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 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 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 , , , and .

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 may be of importance in Druze patients with Crohn's disease.