Genetic analysis of four consanguineous multiplex families with inflammatory bowel disease

Noam Ben-Yosef; Matthew Frampton; Elena R Schiff; Saleh Daher; Fadi Abu Baker; Rifaat Safadi; Eran Israeli; Anthony W Segal; Adam P Levine

doi:10.1093/gastro/goab007

Genetic analysis of four consanguineous multiplex families with inflammatory bowel disease

Gastroenterol Rep (Oxf). 2021 Jul 13;9(6):521-532. doi: 10.1093/gastro/goab007. eCollection 2021 Dec.

Authors

Noam Ben-Yosef^{1

2}, Matthew Frampton¹, Elena R Schiff³, Saleh Daher², Fadi Abu Baker⁴, Rifaat Safadi², Eran Israeli⁵, Anthony W Segal¹, Adam P Levine^{1

6}

Affiliations

¹ Centre for Molecular Medicine, Division of Medicine, University College London, London, UK.
² Institute of Gastroenterology and Liver disease, Hadassah Medical Center, Jerusalem, Israel.
³ Institute of Ophthalmology, Moorfields Eye Hospital, University College London, London, UK.
⁴ Institue of Gastroenterology and Hepatology, Hillel Yaffe Medical Center, Hadera, Israel.
⁵ Institute of Gastroenterology and Liver disease, E. Wolfson Medical Center, Holon, Israel.
⁶ Department of Pathology, University College London, London, UK.

Abstract

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.

Keywords: family study; genetics; homozygosity; inflammatory bowel disease.