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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)521-532
Number of pages12
JournalGastroenterology Report
Issue number6
StatePublished - 1 Dec 2021
Externally publishedYes


  • family study
  • genetics
  • homozygosity
  • inflammatory bowel disease


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