Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, disabling, and often misdiagnosed disease with symptoms including post-exertional malaise, fatigue, unrefreshing sleep, cognitive impairment, pain, and orthostatic intolerance. ME/CFS and Long COVID exhibit overlapping symptoms considered by many to be syndromic. Despite extensive research, no definitive cause, diagnostic test, or standardized treatment exists. Studies suggest immune, neurological, and metabolic mechanisms, though findings remain inconsistent. While significant heritability has been noted, genome-wide association studies (GWAS) have not yielded reproducible genetic associations.
We hypothesized that ME/CFS represents a group of diverse Mendelian disorders converging on a common presentation. We analysed whole genome and RNA sequencing data from a well-characterized ME/CFS pilot cohort (31 individuals), to identify variation and genotype-phenotype associations. In over 30% of participants, we identified the molecular etiology: known pathogenic variants with sufficient penetrance to account for all ME/CFS symptoms, impacted mitochondrial, metabolic, hemoglobin, solute transport, and immune function. Additional rare, potentially pathogenic or variants of uncertain significance in genes of interest emerged in many of the remaining participants. Expression changes supported genetic findings. Methods and findings will be presented.
Heterogeneity in ME/CFS has long suggested diverse mechanisms. Our findings reveal involvement of distinct genes and pathways, supporting the hypothesis that ME/CFS encompasses numerous genetically diverse disorders with converging symptoms and often overlapping cellular impact; likely contributing to the lack of statistically significant associations in GWAS.
By identifying definitive and candidate causal loci, this study represents a crucial step toward understanding, diagnosing, and treating the ~2% of the global population with ME/CFS (from SARS-CoV-2 or other causes). We also demonstrate the utility of omics-based precision medicine approaches, which are potentially applicable for other complex syndromes. Most importantly, these findings offer a path towards diagnosis and treatment for ME/CFS patients, many of whom have faced medical skepticism and decades-long diagnostic journeys.