Author(s):
Petersen, BS ; August, D ; Abt, R ; Alddafari, M ; Atarod, L ; Baris, S ; Bhavsar, H ; Brinkert, F ; Buchta, M ; Bulashevska, A ; Chee, R ; Cordeiro, AI ; Dara, N ; Dückers, G ; Elmarsafy, A ; Frede, N ; Galal, N ; Gerner, P ; Glocker, EO ; Goldacker, S ; Hammermann, J ; Hasselblatt, P ; Havlicekova, Z ; Hübscher, K ; Jesenak, M ; Karaca, NE ; Karakoc-Aydiner, E ; Kharaghani, MM ; Kilic, SS ; Kiykim, A ; Klein, C ; Klemann, C ; Kobbe, R ; Kotlarz, D ; Laass, MW ; Leahy, TR ; Mesdaghi, M ; Mitton, S ; Farela Neves, J ; Öztürk, B ; Pereira, LF ; Rohr, J ; Restrepo, JLR ; Ruzaike, G ; Saleh, N ; Seneviratne, S ; Senol, E ; Speckmann, C ; Tegtmeyer, D ; Thankam, P ; van der Werff ten Bosch, J ; von Bernuth, H ; Zeissig, S ; Zeissig, Y ; Franke, A ; Grimbacher, B
Date: 2017
Persistent ID: http://hdl.handle.net/10400.17/4726
Origin: Repositório do Centro Hospitalar de Lisboa Central, EPE
Subject(s): Child, Preschool; Child; Chronic Disease; Diarrhea / etiology*; Exome Sequencing; Genetic Predisposition to Disease*; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Infant, Newborn; Inflammatory Bowel Diseases / genetics*; Mutation; HDE PED
Description
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.
