Dataset Information

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

ABSTRACT:

Background and aims

An 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.

Methods

A 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.

Results

Molecular 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.

Conclusions

Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

SUBMITTER: Charbit-Henrion F

PROVIDER: S-EPMC6113703 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Charbit-Henrion Fabienne F Parlato Marianna M Hanein Sylvain S Duclaux-Loras Rémi R Nowak Jan J Begue Bernadette B Rakotobe Sabine S Bruneau Julie J Fourrage Cécile C Alibeu Olivier O Rieux-Laucat Frédéric F Lévy Eva E Stolzenberg Marie-Claude MC Mazerolles Fabienne F Latour Sylvain S Lenoir Christelle C Fischer Alain A Picard Capucine C Aloi Marina M Dias Jorge Amil JA Hariz Mongi Ben MB Bourrier Anne A Breuer Christian C Breton Anne A Bronsky Jiri J Buderus Stephan S Cananzi Mara M Coopman Stéphanie S Crémilleux Clara C Dabadie Alain A Dumant-Forest Clémentine C Gurkan Odul Egritas OE Fabre Alexandre A Fischer Aude A Diaz Marta German MG Gonzalez-Lama Yago Y Goulet Olivier O Guariso Graziella G Gurcan Neslihan N Homan Matjaz M Hugot Jean-Pierre JP Jeziorski Eric E Karanika Evi E Lachaux Alain A Lewindon Peter P Lima Rosa R Magro Fernando F Major Janos J Malamut Georgia G Mas Emmanuel E Mattyus Istvan I Mearin Luisa M LM Melek Jan J Navas-Lopez Victor Manuel VM Paerregaard Anders A Pelatan Cecile C Pigneur Bénédicte B Pais Isabel Pinto IP Rebeuh Julie J Romano Claudio C Siala Nadia N Strisciuglio Caterina C Tempia-Caliera Michela M Tounian Patrick P Turner Dan D Urbonas Vaidotas V Willot Stéphanie S Ruemmele Frank M FM Cerf-Bensussan Nadine N

Journal of Crohn's & colitis 20180801 9

<h4>Background and aims</h4>An 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.<h4>Methods</h4>A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working ...[more]

PMID: 29788237

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Project description:Background: Vedolizumab (vedo) is effective for induction and maintenance of remission in adults with inflammatory bowel disease (IBD). Pediatric data are still limited, especially for the youngest children with very early onset disease (VEO-IBD). The aim of this study was to assess the safety and efficacy of vedo in VEO-IBD. Methods: We performed a retrospective review of pediatric IBD patients with VEO-IBD (defined as aged <6 years) receiving vedo. Data on demographics, disease behavior, activity, and previous treatments/surgeries were collected. Disease activity was assessed using the pediatric Crohn's disease (CD) activity index (PCDAI) for CD or pediatric ulcerative colitis (UC) activity index (PUCAI) for UC. Primary outcome was clinical response after induction therapy with vedolizumab (4th dose week). It was defined as a decrease in PCDAI of at least 12.5 points between baseline and 4th dose week for CD, and a decrease in PUCAI of at least 20 points between baseline and this time for UC. Descriptive statistics were performed to analyze the data. Results: The study included 16 patients with VEO-IBD who have received vedo: 4/16 (25%) with CD, and 12/16 (75%) with UC at the median age of diagnosis 33.7 months (6.6 months-4.5 years). Median age at vedo initiation was 6.5 years (2.2-16.5 years). Among the analyzed individuals, 56.25% had failed more than one anti-tumor necrosis factor (TNF) alfa agent. Clinical response at 4th dose week was observed in 9/16 (56.3%) patients: mean baseline PCDAI score was 34.4 ± 1.9 and 10.6 ± 1.8 after induction therapy with vedo, while PUCAI score was 26 ± 6 vs. 18 ± 8, respectively. There was improvement in patients' nutritional state: at baseline 2/16 (12.5%) children had body mass index (BMI) below 1 percentile and no child had such BMI after induction therapy with vedo. No infusion reactions or serious adverse events/infections were reported. Conclusion: Vedolizumab is safe and effective in the medical management of pediatric patients with VEO-IBD.

Project description:Epilepsy is one of the most common childhood-onset neurological conditions with a genetic etiology. Genetic diagnosis provides potential for etiologically-based management and treatment. Existing research has focused on early-onset (<24 months) epilepsies; data regarding later-onset epilepsies is limited. The goal of this study was to determine the diagnostic yield of a clinically available epilepsy panel in a selected pediatric epilepsy cohort with epilepsy onset between 24-60 months of life and evaluate whether this approach decreases the age of diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2). Next-generation sequencing (NGS)-based epilepsy panels, including genes associated with epileptic encephalopathies and inborn errors of metabolism (IEMs) that present with epilepsy, were used. Copy-number variant (CNV) detection from NGS data was included. Variant interpretation was performed per American College of Medical Genetics and Genomics (ACMG) guidelines. Results are reported from 211 consecutive patients with the following inclusion criteria: 24-60 months of age at the time of enrollment, first unprovoked seizure at/after 24 months, and at least one additional finding such as EEG/MRI abnormalities, speech delay, or motor symptoms. Median age was 42 months at testing and 30 months at first seizure onset; the mean delay from first seizure to comprehensive genetic testing was 10.3 months. A genetic diagnosis was established in 43 patients (20.4%). CNVs were reported in 25.6% diagnosed patients; 27.3% of CNVs identified were intragenic. Within the diagnosed cohort, 11 (25.6%) patients were diagnosed with an IEM. The predominant molecular diagnosis was CLN2 (14% of diagnosed patients). For these patients, diagnosis was achieved 12-24 months earlier than reported by natural history of the disease. This study supports comprehensive genetic testing for patients whose first seizure occurs ≥ 24 months of age. It also supports early application of testing in this age group, as the identified diagnoses can have significant impact on patient management and outcome.

Dataset Information

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

Background and aims

Methods

Results

Conclusions

Publications

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

Similar Datasets

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