Whole-exome sequencing reveals new variant linked to immunodeficiency


Using whole-exome sequencing, a previously unannotated gene variant involved in immune cell development has recently been uncovered. The results might lead to new therapies for patients with immunodeficiency diseases.

An international group of scientists headed up by Kaan Boztug from the CeMM Research Institute for Molecular Medicine of the Austrian Academy of Sciences published the results in the journal Nature Immunology.

Genetic variants are present in the population and can be either common or rare, both types influencing the health and disease of an individual.

The researchers studied a family with a rare genetic mutation affecting their immune system in which three of the six siblings died of a significant lack of white blood cells with another child fighting for his life with similar complications. Studying the 12-year-old who survived formed the crux of the research.

Using a genome-wide approach, the researchers harnessed a sequencing tool allowing all the exons (the segments of DNA that code for RNA and potentially protein) to be sequenced. They immediately detected a mutation in a gene called RASGRP1, which codes for a protein involved in white blood cell development.

The boy's parents were carriers of the life-threatening mutation since they both had a mutation in one copy of the RASGRP1 gene, meaning the child inherited two faulty copies and therefore presented with the disease condition that the parents avoided by having one healthy copy.

Detecting the downstream effects of the RASGRP1 mutation, the researchers found that two types of white blood cells, B and T, as well as the molecular architecture of natural killer (NK-) cells, were considerably altered by the lack of RASGRP1 in the patient.

Validating this observation in the lab, they showed that they could correct immune cell development in B and T cells by genetically restoring the expression of RASGRP1. They also showed that RASGRP1-deficient NK cells led to defective structure and function of these cells.

Finally, they showed that lenalidomide, a drug that targets RASGRP1, can reverse the effects of RASGRP1-deficient cells, suggesting such an approach could be an option for future patients with a similar genetic mutation.

"The whole process from the discovery of a gene defect as cause for a rare disease to the exploration of the disease-causing mechanism to the development of a personalized therapy does much more than helping the affected patients," said Boztug in a statement. "Virtually every case--such as the immunodeficiency of this young patient--provides profound new insights into the human organism and paves the way towards a future precision medicine."