EpiSign International: Health System Impact Assessment and Expanding Clinical Utilization of Epi/Genomic Testing in Rare Diseases and Beyond

Rare diseases are conditions that affect fewer than 1 in 2,000 individuals and can be serious, chronic or life-threatening. Collectively, rare diseases affect an estimated 3.5-5.9% of the global population, corresponding to approximately 236-446 million people worldwide, with new rare disorders continuing to be identified. Prenatal environmental exposures and maternal conditions may also be considered in the differential diagnosis of rare genetic disorders, as these can affect foetal development. Such factors include exposure to drugs and medications, lifestyle factors such as alcohol consumption, infectious agents, and maternal conditions including diabetes mellitus and epilepsy.

Diagnostic assessment of patients with suspected rare disorders often includes chromosomal microarray analysis (CMA) to identify large structural copy number variations (CNVs), with an average diagnostic yield of approximately 10-15%. Where initial genomic testing is negative or inconclusive, further testing may include targeted gene panels, whole-exome sequencing (WES) or whole-genome sequencing (WGS). These approaches have substantially improved the diagnosis of rare diseases, but a significant proportion of patients remain unresolved following genomic testing. Some unresolved patients may have genetic variants of uncertain significance (VUS), while others may have disease-causing variants or disease mechanisms that are not readily identifiable using current genomic approaches.

Patients with rare diseases may experience prolonged diagnostic journeys, with delays of several years and, in some cases, decades. Recent studies suggest that approximately 25% of patients in the UK may wait between five and thirty years for a final diagnosis, while global estimates of diagnostic delay range from approximately five to twelve years, with some patients remaining undiagnosed for up to thirty years. This diagnostic odyssey can have significant consequences for patients and their families, as well as for healthcare systems. Establishing a molecular diagnosis can inform clinical management, particularly for patients with genetically heterogeneous disorders or atypical presentations. Earlier diagnosis may facilitate timely access to appropriate treatment, surveillance and support, including during critical periods of development, with the potential to improve patient outcomes.

There is therefore a need for additional cost-effective, sensitive and specific approaches that can support the diagnosis of patients who remain unresolved or have ambiguous findings following conventional genomic testing. Such approaches may be particularly valuable where genetic and environmental factors contribute to disease presentation, or where clinical features are atypical or overlap between multiple disorders.

Epigenomic approaches, and specifically DNA methylation analysis, provide one potential avenue for addressing this diagnostic gap. DNA methylation is a reversible epigenetic modification involving the addition of a methyl group to cytosine residues within CpG dinucleotides across the genome. DNA methylation has important roles in genomic imprinting, silencing of retroviral elements, regulation of tissue-specific gene expression, X-chromosome inactivation and chromatin structure. DNA methylation is also important during development, with dynamic changes in DNA methylation and demethylation contributing to the spatiotemporal regulation of gene expression, particularly during neuronal development.