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

Petersen, Britt Sabina; August, Dietrich; Abt, Renate; Al-Ddafari, Moudjahed Saleh; Atarod, Lida; Barış, Safa; Bhavsar, Hemant; Brinkert, Florian; Buchta, Mary; Bulashevska, Alla; Chee, Ronnie; Cordeiro, Ana Isabel; Dara, Naghi; Dückers, Gregor; Elmarsafy, Aisha; Frede, Natalie; Galal, Nermeen; Gerner, Patrick; Glocker, Erik; Goldacker, Sigune; Hammermann, J.; Hasselblatt, Peter; Havlíčeková, Zuzana; Hübscher, Katrin; Jeseňák, Miloš; Karaca, Neslihan Edeer; Karakoç-Aydıner, Elif; Kharaghani, Mahboubeh M.; Kılıç, Sara Şebnem; Kıykım, Ayça; Klein, Christoph; Klemann, Christian; Kobbe, Robin; Kotlarz, Daniel; Laaß, Martin W.; Leahy, T. Ronan; Mesdaghi, Mehrnaz; Mitton, Sally G.; Neves, João Farela; Öztürk, Birol; Pereira, Luis F.; Rohr, Jan; Restrepo, Jessica L.R.; Ruzaike, Gunda; Saleh, Nadia; Seneviratne, Suranjith L.; Şenol, Ebru; Speckmann, Carsten; Tegtmeyer, Daniel; Paul, Thankam; Bosch, Jutte van der Werff ten; Bernuth, Horst von; Zeißig, Sebastian; Zeißig, Yvonne; Franke, André; Grimbacher, Bodo

doi:10.1097/mib.0000000000001235

Cited by 25 publications

(17 citation statements)

References 47 publications

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“…Nonetheless, one needs to analyse separately patients who benefited from TNGS as a first screening test [13 molecular diagnoses out of 49 patients, 26.5%] and patients who were functionally tested [eight molecular diagnoses out of 77 patients, 10%]. Altogether our findings confirm and extend results obtained in two previous studies in smaller cohorts of VEO-IBD patients, in which TNGS could identify causative mutations in 4/25 1 and in 5/71 patients, 14 respectively. Furthermore, in patients with higher genetic heterogeneity such as those with isolated colitis, TNGS is more efficient [68% of monogenic defects were identified by TNGS in this group] as it can reveal diagnosis in patients with atypical clinical presentation, as exemplified in the present study in one girl with XIAP deficiency.…”

Section: Discussionsupporting

confidence: 86%

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Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study

Charbit‐Henrion

Parlato

Hanein

et al. 2018

Journal of Crohn's and Colitis

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Background and AimsAn expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment.MethodsA total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally.ResultsMolecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES.ConclusionsOur results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

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Section: Discussionsupporting

confidence: 86%

“… 9 , 12 , 13 More recently, TNGS could identify causative mutations in small cohorts of VEO-IBD patients. 1 , 14 …”

Section: Introductionmentioning

confidence: 99%

Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study

Charbit‐Henrion

Parlato

Hanein

et al. 2018

Journal of Crohn's and Colitis

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“…Indeed, the huge amount of retrieved data and the risk of incidental findings in other non-PID genes involved in different monogenic or multifactorial pathologies may be confounding and do not corresponding to the first suspicion. Additionally, the confidence of the results decreases with the number of targeted genes and may preclude any variant detection in self-evident known genes (65). Many previously undetected variants do not have a well-defined role in our genome (1.5 × 10 6 million variants in each genome and lesser in exome).…”

Section: Discussionmentioning

confidence: 99%

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

et al. 2019

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Background: Primary Immunodeficiencies (PIDs) are a heterogeneous group of genetic immune disorders. While some PIDs can manifest with more than one phenotype, signs, and symptoms of various PIDs overlap considerably. Recently, novel defects in immune-related genes and additional variants in previously reported genes responsible for PIDs have been successfully identified by Next Generation Sequencing (NGS), allowing the recognition of a broad spectrum of disorders. Objective: To evaluate the strength and weakness of targeted NGS sequencing using custom-made Ion Torrent and Haloplex (Agilent) panels for diagnostics and research purposes. Methods: Five different panels including known and candidate genes were used to screen 105 patients with distinct PID features divided in three main PID categories: T cell defects, Humoral defects and Other PIDs . The Ion Torrent sequencing platform was used in 73 patients. Among these, 18 selected patients without a molecular diagnosis and 32 additional patients were analyzed by Haloplex enrichment technology. Results: The complementary use of the two custom-made targeted sequencing approaches allowed the identification of causative variants in 28.6% ( n = 30) of patients. Twenty-two out of 73 (34.6%) patients were diagnosed by Ion Torrent. In this group 20 were included in the SCID/CID category. Eight out of 50 (16%) patients were diagnosed by Haloplex workflow. Ion Torrent method was highly successful for those cases with well-defined phenotypes for immunological and clinical presentation. The Haloplex approach was able to diagnose 4 SCID/CID patients and 4 additional patients with complex and extended phenotypes, embracing all three PID categories in which this approach was more efficient. Both technologies showed good gene coverage. Conclusions: NGS technology represents a powerful approach in the complex field of rare disorders but its different application should be weighted. A relatively small NGS target panel can be successfully applied for a robust diagnostic suspicion, while when the spectrum of clinical phenotypes overlaps more than one PID an in-depth NGS analysis is required, including also whole exome/genome sequencing to identify the causative gene.

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“…4,13 Petersen et al reported that targeted gene panel sequencing revealed monogenic disease in 5 of 71 patients with earlyonset inflammatory bowel disease and chronic diarrhea. 14 In another large cohort of inflammatory bowel disease patients presenting before 2 years of age, 31% of 62 patients had monogenic diseases. 15 In our study, the diagnostic rates were 71.9% (46/64) for targeted gene panel sequencing and 57.5% (42/73) for exome sequencing (p = 0.081).…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic spectrum of children with congenital diarrhea and enteropathy in China

Huang

Zheng

Wang

et al. 2019

Genetics in Medicine

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Purpose: Genetic sequencing for children with congenital diarrhea and enteropathy (CODE) has important implications for the diagnosis, prognosis, and implementation of precision medicine. Methods: We performed exome sequencing or targeted panel sequencing on 137 children with CODE. Endoscopic, imaging, histological, and immunological assessments were also applied. Patients were divided into three subgroups: watery, fatty, and bloody diarrhea. Results: The median age of onset among patients was 28.0 (interquartile range: 7.5-120.0) days. Genetic diagnosis was achieved in 88/137 (64.2%) of patients. The diagnostic rate was significantly higher in the neonatal group than in the group of patients who had disease onset within 2 years of age (p = 0.033). The diagnostic rates were 71.9% (46/64) for targeted gene panel sequencing and 57.5% (42/73) for exome sequencing (p = 0.081). We identified pathogenic variants in 17 genes. Based on genetic sequencing, 59.9% of patients were diagnosed with medically actionable disorders. Precision medicine was carried out by means of hematopoietic stem cell transplantation for patients with IL10RA, CYBB, or FOXP3 deficiency; pancreatic enzyme replacement for patients with SBDS or UBR1 deficiency; and a special diet for patients with SLC5A1 deficiency. The overall mortality rate was 14.6%. Conclusion: Single-gene disorders are common among CODE patients. Genetic diagnosis can improve therapy by enabling precision medicine.

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

Abstract: 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.

Cited by 25 publications

References 47 publications

Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study

Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

Clinical and genetic spectrum of children with congenital diarrhea and enteropathy in China

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