EpiSign International: Expanding Epigenomic Testing in Rare Disease

The purpose of this study is to assess the utility of EpiSign software and an integrated DNA methylation and copy number variant (CNV) microarray technology in helping to diagnose individuals with rare diseases. EpiSign is a proprietary technology developed by EpiSign Inc. that uses DNA methylation patterns as biomarkers for rare diseases, including genetic disorders and conditions associated with environmental exposures. DNA methylation microarrays measure DNA methylation levels at specific locations across the genome. CNV microarray technology uses a similar approach to identify gains or losses of DNA. CNV microarray analysis is an established methodology used in the diagnosis of rare diseases. The first phase of the study will assess the utility of EpiSign analysis using standard EPIC DNA methylation microarrays as part of the diagnostic assessment of individuals with suspected rare diseases. The second phase will assess the utility of EpiSign analysis using newly developed integrated EPIC/CNV microarrays and evaluate the technical performance of these microarrays in detecting CNVs, as part of the diagnostic assessment of individuals with suspected rare diseases. Patients with suspected rare diseases will be recruited from Manchester University NHS Foundation Trust. Participants will provide a blood sample, which will be used to analyse their DNA methylation profile and detect CNVs. The study is expected to last approximately 24 months from study initiation.

Inclusion Criteria: * Eligible for, or have undergone, standard-of-care first-tier genetic testing at the participating site with a negative or inconclusive result. * No established molecular or clinical diagnosis explaining their presentation. * No diagnostic result from subsequent/reflex genetic testing available at enrolment. * For Phase 2 CNV-positive participants: have undergone standard-of-care CNV testing at the participating site and have a CNV reported by standard-of-care testing. * For Phase 2 first-tier participants: meet the Phase 1 inclusion criteria. * For Phase 2 CNV-positive participants, priority will be given to those with VUS, pathogenic/likely pathogenic, or other CNVs where EpiSign analysis may provide clinically relevant information. Exclusion Criteria: * Do not meet the applicable inclusion criteria. * Isolated, non-syndromic autism or isolated learning disability without additional features suggestive of a syndromic rare disorder.