Genetic Sequencing in Rheumatology Save

Genetic sequencing as a research and diagnostic tool has expanded in medicine and rheumatology. An interesting review in Arthritis and Rheumatology suggests that despite currently modest use, there will be an expanded role for genetic sequencing in the field of rheumatology. 

Currently, genetic sequencing in rheumatology has been primarily used in diagnosing monogenic diseases or inborn errors of immunity, primarily in pediatric rheumatology.  There are nearly 500 monogenic diseases that can lead to immune dysregulation, immunodeficiency, autoimmunity, autoinflammation, allergic conditions, malignancies. 

The authors point out that patients with like genetic pathways may have divergent clinical phenotypes, especially with regard to symptoms, severity, etc. 

Pediatric rheumatologists can attest to the fact that monogenic diseases may masquerade as common rheumatologic conditions, such as FUO, arthritis and even relapsing polychondritis; the later sometimes being linked to the VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic mutation). 

More prevalent in the population, are genetic polymorphisms, with resultant polygenic disorders, like lupus or rheumatoid arthritis. Research on polygenic risk scores (PRS) and genome-wide association studies (GWAS) has advanced our understanding of many common diseases, such as venous thromboembolism (Factor V Leiden), cardiovascular risk assessments, etc. 

The authors postulate on the use of genetic risk assessment into routine clinical care, especially in rheumatology, which lags behind other specialties. Would PRS for ankylosing spondylitis be superior diagnostically when compared to HLA-B27 testing?  While the utility of PRS in the general population is likely to be limited given a low pre-test probability. They point out that "a rare disease having a prevalence of 0.1% in the general population, even an individual with a 10-fold increased risk would have an absolute risk of only 1%".

Other applications of PRS may include use in RA or preclinical RA, risk stratification in “undifferentiated connective tissue disease, examining the interplay between genetics and environmental factors. 

One of the challenges of genetic sequencing in clinical care would be the proper use and interpretation of results, that may require a multidisciplinary team (rheumatologist, immunogeneticists, genetic counselors). Such a team could facilitat patient and test selection, results interpretation, and subsequent clinical decision-making.

Will genetic sequencing be key to the future of precision rheumatology?