Non-Invasive Multi-Modal Neuromonitoring in Adults Undergoing Extracorporeal Membrane Oxygenation - Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease that affects approximately 1.5 million people in the U.S. Evidence exists for a genetic component to ME/CFS based on familiality studies performed by us and others, as well as twin studies. While multiple candidate ME/CFS genes have been identified by candidate gene and genome-wide association studies, no validated functional ME/CFS variants have been identified. As there is strong evidence that ME/CFS is heritable, we plan to overcome the limitations of prior genetic studies by studying related ME/CFS cases in high-risk ME/CFS pedigrees, or individuals with likely a stronger genetic contribution to ME/CFS. We propose to identify rare, candidate ME/CFS variants using a family-based, discovery design defined by affected cousins. We will leverage high-risk ME/CFS pedigrees with a statistical excess of ME/CFS that we have identified in the Utah Population Database, a database that links genealogy data back to the 1800s to medical record data, to identify high-risk ME/CFS pedigrees that include an affected cousin pair. We will recruit 50 unique, affected cousin pairs (100 total subjects) as well as other affected family members. For the variant discovery phase, we will perform whole genome sequencing of the affected cousin pairs to identify shared, rare variants. We will then evaluate the identified genes and regulatory variants in other existing ME/CFS genetic data sets, including DecodeME and All of Us. We will test for segregation of biologically plausible variants in other affected relatives, examine the gene’s role in pathways with other ME/CFS candidate genes, perform in silico protein prediction of the identified candidates, and characterize the studied ME/CFS cases and their pedigrees for risk of ME/CFS associated comorbid conditions (e.g., fibromyalgia). Our expected outcome is the identification of a set of ME/CFS predisposition variants/genes with segregation evidence in the families in which they were observed and validation in other datasets. Study of familial ME/CFS cases complements prior genome-wide association studies (GWAS) through identification of rare variants that contribute to ME/CFS. Our work has the potential to enhance understanding of the pathophysiology of ME/CFS, and it has the strong likelihood of providing targets for ME/CFS treatment and earlier diagnosis of ME/CFS.
