Three researchers at the University of Alabama at Birmingham—Dr. Elizabeth Worthey (director of the Center for Computational Genomics and Data Science); Dr. Camille Birch (genome analyst); and Dr. Jarred Younger (director of the Neuro-inflammation, Pain and Fatigue Laboratory)—recently teamed up for an exciting study exploring whether genetic mutations cause some cases of ME/CFS. Earlier studies had produced conflicting results. Some concluded that some people are genetically predisposed to develop ME/CFS, while others did not. The team hypothesized that these conflicting results arise because ME/CFS is not actually a single disease but a collection of many distinct disorders, and that some of these distinct disorders are caused by distinct genetic variants. Instead of searching for a single genetic variant that causes ME/CFS, the researchers reasoned we should look for variants underlying each of the distinct disorders grouped under the ME/CFS classification.
To test their hypotheses, the team performed two unique analyses. First, they cataloged all possible symptom combinations qualifying for a diagnosis of ME/CFS. Incredibly, they found over 110,000 possible combinations. These combinations varied greatly; two people could share the ME/CFS diagnosis but still have very different symptoms. Among the combinations of symptoms, 135 matched symptoms of known monogenic diseases.[1] For example, one possible combination of ME/CFS symptoms matched symptoms of monogenic thyroid hormone metabolism disorders (caused by mutations in THRA or THRB).[2] Another combination matched those of fatty acid oxidation disorders (caused by mutations in HADHA or ACADM). This overlap in symptoms suggested that single-gene variants cause some cases of ME/CFS too.
In the second analysis, the team scrutinized genetic and clinical data of 31 people with ME/CFS, not with the intent of finding the same disease-driving variant in all people, but to find variants explaining each person’s unique set of ME/CFS symptoms. Twelve participants (39%) had variants that probably explained their symptoms. Variants included those corresponding to 14 genetic disorders, including those in ACADM and HADHA (causing fatty acid oxidation disorders); MYH7 (skeletal muscle disorders); ENO3 (glycogen storage disease); KCNJ18 (thyrotoxic periodic paralysis); SLC12A3 (Gitelman syndrome); and SPTA1 (erythrocyte disorders). These variants often impaired cellular metabolism, responses to stress, and post-exertional functions, consistent with the hallmark ME/CFS symptoms of chronic fatigue, cognitive dysfunction, and post-exertional malaise.
Overall, this study is important because it reframes ME/CFS as a collection of disorders, some driven by genetic variants or mutations. This is valuable because by knowing these variants (and their associated monogenetic disorders), we may understand how to treat patients (e.g., special diets for people with variants affecting fatty acid oxidation; beta-blockers for those with variants affecting thyroid function). We may also use this information for targeted recruitment for clinical trials (e.g., recruit people whose genetic variants suggest they will respond to specific interventions). The researchers acknowledged some limitations, including the small, racially homogenous cohort, and discussed the need for larger, more diverse studies. They also acknowledged funding from Solve (Dr. Worthey and Dr. Birch were Solve Ramsay Research Awardees in 2018, and Dr. Younger in 2016).
This study appeared in the Journal of Translational Medicine.
Why This Study Matters:
- Provides critical information for future clinical trials: Advances a new way of thinking about ME/CFS—not as a single disease, but as a collection of diseases, some driven by genetic variants. Shows how genotyping participants can help researchers recruit people who are more likely to respond to specific interventions.
- Lays the Groundwork for Preventative Treatments: Shows how specific interventions may help people with some types of genetically driven ME/CFS (e.g., special diets for people with genetic variants disrupting fatty acid oxidation).
- Centers Patient Experience: Explains why people with ME/CFS present such an extraordinarily diverse range of symptoms, emphasizing the complexity and diversity of this condition.
[1] In monogenic disorders, variants or mutations of a single gene cause the disease. For example, mutations in CFTR cause cystic fibrosis; mutations in HBB cause sickle cell disease; and mutations in DMD cause Duchenne muscular dystrophy.
[2] Gene names: ACADM, acyl-CoA dehydrogenase medium chain; CFTR, cystic fibrosis transmembrane conductance regulator; DMD, dystrophin; ENO3, enolase 3; HADHA, hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha; HBB, hemoglobin subunit beta; KCNJ18, potassium inwardly rectifying channel subfamily J member 18; MYH7, myosin heavy chain 7; SLC12A3, solute carrier family 12 member 3; SPTA1, spectrin alpha, erythrocytic 1; THRA, thyroid hormone receptor alpha; THRB, thyroid hormone receptor beta.
