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Genetic Sequencing of Pediatric Patients Identifies Mutations in Monogenic Inflammatory Bowel Disease Genes that Translate to Distinct Clinical Phenotypes

Genetic Sequencing of Pediatric Patients Identifies Mutations in Monogenic Inflammatory Bowel Disease Genes that Translate to Distinct Clinical Phenotypes
Genetic Sequencing of Pediatric Patients Identifies Mutations in Monogenic Inflammatory Bowel Disease Genes that Translate to Distinct Clinical Phenotypes

OBJECTIVES: Monogenic inflammatory bowel disease (IBD) comprises rare Mendelian causes of gut inflammation, often presenting in infants with severe and atypical disease. This study aimed to identify clinically relevant variants within 68 monogenic IBD genes in an unselected pediatric IBD cohort. METHODS: Whole exome sequencing was performed on patients with pediatric-onset disease. Variants fulfilling the American College of Medical Genetics criteria as "pathogenic" or "likely pathogenic" were assessed against phenotype at diagnosis and follow-up. Individual patient variants were assessed and processed to generate a per-gene, per-individual, deleteriousness score. RESULTS: Four hundred one patients were included, and the median age of disease-onset was 11.92 years. In total, 11.5% of patients harbored a monogenic variant. TRIM22-related disease was implicated in 5 patients. A pathogenic mutation in the Wiskott-Aldrich syndrome (WAS) gene was confirmed in 2 male children with severe pancolonic inflammation and primary sclerosing cholangitis. In total, 7.3% of patients with Crohn's disease had apparent autosomal recessive, monogenic NOD2-related disease. Compared with non-NOD2 Crohn's disease, these patients had a marked stricturing phenotype (odds ratio 11.52, significant after correction for disease location) and had undergone significantly more intestinal resections (odds ratio 10.75). Variants in ADA, FERMT1, and LRBA did not meet the criteria for monogenic disease in any patients; however, case-control analysis of mutation burden significantly implicated these genes in disease etiology. DISCUSSION: Routine whole exome sequencing in pediatric patients with IBD results in a precise molecular diagnosis for a subset of patients with IBD, providing the opportunity to personalize therapy. NOD2 status informs risk of stricturing disease requiring surgery, allowing clinicians to direct prognosis and intervention.

1-11
Ashton, James
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Mossotto, Enrico
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Stafford, Imogen
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Haggarty, Rachel
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Coelho, Tracy
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Batra, Akshay
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Afzal, Nadeem A.
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Mort, Matthew
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Bunyan, David
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Beattie, R. Mark
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Ennis, Sarah
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Ashton, James
03369017-99b5-40ae-9a43-14c98516f37d
Mossotto, Enrico
a2a572db-3e95-41c6-94f6-f1b019594372
Stafford, Imogen
50987dc1-3772-408f-9093-9124f3d6b2cd
Haggarty, Rachel
d79fd59d-2cdc-465a-93e4-b0aeb78583c6
Coelho, Tracy
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Batra, Akshay
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Afzal, Nadeem A.
62505946-2503-42ba-9b02-85513bb3ec87
Mort, Matthew
fcdab88f-f80c-41c9-ad81-1aec03536b77
Bunyan, David
d57bd2a7-d531-4892-bcce-e096dc95eee7
Beattie, R. Mark
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Ennis, Sarah
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Ashton, James, Mossotto, Enrico, Stafford, Imogen, Haggarty, Rachel, Coelho, Tracy, Batra, Akshay, Afzal, Nadeem A., Mort, Matthew, Bunyan, David, Beattie, R. Mark and Ennis, Sarah (2020) Genetic Sequencing of Pediatric Patients Identifies Mutations in Monogenic Inflammatory Bowel Disease Genes that Translate to Distinct Clinical Phenotypes. Clinical and Translational Gastroenterology, 11 (2), 1-11, [e00129]. (doi:10.14309/ctg.0000000000000129).

Record type: Article

Abstract

OBJECTIVES: Monogenic inflammatory bowel disease (IBD) comprises rare Mendelian causes of gut inflammation, often presenting in infants with severe and atypical disease. This study aimed to identify clinically relevant variants within 68 monogenic IBD genes in an unselected pediatric IBD cohort. METHODS: Whole exome sequencing was performed on patients with pediatric-onset disease. Variants fulfilling the American College of Medical Genetics criteria as "pathogenic" or "likely pathogenic" were assessed against phenotype at diagnosis and follow-up. Individual patient variants were assessed and processed to generate a per-gene, per-individual, deleteriousness score. RESULTS: Four hundred one patients were included, and the median age of disease-onset was 11.92 years. In total, 11.5% of patients harbored a monogenic variant. TRIM22-related disease was implicated in 5 patients. A pathogenic mutation in the Wiskott-Aldrich syndrome (WAS) gene was confirmed in 2 male children with severe pancolonic inflammation and primary sclerosing cholangitis. In total, 7.3% of patients with Crohn's disease had apparent autosomal recessive, monogenic NOD2-related disease. Compared with non-NOD2 Crohn's disease, these patients had a marked stricturing phenotype (odds ratio 11.52, significant after correction for disease location) and had undergone significantly more intestinal resections (odds ratio 10.75). Variants in ADA, FERMT1, and LRBA did not meet the criteria for monogenic disease in any patients; however, case-control analysis of mutation burden significantly implicated these genes in disease etiology. DISCUSSION: Routine whole exome sequencing in pediatric patients with IBD results in a precise molecular diagnosis for a subset of patients with IBD, providing the opportunity to personalize therapy. NOD2 status informs risk of stricturing disease requiring surgery, allowing clinicians to direct prognosis and intervention.

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Accepted/In Press date: 3 January 2020
e-pub ahead of print date: 18 February 2020
Published date: 18 February 2020

Identifiers

Local EPrints ID: 436880
URI: http://eprints.soton.ac.uk/id/eprint/436880
PURE UUID: 3182ac73-e7c2-413e-a700-8a74424f7b12
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869

Catalogue record

Date deposited: 13 Jan 2020 17:31
Last modified: 26 Nov 2021 02:42

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Contributors

Author: James Ashton
Author: Enrico Mossotto
Author: Imogen Stafford
Author: Rachel Haggarty
Author: Tracy Coelho
Author: Akshay Batra
Author: Nadeem A. Afzal
Author: Matthew Mort
Author: David Bunyan
Author: R. Mark Beattie
Author: Sarah Ennis ORCID iD

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