Donna Brown, Camille Birch, Jarred Younger, Elizabeth Worthey UAB Medicine Link to the abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) also referred to as Systemic Exertion Intolerance Disease (SEID) or Chronic Fatigue Immune Dysfunction Syndrome, is a disabling and complex illness. It is characterized by unexplained and persistent post- exertional malaise (PEM) accompanied by a variety of symptoms related to cognitive, immunological, endocrinological, and autono- mous dysfunction. A hypothalamic–pituitary–adrenal network dis- ruption is often discussed as a probable focus for study. The disease predominantly affects adults, with a peak age of onset of between 20 and 45 years with a female-to-male ratio of up to 3:1. Post-exertional malaise, fibromyalgia, and weakness are regarded as the most salient features. After a long history of misdiagnosis of ME/CFS as: psychosis, cognitive conversion syndrome, hysteria, some sort of un-named autoimmune disease, hypochondria, depression, anxiety, among other entities, we and others have been working toward a more refined definition of ME/ CFS phenotypes. Currently, there exists at least 2 widely used diagnostic standards; the Canadian (Carruthers, 2011) and the CDC- 1994 criteria (Fukuda, 2004) for ME/CFS. The variety of diagnostic criteria result in a range of estimates of prevalence; most recently using the CDC-1994 criteria and meta-analysis the prevalence was assessed at 0.89% (Lim, 2020). Even with these standards in place, current patients can be misdiagnosed. Hypothesizing that ME/CFS is the result of an intrinsic genetic defect (s) and each patient is best considered individually, we performed whole genome sequencing (WGS) combined with informatics approaches to identify molecular variants of interest in a pilot cohort of ME/CFS patients. Among this pilot we identified a patient harboring a likely pathogenic ENO3 variant. Other variants in ENO3, the beta- enolase gene, are identified to be affected in patients with glycogen storage disease type 13 (GSD13), a rare autosomal recessive adult- onset disorder. Symptoms of GSD13 include exercise intolerance and muscle pains and it is thought to present with symptoms milder than other glycogen storage diseases. This patient reports feeling pain, spasms, and heaviness in her limbs (especially her legs), restricting her physical activity to once or twice a week, and has problems with concentration and other complaints typical of a subset of ME/CFS patients. It has been estimated that between 836,000 and 2.5 million Americans suffer from ME/CFS and yet little is known about the molecular underpinnings of disease. Clearly, the time has come to consider genomic sequencing as part of the standard of care to diagnose and classify these patients.