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Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes

Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes
Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes
BACKGROUND: Multiple genes have been implicated by association studies in altering inflammatory bowel disease (IBD) predisposition. Paediatric patients often manifest more extensive disease and a particularly severe disease course. It is likely that genetic predisposition plays a more substantial role in this group.

OBJECTIVE: To identify the spectrum of rare and novel variation in known IBD susceptibility genes using exome sequencing analysis in eight individual cases of childhood onset severe disease.

DESIGN: DNA samples from the eight patients underwent targeted exome capture and sequencing. Data were processed through an analytical pipeline to align sequence reads, conduct quality checks, and identify and annotate variants where patient sequence differed from the reference sequence. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued.

RESULTS: Across the panel of 169 known IBD susceptibility genes, approximately 300 variants in 104 genes were found. Excluding splicing and HLA-class variants, 58 variants across 39 of these genes were classified as rare, with an alternative allele frequency of <5%, of which 17 were novel. Only two patients with early onset Crohn's disease exhibited rare deleterious variations within NOD2: the previously described R702W variant was the sole NOD2 variant in one patient, while the second patient also carried the L1007 frameshift insertion. Both patients harboured other potentially damaging mutations in the GSDMB, ERAP2 and SEC16A genes. The two patients severely affected with ulcerative colitis exhibited a distinct profile: both carried potentially detrimental variation in the BACH2 and IL10 genes not seen in other patients.

CONCLUSION: For each of the eight individuals studied, all non-synonymous, truncating and frameshift mutations across all known IBD genes were identified. A unique profile of rare and potentially damaging variants was evident for each patient with this complex disease.
0017-5749
977-984
Christodoulou, K.
6c678f2d-2c28-4077-b127-61c5cbcdb91b
Wiskin, A.E.
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Gibson, J.
855033a6-38f3-4853-8f60-d7d4561226ae
Tapper, W.
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Willis, C.
2c4f6481-4fd1-4833-80cf-e2dcb462fccc
Afzal, N.A.
5148f35e-6788-4dbd-a50f-c303a4948d60
Upstill-Goddard, R.
db6c4d69-2a08-4185-9fc8-cad65f27dde6
Holloway, J.W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Simpson, M.A.
5b8ababc-1421-44eb-8b14-e149beba801a
Beattie, R.M.
977a2f68-2bcf-4436-87e7-28a39952adda
Collins, A.
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Ennis, S.
7b57f188-9d91-4beb-b217-09856146f1e9
Christodoulou, K.
6c678f2d-2c28-4077-b127-61c5cbcdb91b
Wiskin, A.E.
2f0070e1-9a80-4856-8c5f-0c91c3d06260
Gibson, J.
855033a6-38f3-4853-8f60-d7d4561226ae
Tapper, W.
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Willis, C.
2c4f6481-4fd1-4833-80cf-e2dcb462fccc
Afzal, N.A.
5148f35e-6788-4dbd-a50f-c303a4948d60
Upstill-Goddard, R.
db6c4d69-2a08-4185-9fc8-cad65f27dde6
Holloway, J.W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Simpson, M.A.
5b8ababc-1421-44eb-8b14-e149beba801a
Beattie, R.M.
977a2f68-2bcf-4436-87e7-28a39952adda
Collins, A.
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Ennis, S.
7b57f188-9d91-4beb-b217-09856146f1e9

Christodoulou, K., Wiskin, A.E., Gibson, J., Tapper, W., Willis, C., Afzal, N.A., Upstill-Goddard, R., Holloway, J.W., Simpson, M.A., Beattie, R.M., Collins, A. and Ennis, S. (2013) Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes. Gut, 62 (7), 977-984. (doi:10.1136/gutjnl-2011-301833). (PMID:22543157)

Record type: Article

Abstract

BACKGROUND: Multiple genes have been implicated by association studies in altering inflammatory bowel disease (IBD) predisposition. Paediatric patients often manifest more extensive disease and a particularly severe disease course. It is likely that genetic predisposition plays a more substantial role in this group.

OBJECTIVE: To identify the spectrum of rare and novel variation in known IBD susceptibility genes using exome sequencing analysis in eight individual cases of childhood onset severe disease.

DESIGN: DNA samples from the eight patients underwent targeted exome capture and sequencing. Data were processed through an analytical pipeline to align sequence reads, conduct quality checks, and identify and annotate variants where patient sequence differed from the reference sequence. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued.

RESULTS: Across the panel of 169 known IBD susceptibility genes, approximately 300 variants in 104 genes were found. Excluding splicing and HLA-class variants, 58 variants across 39 of these genes were classified as rare, with an alternative allele frequency of <5%, of which 17 were novel. Only two patients with early onset Crohn's disease exhibited rare deleterious variations within NOD2: the previously described R702W variant was the sole NOD2 variant in one patient, while the second patient also carried the L1007 frameshift insertion. Both patients harboured other potentially damaging mutations in the GSDMB, ERAP2 and SEC16A genes. The two patients severely affected with ulcerative colitis exhibited a distinct profile: both carried potentially detrimental variation in the BACH2 and IL10 genes not seen in other patients.

CONCLUSION: For each of the eight individuals studied, all non-synonymous, truncating and frameshift mutations across all known IBD genes were identified. A unique profile of rare and potentially damaging variants was evident for each patient with this complex disease.

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e-pub ahead of print date: 28 April 2012
Published date: July 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 337649
URI: http://eprints.soton.ac.uk/id/eprint/337649
ISSN: 0017-5749
PURE UUID: 099bfbb6-45e3-4321-915e-a5b5bdb15830
ORCID for J. Gibson: ORCID iD orcid.org/0000-0002-0973-8285
ORCID for W. Tapper: ORCID iD orcid.org/0000-0002-5896-1889
ORCID for J.W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464
ORCID for A. Collins: ORCID iD orcid.org/0000-0001-7108-0771
ORCID for S. Ennis: ORCID iD orcid.org/0000-0003-2648-0869

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Date deposited: 01 May 2012 16:55
Last modified: 27 Oct 2023 01:44

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Contributors

Author: K. Christodoulou
Author: A.E. Wiskin
Author: J. Gibson ORCID iD
Author: W. Tapper ORCID iD
Author: C. Willis
Author: N.A. Afzal
Author: R. Upstill-Goddard
Author: J.W. Holloway ORCID iD
Author: M.A. Simpson
Author: R.M. Beattie
Author: A. Collins ORCID iD
Author: S. Ennis ORCID iD

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