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Identification of variants in genes associated with single gene inflammatory bowel disease by whole exome sequencing

Identification of variants in genes associated with single gene inflammatory bowel disease by whole exome sequencing
Identification of variants in genes associated with single gene inflammatory bowel disease by whole exome sequencing


Background: Most cases of inflammatory bowel disease (IBD) are caused by complex host–environment interaction. There are a number of conditions associated with a single-gene mutation, most cases are very early onset (aged < 6 yr), present with a unique form of disease and often have atypical features.

Methods: Whole-exome data for 147 pediatric patients with IBD were interrogated for a panel of 51 genes associated with monogenic IBD. Observed variation was categorized according to the American College of Medical Genetics (ACMG) guidelines to identify rare, novel, and known variants that might contribute to IBD.

Results: Five hundred seventy-four variants were identified across 51 genes. These were categorized in line with ACMG guidance to remove benign variants and to identify “pathogenic” and “likely pathogenic” variants. In 6 patients, we observed 6 pathogenic variants of which CYBA(c.287+2T>C), COL7A1(c.6501+1G>C), LIG4(p.R814X), and XIAP(p.T470S) were known causative mutations, and FERMT1(p.R271Q) and SKIV2L(c.354+5G>A) were novel. In the 3 patients with XIAP, SKIV2L, and FERMT1 variants, individuals' disease features resembled the monogenic phenotype. This was despite apparent heterozygous carriage of pathogenic variation for the latter 2 genes. The XIAP variant was observed in a hemizygous male.

Conclusions: Whole-exome sequencing allows for identification of known and de novo potentially causative mutations in genes associated with monogenic IBD. Although these are rare conditions, it is vital to identify causative mutations early to improve prognosis. We postulate that in a subset of IBD, heterozygous mutations (in genes believed to manifest IBD through autosomal recessive inheritance) may contribute to clinical presentation.
inflammatory bowel disease, paediatric, monogenic IBD, exome sequencing
2317-2327
Ashton, James
03369017-99b5-40ae-9a43-14c98516f37d
Andreoletti, Gaia
75cfc74e-f938-48c8-b3d5-5b377297d008
Coelho, Tracy
a78b627c-ea78-41e1-9553-0390921e3c93
Haggarty, Rachel
d79fd59d-2cdc-465a-93e4-b0aeb78583c6
Batra, Akshay
822f891e-87ca-41d9-b68d-27c395e88809
Afzal, Nadeem
5148f35e-6788-4dbd-a50f-c303a4948d60
Beattie, R. Mark
55d81c7b-08c9-4f42-b6d3-245869badb71
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Ashton, James
03369017-99b5-40ae-9a43-14c98516f37d
Andreoletti, Gaia
75cfc74e-f938-48c8-b3d5-5b377297d008
Coelho, Tracy
a78b627c-ea78-41e1-9553-0390921e3c93
Haggarty, Rachel
d79fd59d-2cdc-465a-93e4-b0aeb78583c6
Batra, Akshay
822f891e-87ca-41d9-b68d-27c395e88809
Afzal, Nadeem
5148f35e-6788-4dbd-a50f-c303a4948d60
Beattie, R. Mark
55d81c7b-08c9-4f42-b6d3-245869badb71
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9

Ashton, James, Andreoletti, Gaia, Coelho, Tracy, Haggarty, Rachel, Batra, Akshay, Afzal, Nadeem, Beattie, R. Mark and Ennis, Sarah (2016) Identification of variants in genes associated with single gene inflammatory bowel disease by whole exome sequencing. Inflammatory Bowel Diseases, 22 (10), 2317-2327. (doi:10.1097/MIB.0000000000000890). (PMID:27537055)

Record type: Article

Abstract



Background: Most cases of inflammatory bowel disease (IBD) are caused by complex host–environment interaction. There are a number of conditions associated with a single-gene mutation, most cases are very early onset (aged < 6 yr), present with a unique form of disease and often have atypical features.

Methods: Whole-exome data for 147 pediatric patients with IBD were interrogated for a panel of 51 genes associated with monogenic IBD. Observed variation was categorized according to the American College of Medical Genetics (ACMG) guidelines to identify rare, novel, and known variants that might contribute to IBD.

Results: Five hundred seventy-four variants were identified across 51 genes. These were categorized in line with ACMG guidance to remove benign variants and to identify “pathogenic” and “likely pathogenic” variants. In 6 patients, we observed 6 pathogenic variants of which CYBA(c.287+2T>C), COL7A1(c.6501+1G>C), LIG4(p.R814X), and XIAP(p.T470S) were known causative mutations, and FERMT1(p.R271Q) and SKIV2L(c.354+5G>A) were novel. In the 3 patients with XIAP, SKIV2L, and FERMT1 variants, individuals' disease features resembled the monogenic phenotype. This was despite apparent heterozygous carriage of pathogenic variation for the latter 2 genes. The XIAP variant was observed in a hemizygous male.

Conclusions: Whole-exome sequencing allows for identification of known and de novo potentially causative mutations in genes associated with monogenic IBD. Although these are rare conditions, it is vital to identify causative mutations early to improve prognosis. We postulate that in a subset of IBD, heterozygous mutations (in genes believed to manifest IBD through autosomal recessive inheritance) may contribute to clinical presentation.

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Accepted/In Press date: 9 June 2016
e-pub ahead of print date: 17 August 2016
Published date: October 2016
Keywords: inflammatory bowel disease, paediatric, monogenic IBD, exome sequencing
Organisations: Cancer Sciences, Human Development & Health, Medical Education

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Local EPrints ID: 396913
URI: https://eprints.soton.ac.uk/id/eprint/396913
PURE UUID: e33329ab-a065-4235-8e52-f8f47c5cfaa4
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869

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Date deposited: 15 Jun 2016 13:12
Last modified: 15 Aug 2019 05:26

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Contributors

Author: James Ashton
Author: Gaia Andreoletti
Author: Tracy Coelho
Author: Rachel Haggarty
Author: Akshay Batra
Author: Nadeem Afzal
Author: R. Mark Beattie
Author: Sarah Ennis ORCID iD

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