5, Rola Abou Taam6, Véronique Houdouin7, Claire Bardel3, Pascal Roy3, Gilles Devouassoux8, Vincent Cottin9, Pascal Seve10, Jean-François Bernaudin11, Clarice X. Lim12, Thomas Weichhart12, Dominique Valeyre13,14, Yves Pacheco2, Annick Clement15, Nadia Nathan15
1Genetics Department, Hospices Civils de LYON (HCL), University Hospital, East Pathology Center, LYON, B-A3, BRON Cedex, France
2Inflammation & Immunity of the Respiratory Epithelium - EA7426 (PI3) – South Medical University Hospital – Lyon 1 Claude Bernard University, Pierre-Bénite, France
3Department of biostatistics, University Hospital, Hospices Civils de LYON (HCL), Lyon, France
4Cancer Research Center, INSERM U-1052, CNRS 5286, Lyon, France
5Pediatric pulmonology and Reference Center for rare lung diseases RespiRare, Hôpital Trousseau, AP-HP, INSERM UMR-S938, Sorbonne University, Paris, France
6Pediatric pulmonology and Reference Center for rare lung diseases RespiRare, Hôpital Necker, Paris, France
7Pediatric pulmonology and Reference Center for rare lung diseases RespiRare, Hôpital Robert Debré, INSERM U-1142, University Paris Diderot VII, Paris, France
8Department of Pulmonology, University Hospital, Hôpital Croix Rousse, Lyon, France
9Department of Pulmonology, University Hospital, Hôpital Louis Pradel, Lyon, France
10Department of Internal medicine, University Hospital, Hôpital Croix Rousse, Lyon, France
11Histology and Tumor Biology, ER2 UPMC, Hôpital Tenon, Paris, France
12Medical University of Vienna, Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Vienna, Austria
13EA2363, University Paris 13, Bobigny, France
14Assistance Publique Hôpitaux de Paris, Department of Pulmonology, Avicenne University Hospital, Bobigny, France
15AP-HP Pediatric pulmonology and Reference Center for rare lung diseases RespiRare, Hôpital Trousseau, INSERM UMR-S933, Sorbonne University, Paris, France

Tóm tắt

Sarcoidosis (OMIM 181000) là một rối loạn đa hệ thống dạng hạt có nguyên nhân chưa xác định. Mặc dù đã có nhiều nghiên cứu liên kết toàn bộ genome (GWAS), cho đến nay chưa xác định được con đường bệnh sinh chính nào. Để tìm ra các gen liên quan đến nguy cơ mắc sarcoidosis, chúng tôi đã tìm kiếm các đột biến de novo và lặn ở 3 trường hợp trẻ em mắc sarcoidosis và cha mẹ khỏe mạnh của chúng sử dụng phương pháp giải trình tự toàn bộ exon (WES). Từ dự án SARCFAM dựa trên một mạng lưới quốc gia thu thập các trường hợp gia đình mắc sarcoidosis, chúng tôi đã chọn ba gia đình (trio) trong đó có một trẻ em, mặc dù cha mẹ khỏe mạnh, nhưng đã phát triển bệnh trước tuổi 15. Mỗi trio đã được genotyped bằng WES (Illumina HiSEQ 2500) và chúng tôi đã chọn các biến thể gen phân ly như 1) đột biến mới chỉ xảy ra ở trẻ em bị ảnh hưởng và 2) như đặc tính lặn truyền từ mỗi cha mẹ. Các biến thể mã hóa được xác định đã được so sánh giữa ba gia đình. Tần suất alen và các kết quả chức năng in silico được phân tích bằng cách sử dụng các cơ sở dữ liệu ExAC, SIFT và Polyphenv2. Các nghiên cứu lâm sàng và di truyền đã được đăng ký bởi hệ thống Đăng ký và Kết quả Thử nghiệm Lâm sàng (ClinicalTrials.gov - Protocol Registration and Results System) dưới tham chiếu NCT02829853 và đã được phê duyệt bởi ủy ban đạo đức (CPP LYON SUD EST – 2 – REF IRB 00009118 – 21 tháng 9 năm 2016). Chúng tôi đã xác định 37 gen chia sẻ các biến thể mã hóa xảy ra như các đột biến lặn ở ít nhất 2 trio hoặc các đột biến de novo ở một trong ba trẻ em bị ảnh hưởng. Các gen này được phân loại theo vai trò tiềm năng của chúng trong các con đường liên quan đến miễn dịch: 9 gen liên quan đến quá trình tự thực bào và vận chuyển nội bào, 6 gen liên quan đến điều hòa protein G, 4 gen liên quan đến hoạt hóa tế bào T, 4 gen liên quan đến chu kỳ tế bào và khớp miễn dịch, 2 gen liên quan đến miễn dịch bẩm sinh. Mười trong số 37 gen đã được nghiên cứu theo cách thư mục để đánh giá liên kết chức năng với sarcoidosis. Phân tích toàn bộ exon của các trio cha mẹ-cá thể có ích trong việc xác định các gen làm tăng nguy cơ mắc các bệnh di truyền phức tạp như sarcoidosis. Dữ liệu của chúng tôi đã xác định 37 gen có thể liên quan đến một thể sarcoidosis ở trẻ em trong ba trio. Sự tập trung sâu vào 10 trong số 37 gen này có thể cho thấy rằng sự hình thành tổn thương đặc trưng trong sarcoidosis, granuloma, là kết quả của sự thiếu hụt kết hợp trong tự thực bào và vận chuyển nội bào (ví dụ: Sec16A, AP5B1 và RREB1), điều hòa protein G (ví dụ: OBSCN, CTTND2 và DNAH11), hoạt hóa tế bào T (ví dụ: IDO2, IGSF3), nguyên phân và/hoặc khớp miễn dịch (ví dụ: SPICE1 và KNL1). Ý nghĩa của những phát hiện này cần được xác nhận qua các thử nghiệm chức năng trên các biến thể gen được chọn.

Từ khóa

#sarcoidosis #rối loạn đa hệ thống #đột biến gen #giải trình tự toàn bộ exon #miễn dịch

Tài liệu tham khảo

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