Targeted Gene Panel Sequencing for Early-onset Inflammatory Bowel Disease and Chronic Diarrhea

被引：25

作者：

Petersen, Britt-Sabina ^{[1
]}

August, Dietrich ^{[2
]}

Abt, Renate ^{[3
]}

Alddafari, Moudjahed ^{[4
]}

Atarod, Lida ^{[5
]}

Baris, Safa ^{[6
]}

Bhavsar, Hemant ^{[7
]}

Brinkert, Florian ^{[8
]}

Buchta, Mary ^{[2
]}

Bulashevska, Alla ^{[2
]}

Chee, Ronnie ^{[9
]}

Cordeiro, Ana I. ^{[10
,11
]}

Dara, Naghi ^{[12
]}

Duckers, Gregor ^{[13
]}

Elmarsafy, Aisha ^{[14
]}

Frede, Natalie ^{[2
]}

Galal, Nermeen ^{[14
]}

Gerner, Patrick ^{[15
]}

Glocker, Erik-Oliver ^{[16
,41
]}

Goldacker, Sigune ^{[2
]}

Hammermann, Jutta ^{[17
]}

Hasselblatt, Peter ^{[18
,19
]}

Havlicekova, Zuzana ^{[20
]}

Hubscher, Katrin ^{[2
]}

Jesenak, Milos ^{[20
]}

Karaca, Neslihan E. ^{[21
]}

Karakoc-Aydiner, Elif ^{[6
]}

Kharaghani, Mahboubeh M. ^{[22
]}

Kilic, Sara S. ^{[23
]}

Kiykim, Ayca ^{[6
]}

Klein, Christoph ^{[24
]}

Klemann, Christian ^{[25
,26
]}

Kobbe, Robin ^{[8
]}

Kotlarz, Daniel ^{[24
]}

Laass, Martin W. ^{[17
]}

Leahy, T. Ronan ^{[27
]}

Mesdaghi, Mehrnaz ^{[28
]}

Mitton, Sally ^{[29
,30
]}

Neves, Joao F. ^{[10
,11
]}

Ozturk, Birol ^{[31
]}

Pereira, Luis F. ^{[32
]}

Rohr, Jan ^{[2
]}

Restrepo, Jessica L. R. ^{[2
]}

Ruzaike, Gunda ^{[33
]}

Saleh, Nadia ^{[34
]}

Seneviratne, Suranjith ^{[35
]}

Senol, Ebru ^{[31
]}

Speckmann, Carsten ^{[2
]}

Tegtmeyer, Daniel ^{[15
]}

Thankam, Paul ^{[36
]}

机构：

[1] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[2] DZIF Satellite Ctr, Med Ctr, Fac Med, Ctr Chron Immunodeficiency, Braunschweig, Germany

[3] Klinikum Nurnberg, Paediat Gastroenterol, Nurnberg, Germany

[4] Univ Abou Bekr Belkaid Tlemcen, Lab Appl Mol Biol & Immunol, Tilimsen, Algeria

[5] Univ Tehran Med Sci, Dept Pediat, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran

[6] Marmara Univ, Pendik Training & Res Hosp, Clin Pediat Allergy & Immunol, Istanbul, Turkey

[7] Birmingham Childrens Hosp, Dept Gastroenterol & Clin Nutr, Birmingham, W Midlands, England

[8] Univ Med Ctr Hamburg Eppendorf, Dept Paediat, Hamburg, Germany

[9] Royal Free Hosp, Dept Immunol, London, England

[10] Pediat Univ Hosp, Hosp Dona Estefania, Primary Immunodeficiencies Unit, Lisbon, Portugal

[11] NOVA Med Sch, Chron Dis Res Ctr, CEDOC, Lisbon, Portugal

[12] Shahid Beheshti Univ Med Sci, Mofid Childrens Hosp, Dept Pediat Gastroenterol & Hepatol, Tehran, Iran

[13] Childrens Hosp, Helios Kliniken, Krefeld, Germany

[14] Cairo Univ, Fac Med, Pediat Dept, Cairo, Egypt

[15] Univ Freiburg, Paediat Gastroenterol Hepatol, Freiburg, Germany

[16] Univ Freiburg, Inst Med Microbiol & Hyg, Freiburg, Germany

[17] Tech Univ Dresden, Univ Med Ctr Dresden, Dept Pediat, Dresden, Germany

[18] Univ Freiburg, Univ Hosp, Dept Med 2, Freiburg, Germany

[19] Univ Freiburg, Fac Med, Freiburg, Germany

[20] Commenius Univ Bratislava, Jessenius Fac Med, Dept Paediat, Ctr Diag & Treatment Primary Immunodeficiencies, Martin, Slovakia

[21] Ege Univ, Dept Pediat, Fac Med, Izmir, Turkey

[22] Shahid Beheshti Univ Med Sci, Dept Allergy & Clin Immunol, Mofid Childrens Hosp, Tehran, Iran

[23] Uludag Univ, Fac Med, Pediat Immunol Div, Dept Pediat, Bursa, Turkey

[24] Ludwig Maximilians Univ Munchen, Dr Von Hauner Childrens Hosp, Dept Pediat, Munich, Germany

[25] Univ Freiburg, Fac Med, Ctr Chron Immunodeficiency, Med Ctr, Freiburg, Germany

[26] Univ Freiburg, Fac Med, Univ Med Ctr, Ctr Pediat,Dept Pediat Hematol & Oncol, Freiburg, Germany

[27] Our Ladys Childrens Hosp, Dept Paediat Immunol & Infect Dis, Dublin, Ireland

[28] Shahid Beheshti Univ Med Sci, Mofid Children Hosp, Dept Immunol, Tehran, Iran

[29] St Georges Healthcare NHS Trust, Dept Paediat Gastroenterol, London, England

[30] Univ London, London, England

[31] Marmara Univ, Med Fac, Dept Gastroenterol & Clin Nutr, Istanbul, Turkey

[32] San Pedro Alcantara Hosp, Serv Clin Lab, Div Immunol, Caceres, Spain

[33] Univ Freiburg, Div Pediat Hematol & Oncol, Bone Marrow Failure Grp, Freiburg, Germany

[34] Univ Bonn, Childrens Hosp, Bonn, Germany

[35] UCL, Inst Immun & Transplantat, Royal Free Campus, London, England

[36] Univ London, St Georges Hosp, Dept Paediat, London, England

[37] Univ Ziekenhuis Brussel, Dept Pediat, Brussels, Belgium

[38] Charite, Med Labor Berlin Charite Vivantes GmbH, Dept Immunol, Pediat Pneumol & Immunol, Berlin, Germany

[39] Tech Univ Dresden, Dept Med 1, Univ Med Ctr Dresden, Dresden, Germany

[40] Tech Univ Dresden, Ctr Regenerat Therapies, Dresden, Germany

[41] Brandenburg Hosp, Brandenburg Med Sch, Inst Lab Med, Brandenburg Havel, Germany

来源：

INFLAMMATORY BOWEL DISEASES | 2017年 / 23卷 / 12期

关键词：

early-onset IBD; infant colitis; chronic diarrhea; next-generation sequencing; genetic screening; immunodeficiency; WISKOTT-ALDRICH SYNDROME; DYSKERATOSIS-CONGENITA; HUMAN GENOME; MUTATIONS; VARIANTS; TELOMERE; PATHOGENICITY; PREVALENCE; DISORDERS; FRAMEWORK;

D O I：

10.1097/MIB.0000000000001235

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background: In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients. Methods: We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients. Results: Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients. Conclusions: Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers.

引用

页码：2109 / 2120

页数：12

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