Whole genome of primary immunodeficiency patients provides new genetic information
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Whole genome sequencing reveals that primary immunodeficiency is characterized by some common genetic variants and suggests that the disorder might not be as mysterious as we thought.
Primary immunodeficiency (PID) is a broad term used to refer to a diverse group of disorders that negatively affect the immune system1. There are numerous types of disorders that primary immunodeficiency can lead to, each one impacting a specific immune function. These disorders can lead to recurring, life-threatening infections, autoimmunity, and cancers. While many severe forms of PID are identified during one’s childhood, most patients are adults who experienced symptom onset after their childhood years.2 This symptom onset in adults is often characterized as sporadic, with there being no clear family genetic history that would suggest the development of PID. While there is already a great phenotypic variance in PID, there are numerous genetic mechanisms that may lead to one specific manifestation of the disorder. The heterogeneity of PID provides an additional layer of complication when it comes to diagnoses and treatments3.
Currently, the genetic cause of PID has only been identified in 29% of patients. Those who present in adulthood with no clear family genetic history only make up a small portion of that percentage. The difficulty that comes with the identifying of each case of sporadic PID has led researchers to explore new genetic techniques that will help us learn more about the disorder. Whole genome sequencing (WGS) is one of these techniques that can be extremely beneficial in identifying genetic causes of disease. This comprehensive method gathers the entire sequence of an individual’s genome. This information can then be compared to an already available genome of reference to identify variants in the sequence that may be the cause of deficiency4.
To identify genetic variants that lead to PID, and get a better overall understanding of the specific genetic causes of the disorders, researchers performed whole genome sequencing on a large group of patients with different PID conditions. First, the authors looked at genes that were already known to be associated with PID. Of all the sequence variants that were seen on these associated genes, 67% had not been previously identified. Also, of all the gene variants that were analyzed, 34% showed a clinical presentation in patients that was different from the normally associated phenotype. This portion of the study provided further evidence for the necessity of whole genome sequencing to further investigate genotype-phenotype relationships related to PID.
Next, researchers looked for mutations on genes that were associated with PID. WGS allowed them to detect a deletion on a specific gene that resulted in compound heterozygosity. The deletion of these nucleotides resulted in two different, defective alleles that caused PID. Noncoding regions of the genome were also analyzed to see if they play a role in disorder.
Not only did whole genome sequencing allow authors to look at genes that were common to PID, it also allowed them to analyze noncoding regions of the genome to see if they impact disease outcome. Many noncoding regions of the genome are known to regulate gene functions even though the material is not creating proteins. The researchers found a deletion mutation in a noncoding region of PID patients. These two findings further emphasize the advantage that the WGS method has when trying to find genetic patterns associated with a disease or disorder.
WGS allowed for genome wide association studies to be performed in order to find further PID-genetic associations. The GWAS compared the genomes of PID patients to reference genomes in order to find disorder causing variants. At certain locations in the genome that were associated with immune function, PID patients had sequence variants that were not commonly seen. The GWAS also showed genetic variations that were responsible for specific types of PID. Sequencing the whole genome of PID patients allows for more insight into the genetic variations that cause the disorder. This method also gives us more clues about the patterns in which PID is passed through family members.
Addressing the question of inheritance is the most logical direction after this study. A family GWAS showed that the main genetic drivers of PID can vary between family members. A mother and son who with two different PID phenotypes were also heterozygous for two different genetic traits relating to the disorder. Why did the son have an even further mutated gene from the variant inherited from his mother? With this, his brother carried some of the same alleles of focus, but had a very different form of PID. There is still much to be learned about the genotype-phenotype relationship of PID. Research has shown that the genetic makeup of a person that presents a specific form of PID can heavily vary from what is expected. Hopefully, these whole genome sequencing techniques will provide a clearer genetic picture of PID, and will uncover all of the genetic variations that create the diversity of this disorder.
Whole genome sequencing provides more promise than ever before for the early detection and diagnosis of genetic defects. The way in which this method explores the noncoding region of the genome creates opportunities for new discoveries in lesser known sections of the genome. With this additional knowledge, better, more advanced treatment plans will eventually be developed to combat PID, and there is a much greater chance for the disorder to be identified in earlier stages. We could be closing in on these advancements, or they could lay far into the future, but it is now quite evident that whole genome sequencing creates a newfound hope when it comes to combating primary immunodeficiency.
Miles Davis is a Biology major at Davidson College in Davidson, NC. Contact him at midavis@davidsion.edu
REferences
1. McCusker, C. & Warrington, R. Primary immunodeficiency. Allergy Asthma Clin. Immunol. Off. J. Can. Soc. Allergy Clin. Immunol. 7, S11 (2011). https://doi.org/10.1186/1710-1492-7-S1-S11
2. Rosenberg, E., Dent, P. B. & Denburg, J. A. Primary Immune Deficiencies in the Adult: A Previously Underrecognized Common Condition. J. Allergy Clin. Immunol. Pract. 4, 1101–1107 (2016). https://doi.org/10.1016/j.jaip.2016.09.004
3. Derpoorter, C., Bordon, V., Laureys, G., Haerynck, F. & Lammens, T. Genes at the Crossroad of Primary Immunodeficiencies and Cancer. Front. Immunol. 9, (2018). https://doi.org/10.3389/fimmu.2018.02544
4. Ng, P. C. & Kirkness, E. F. Whole Genome Sequencing. in Genetic Variation: Methods and Protocols (eds. Barnes, M. R. & Breen, G.) 215–226 (Humana Press, 2010). https://doi.org/10.1007/978-1-60327-367-1_12
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