Ulcerative Colitis Resource Center

Ulcerative Colitis Resource Center

September 08, 2015
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Newly identified gene variants may contribute to development of very early onset IBD

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Researchers have identified novel gene variants that regulate B- and T-cell functions in patients with very early onset inflammatory bowel disease, which may contribute to disease development.

“There has been extensive research in the genes contributing to adult-onset IBD and in children aged 10 and older, but relatively little research has been performed in the very-early onset subtype of the disease,” Judith R. Kelsen, MD, from the Center for Pediatric IBD at The Children's Hospital of Philadelphia, said in a press release.

Judith R. Kelsen*

“Furthermore, she added, much of the previous work relied on genome-wide association studies (GWAS), which often do not find rare gene variants. The current study used newer technology, whole exome sequencing, which has revolutionized the ability to study rare gene variants,” the release said.

Kelsen and colleagues performed whole exome sequencing using DNA samples from 125 patients with IBD onset at age 5 years or younger (range, 3 weeks to 4 years; 84% younger than 2 years) and 19 parents (four with IBD) recruited at CHOP from March 2013 through July 2014. For controls, they also included exome samples from 45 pediatric patients with IBD (age of onset, 6-18 years), 20 patients with adult-onset Crohn’s disease and 145 healthy individuals obtained from the University of Kiel in Germany.

From the whole exome data, the researchers selected 400 genes and genomic regions associated with primary immunodeficiencies and related pathways, which covered around 6,500 coding exons totaling over 1 Mbp of coding sequence. Within these genes they identified novel and rare variants that may contribute to the development of very early onset IBD. These include rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19.

“Our findings reinforce other research that has revealed considerable overlap among genes involved in different immune-related diseases,” Kelsen said in the press release. “This overlap is reflected in the fact that [very early onset] IBD may be a form of primary immunodeficiency,” she said, adding that “she expects further whole-exome studies to identify additional immune-related gene variants and pathways.”

Furthermore, she said these findings highlight “the importance of doing complete immunological workups for these patients, in addition to IBD evaluations,” and sometimes a genetic workup, as well. “Evaluation and treatment guidelines are not yet standardized for children with very early-onset IBD, but we have found that this subtype of IBD is somewhat different from IBD that begins later. As we better understand the specific components of the immune system that may be involved in this disease, clinicians will be better prepared to individualize treatment to each patient.” – by Adam Leitenberger

Disclosure: The researchers report no relevant financial disclosures.

*Photo courtesy of The Children's Hospital of Philadelphia.