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Genetic analysis of four consanguineous multiplex families with inflammatory bowel disease
BACKGROUND: Family studies support a genetic predisposition to inflammatory bowel diseases (IBD), but known genetic variants only partially explain the disease heritability. Families with multiple affected individuals potentially harbour rare and high-impact causal variants. Long regions of homozygo...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677555/ https://www.ncbi.nlm.nih.gov/pubmed/34925849 http://dx.doi.org/10.1093/gastro/goab007 |
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author | Ben-Yosef, Noam Frampton, Matthew Schiff, Elena R Daher, Saleh Abu Baker, Fadi Safadi, Rifaat Israeli, Eran Segal, Anthony W Levine, Adam P |
author_facet | Ben-Yosef, Noam Frampton, Matthew Schiff, Elena R Daher, Saleh Abu Baker, Fadi Safadi, Rifaat Israeli, Eran Segal, Anthony W Levine, Adam P |
author_sort | Ben-Yosef, Noam |
collection | PubMed |
description | BACKGROUND: Family studies support a genetic predisposition to inflammatory bowel diseases (IBD), but known genetic variants only partially explain the disease heritability. Families with multiple affected individuals potentially harbour rare and high-impact causal variants. Long regions of homozygosity due to recent inbreeding may increase the risk of individuals bearing homozygous loss-of-function variants. This study aimed to identify rare and homozygous genetic variants contributing to IBD. METHODS: Four families with known consanguinity and multiple cases of IBD were recruited. In a family-specific analysis, we utilised homozygosity mapping complemented by whole-exome sequencing. RESULTS: We detected a single region of homozygosity shared by Crohn's disease cases from a family of Druze ancestry, spanning 2.6 Mb containing the NOD2 gene. Whole-exome sequencing did not identify any potentially damaging variants within the region, suggesting that non-coding variation may be involved. In addition, affected individuals in the families harboured several rare and potentially damaging homozygous variants in genes with a role in autophagy and innate immunity including LRRK1, WHAMM, DENND3, and C5. CONCLUSION: This study examined the potential contribution of rare, high-impact homozygous variants in consanguineous families with IBD. While the analysis was not designed to achieve statistical significance, our findings highlight genes or loci that warrant further research. Non-coding variants affecting NOD2 may be of importance in Druze patients with Crohn's disease. |
format | Online Article Text |
id | pubmed-8677555 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-86775552021-12-17 Genetic analysis of four consanguineous multiplex families with inflammatory bowel disease Ben-Yosef, Noam Frampton, Matthew Schiff, Elena R Daher, Saleh Abu Baker, Fadi Safadi, Rifaat Israeli, Eran Segal, Anthony W Levine, Adam P Gastroenterol Rep (Oxf) Original Articles BACKGROUND: Family studies support a genetic predisposition to inflammatory bowel diseases (IBD), but known genetic variants only partially explain the disease heritability. Families with multiple affected individuals potentially harbour rare and high-impact causal variants. Long regions of homozygosity due to recent inbreeding may increase the risk of individuals bearing homozygous loss-of-function variants. This study aimed to identify rare and homozygous genetic variants contributing to IBD. METHODS: Four families with known consanguinity and multiple cases of IBD were recruited. In a family-specific analysis, we utilised homozygosity mapping complemented by whole-exome sequencing. RESULTS: We detected a single region of homozygosity shared by Crohn's disease cases from a family of Druze ancestry, spanning 2.6 Mb containing the NOD2 gene. Whole-exome sequencing did not identify any potentially damaging variants within the region, suggesting that non-coding variation may be involved. In addition, affected individuals in the families harboured several rare and potentially damaging homozygous variants in genes with a role in autophagy and innate immunity including LRRK1, WHAMM, DENND3, and C5. CONCLUSION: This study examined the potential contribution of rare, high-impact homozygous variants in consanguineous families with IBD. While the analysis was not designed to achieve statistical significance, our findings highlight genes or loci that warrant further research. Non-coding variants affecting NOD2 may be of importance in Druze patients with Crohn's disease. Oxford University Press 2021-07-13 /pmc/articles/PMC8677555/ /pubmed/34925849 http://dx.doi.org/10.1093/gastro/goab007 Text en © The Author(s) 2021. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Ben-Yosef, Noam Frampton, Matthew Schiff, Elena R Daher, Saleh Abu Baker, Fadi Safadi, Rifaat Israeli, Eran Segal, Anthony W Levine, Adam P Genetic analysis of four consanguineous multiplex families with inflammatory bowel disease |
title | Genetic analysis of four consanguineous multiplex families with inflammatory bowel disease |
title_full | Genetic analysis of four consanguineous multiplex families with inflammatory bowel disease |
title_fullStr | Genetic analysis of four consanguineous multiplex families with inflammatory bowel disease |
title_full_unstemmed | Genetic analysis of four consanguineous multiplex families with inflammatory bowel disease |
title_short | Genetic analysis of four consanguineous multiplex families with inflammatory bowel disease |
title_sort | genetic analysis of four consanguineous multiplex families with inflammatory bowel disease |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677555/ https://www.ncbi.nlm.nih.gov/pubmed/34925849 http://dx.doi.org/10.1093/gastro/goab007 |
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