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Whole exome sequencing in three families segregating a pediatric case of sarcoidosis

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العنوان: Whole exome sequencing in three families segregating a pediatric case of sarcoidosis
المؤلفون: Alain Calender, Pierre Antoine Rollat Farnier, Adrien Buisson, Stéphane Pinson, Abderrazzaq Bentaher, Serge Lebecque, Harriet Corvol, Rola Abou Taam, Véronique Houdouin, Claire Bardel, Pascal Roy, Gilles Devouassoux, Vincent Cottin, Pascal Seve, Jean-François Bernaudin, Clarice X. Lim, Thomas Weichhart, Dominique Valeyre, Yves Pacheco, Annick Clement, Nadia Nathan, in the frame of GSF (Groupe Sarcoïdose France)
المصدر: BMC Medical Genomics, Vol 11, Iss 1, Pp 1-19 (2018)
بيانات النشر: BMC, 2018.
سنة النشر: 2018
المجموعة: LCC:Internal medicine
LCC:Genetics
مصطلحات موضوعية: Sarcoidosis, Whole-exome sequencing (WES), Candidate genes, Internal medicine, RC31-1245, Genetics, QH426-470
الوصف: Abstract Background Sarcoidosis (OMIM 181000) is a multi-systemic granulomatous disorder of unknown origin. Despite multiple genome-wide association (GWAS) studies, no major pathogenic pathways have been identified to date. To find out relevant sarcoidosis predisposing genes, we searched for de novo and recessive mutations in 3 young probands with sarcoidosis and their healthy parents using a whole-exome sequencing (WES) methodology. Methods From the SARCFAM project based on a national network collecting familial cases of sarcoidosis, we selected three families (trios) in which a child, despite healthy parents, develop the disease before age 15 yr. Each trio was genotyped by WES (Illumina HiSEQ 2500) and we selected the gene variants segregating as 1) new mutations only occurring in affected children and 2) as recessive traits transmitted from each parents. The identified coding variants were compared between the three families. Allelic frequencies and in silico functional results were analyzed using ExAC, SIFT and Polyphenv2 databases. The clinical and genetic studies were registered by the ClinicalTrials.gov - Protocol Registration and Results System (PRS) (https://clinicaltrials.gov) receipt under the reference NCT02829853 and has been approved by the ethical committee (CPP LYON SUD EST – 2 – REF IRB 00009118 – September 21, 2016). Results We identified 37 genes sharing coding variants occurring either as recessive mutations in at least 2 trios or de novo mutations in one of the three affected children. The genes were classified according to their potential roles in immunity related pathways: 9 to autophagy and intracellular trafficking, 6 to G-proteins regulation, 4 to T-cell activation, 4 to cell cycle and immune synapse, 2 to innate immunity. Ten of the 37 genes were studied in a bibliographic way to evaluate the functional link with sarcoidosis. Conclusions Whole exome analysis of case-parent trios is useful for the identification of genes predisposing to complex genetic diseases as sarcoidosis. Our data identified 37 genes that could be putatively linked to a pediatric form of sarcoidosis in three trios. Our in-depth focus on 10 of these 37 genes may suggest that the formation of the characteristic lesion in sarcoidosis, granuloma, results from combined deficits in autophagy and intracellular trafficking (ex: Sec16A, AP5B1 and RREB1), G-proteins regulation (ex: OBSCN, CTTND2 and DNAH11), T-cell activation (ex: IDO2, IGSF3), mitosis and/or immune synapse (ex: SPICE1 and KNL1). The significance of these findings needs to be confirmed by functional tests on selected gene variants.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1755-8794
Relation: http://link.springer.com/article/10.1186/s12920-018-0338-x; https://doaj.org/toc/1755-8794
DOI: 10.1186/s12920-018-0338-x
URL الوصول: https://doaj.org/article/4056fb49f80d4471b504aa3aa69fdf58
رقم الانضمام: edsdoj.4056fb49f80d4471b504aa3aa69fdf58
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:17558794
DOI:10.1186/s12920-018-0338-x