Published online Sep 8, 2020. doi: 10.4292/wjgpt.v11.i4.69
Peer-review started: March 28, 2020
First decision: April 25, 2020
Revised: June 25, 2020
Accepted: August 15, 2020
Article in press: August 15, 2020
Published online: September 8, 2020
The existence of genetic anticipation, a phenomenon in which an inherited disorder manifests at a younger age and often more severely in offspring than in the affected parent, has been long disputed in inflammatory bowel disease (IBD). In the absence of the explanatory mechanism, it has been suggested that anticipation may result from observation bias. In monogenetic degenerative neurological disorders the mechanism for genetic anticipation was identified as unstable genomic triple repeats. In polygenic diseases, such as IBD, the complexity of multifactorial inheritance makes the identification of genetic mechanism very challenging. I Most recently, mutations in the telomerase reverse transcriptase, have been shown to lead to progressive telomere shortening, causing earlier onset of disease in successive generations with telemeropahities. Telomere length (TL) has also been found to be associated with severity of inflammation and colon cancer in IBD.
The role of TL in genetic anticipation of patients with IBD has not been studied.
In our study, the primary objective was to evaluate generational changes in TL in parent-child pairs of familial IBD, to determine the role of telomere shortening, and its potential implication as a mechanism of anticipation in familial IBD. The secondary objective focused on investigating potential candidate gene variants for autosomal inheritance in these multi-generation IBD families.
We studied three IBD families with multiple affected members in three successive generations. We determined TL in lymphocytes and granulocytes from peripheral blood of the affected members using flow cytometry and fluorescence in-situ hybridization (flow FISH). We also performed whole exome sequencing (WES) in the blood of all available family members and used PhenoDB to identify potential candidate gene variants for recessive or dominant modes of inheritance.
Out of twenty-four patients of European descent selected to participate in the study, eleven patients, eight parent-child pairs affected by IBD, were included in the genetic anticipation analysis. Median difference in age at diagnosis between two successive generations was 16.5 years, with earlier age at onset in the younger generations. Five patients were affected by ulcerative colitis, four patients by Crohn’s disease and two patients by IBD-Unclassified. In most of the affected members, the disease harbored similar gastrointestinal and extraintestinal involvement but was more aggressive among the younger generations. TL was not associated with earlier age at onset or with more severe disease in members of successive generations affected by IBD. NOD2 gene mutations were present in the Crohn’s affected patients of one family. However, no gene variants were identified as potential candidates for Mendelian inheritance.
The study represents the first evaluation of TL defects in genetic anticipation of IBD. Even though no association was found between TL and age at disease onset among members of successive generations, this pilot study is very valuable as an attempt to find the molecular mechanism of genetic anticipation in IBD.
While we have shown that genetic anticipation is unlikely to be the result of telomere shortening, our results do point the way to exploration of other mechanisms. Further studies to confirm our findings should address a larger population of familial IBD that likewise have strong evidence for anticipation among successive generations.