Undiagnosed 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.

The primary purpose of this study is to discover new disease genes for rare Mendelian disorders and its secondary purpose include diagnosing people with rare genetic disorders that have not been previously diagnosed through conventional clinical means, learning more about the pathobiology of genetic disorders, and developing novel diagnostic technologies and analytics. 500 participants with undiagnosed and suspected genetic disorders will be recruited.

This study is designed to utilize whole exome and whole genome sequencing techniques to identify underlying genetic causes for undiagnosed disorders in the Plain Communities, and to do population genetic studies looking at genetic drift and founder mutations in this unique population.

General aim of the study is the improvement of the clinical knowledge of ultra-rare inherited metabolic and degenerative neurological diseases (prevalence less than 5:100,000) in adulthood through the systematic longitudinal collection of clinical, laboratory and instrumental data.