Clinical and cellular phenotypes resulting from a founder mutation in IL10RB

Area of Science:

• Immunology
• Genetics
• Gastroenterology

Background:

• Inborn errors of immunity (IEI) are rare genetic disorders affecting immune system development and function.
• Immune dysregulation, autoimmunity, and autoinflammation are common in IEI.
• Very early onset inflammatory bowel disease (VEOIBD) can be caused by monogenic immune dysregulation disorders.

Purpose of the Study:

• To identify the genetic cause of VEOIBD in a patient.
• To characterize the immunophenotype associated with the identified genetic defect.
• To investigate the population genetics of the identified mutation.

Main Methods:

• Whole exome sequencing to identify genetic mutations.
• Cytometry by time-of-flight (CBTF) with a broad antibody panel to analyze immune cell populations.
• Haplotype analysis to determine the founder status and age of the mutation.

Main Results:

• A novel homozygous loss-of-function mutation in IL10RB was identified as the cause of VEOIBD.
• Immunophenotyping revealed reduced frequencies of CD4 and CD8 T cells, with additional defects in T helper cells, innate-like T cells, and memory B cells.
• The mutation was identified as a founder allele in an isolated indigenous population, with its age estimated through haplotype analysis.

Conclusions:

• Monogenic mutations in IL10RB can cause VEOIBD.
• The identified IL10RB mutation leads to significant defects in adaptive and innate immune cell populations.
• The founder status of the mutation in an isolated population provides insights into its prevalence and evolutionary history.