Genomics of Immune Diseases and New Therapies

Abstract

Genomic DNA sequencing technologies have been one of the great advances of the 21st century, having decreased in cost by seven orders of magnitude and opening up new fields of investigation throughout research and clinical medicine. Genomics coupled with biochemical investigation has allowed the molecular definition of a growing number of new genetic diseases that reveal new concepts of immune regulation. Also, defining the genetic pathogenesis of these diseases has led to improved diagnosis, prognosis, genetic counseling, and, most importantly, new therapies. We highlight the investigational journey from patient phenotype to treatment using the newly defined XMEN disease, caused by the genetic loss of the MAGT1 magnesium transporter, as an example. This disease illustrates how genomics yields new fundamental immunoregulatory insights as well as how research genomics is integrated into clinical immunology. At the end, we discuss two other recently described diseases, CHAI/LATAIE (CTLA-4 deficiency) and PASLI (PI3K dysregulation), as additional examples of the journey from unknown immunological diseases to new precision medicine treatments using genomics.

Keywords: biochemical; genomics; immune disorder; mechanism; targeted therapy.

Figure 1

The causes of variable penetrance and expressivity of disease gene mutations.

Figure 2

The bottleneck to genetic disease discovery is the biochemical and molecular validation of candidate disease variants obtained through next-generation DNA sequencing. Although computational methods can reduce and prioritize variants, further validation through direct experiments is required. The benefits of clinical application can only pertain once validation has been carried out.