EpiSign International: Expanding Epigenomic Testing in Rare Disease

NCT07839754 | Not Yet Recruiting

• 1 other identifier: IRAS 353927
• Study Type: observational
• Target: 192
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Congenital Abnormalities; Rare Disease; Undiagnosed Disease; Genetic Diseases, Inborn

Keywords

Rare Disease; DNA Methylation; Rare Diseases; Copy Number Variation; DNA methylation microarray; Epigenetics; EPIC microarray; Undiagnosed rare disease

Outcome Measures

Primary Outcomes (1)

• Additional diagnostic yield of EpiSign analysis

  Proportion (%) of participants for whom EpiSign identifies a relevant episignature that contributes to a molecular or clinical diagnosis.

  Following completion of relevant genetic and EpiSign testing and collection of clinical data, expected approximately 12-18 months after study initiation.

Secondary Outcomes (5)

• Change in clinical management following EpiSign analysis

  Following completion of relevant genetic and EpiSign testing and collection of clinical data, expected approximately 12-18 months after study initiation.

• Change in diagnostic pathway following EpiSign analysis

  Following completion of relevant genetic and EpiSign testing and collection of clinical data, expected approximately 12-18 months after study initiation.

• Time to diagnosis following EpiSign analysis

  Following completion of relevant genetic and EpiSign testing and collection of clinical data, expected approximately 12-18 months after study initiation.

• Additional diagnostic investigations prompted by EpiSign analysis

  Following completion of relevant genetic and EpiSign testing and collection of clinical data, expected approximately 12-18 months after study initiation.

• Genetic findings that would otherwise have remained unidentified

  Following completion of relevant genetic and EpiSign testing and collection of clinical data, expected approximately 12-18 months after study initiation.

Study Arms (2)

Phase 1: EpiSign with EPIC DNA Methylation Array

Participants undergoing standard-of-care first-tier genetic testing who remain without an established diagnosis will undergo DNA methylation analysis using the standard EPIC microarray. DNA methylation data will be analysed using EpiSign to assess for disease-associated episignatures. EpiSign results will be evaluated alongside clinical and genetic information to assess diagnostic and clinical utility.

Diagnostic Test: EpiSign analysis with EPIC DNA methylation microarray

Phase 2: Integrated EPIC/CNV Array and EpiSign

Participants will undergo analysis using a newly developed integrated EPIC/CNV microarray, which enables assessment of both genome-wide DNA methylation and copy number variation from a single array. DNA methylation data will be analysed using EpiSign to assess for disease-associated episignatures, while CNV data will be assessed to evaluate the technical performance and analytical yield of the integrated array for CNV detection.

Diagnostic Test: Integrated EPIC/CNV microarray with EpiSign analysis

Interventions

Integrated EPIC/CNV microarray with EpiSign analysis DIAGNOSTIC_TEST

Participants will undergo analysis using a newly developed integrated EPIC/CNV microarray capable of measuring genome-wide DNA methylation and detecting copy number variations from a single array. DNA methylation data will be analysed using EpiSign software to identify disease-associated episignatures. CNV data will be analysed to assess the technical performance and analytical yield of the integrated microarray for CNV detection. The study will also assess the potential utility of combining DNA methylation and CNV analysis within a single diagnostic assay.

Phase 2: Integrated EPIC/CNV Array and EpiSign

EpiSign analysis with EPIC DNA methylation microarray DIAGNOSTIC_TEST

Participants will undergo genome-wide DNA methylation analysis using the standard Illumina EPIC DNA methylation microarray. The resulting DNA methylation data will be analysed using EpiSign software to identify disease-associated DNA methylation episignatures. EpiSign results will be assessed alongside clinical and genetic information to determine the additional diagnostic yield and clinical utility of EpiSign analysis in patients with suspected rare disease.

Phase 1: EpiSign with EPIC DNA Methylation Array

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Individuals with suspected rare diseases undergoing diagnostic assessment at Manchester University NHS Foundation Trust. The study population includes patients who have no established molecular or clinical diagnosis explaining their presentation and who have either negative or inconclusive results from standard-of-care genetic testing or a reported copy number variant (CNV) requiring further assessment. Participants will be recruited into two study phases: Phase 1 includes individuals undergoing first-tier EpiSign assessment using a standard DNA methylation microarray, while Phase 2 includes individuals undergoing EpiSign assessment using an integrated DNA methylation/CNV microarray.

You may qualify if:

• 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 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.

You may not qualify if:

• Isolated, non-syndromic autism or isolated learning disability without additional features suggestive of a syndromic rare disorder.

Sponsors & Collaborators

• University of Manchester: lead

Study Sites (1)

Manchester Centre for Genomic Medicine, 6th Floor, St Mary's Hospital, Oxford Road

Manchester, UK, M13 9WL, United Kingdom

Location

Related Publications (5)

• Aref-Eshghi E, Bend EG, Colaiacovo S, Caudle M, Chakrabarti R, Napier M, Brick L, Brady L, Carere DA, Levy MA, Kerkhof J, Stuart A, Saleh M, Beaudet AL, Li C, Kozenko M, Karp N, Prasad C, Siu VM, Tarnopolsky MA, Ainsworth PJ, Lin H, Rodenhiser DI, Krantz ID, Deardorff MA, Schwartz CE, Sadikovic B. Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions. Am J Hum Genet. 2019 Apr 4;104(4):685-700. doi: 10.1016/j.ajhg.2019.03.008. Epub 2019 Mar 28.

  PMID: 30929737 BACKGROUND

• Levy MA, McConkey H, Kerkhof J, Barat-Houari M, Bargiacchi S, Biamino E, Bralo MP, Cappuccio G, Ciolfi A, Clarke A, DuPont BR, Elting MW, Faivre L, Fee T, Fletcher RS, Cherik F, Foroutan A, Friez MJ, Gervasini C, Haghshenas S, Hilton BA, Jenkins Z, Kaur S, Lewis S, Louie RJ, Maitz S, Milani D, Morgan AT, Oegema R, Ostergaard E, Pallares NR, Piccione M, Pizzi S, Plomp AS, Poulton C, Reilly J, Relator R, Rius R, Robertson S, Rooney K, Rousseau J, Santen GWE, Santos-Simarro F, Schijns J, Squeo GM, St John M, Thauvin-Robinet C, Traficante G, van der Sluijs PJ, Vergano SA, Vos N, Walden KK, Azmanov D, Balci T, Banka S, Gecz J, Henneman P, Lee JA, Mannens MMAM, Roscioli T, Siu V, Amor DJ, Baynam G, Bend EG, Boycott K, Brunetti-Pierri N, Campeau PM, Christodoulou J, Dyment D, Esber N, Fahrner JA, Fleming MD, Genevieve D, Kerrnohan KD, McNeill A, Menke LA, Merla G, Prontera P, Rockman-Greenberg C, Schwartz C, Skinner SA, Stevenson RE, Vitobello A, Tartaglia M, Alders M, Tedder ML, Sadikovic B. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders. HGG Adv. 2021 Dec 3;3(1):100075. doi: 10.1016/j.xhgg.2021.100075. eCollection 2022 Jan 13.

  PMID: 35047860 BACKGROUND

• Aref-Eshghi E, Kerkhof J, Pedro VP; Groupe DI France; Barat-Houari M, Ruiz-Pallares N, Andrau JC, Lacombe D, Van-Gils J, Fergelot P, Dubourg C, Cormier-Daire V, Rondeau S, Lecoquierre F, Saugier-Veber P, Nicolas G, Lesca G, Chatron N, Sanlaville D, Vitobello A, Faivre L, Thauvin-Robinet C, Laumonnier F, Raynaud M, Alders M, Mannens M, Henneman P, Hennekam RC, Velasco G, Francastel C, Ulveling D, Ciolfi A, Pizzi S, Tartaglia M, Heide S, Heron D, Mignot C, Keren B, Whalen S, Afenjar A, Bienvenu T, Campeau PM, Rousseau J, Levy MA, Brick L, Kozenko M, Balci TB, Siu VM, Stuart A, Kadour M, Masters J, Takano K, Kleefstra T, de Leeuw N, Field M, Shaw M, Gecz J, Ainsworth PJ, Lin H, Rodenhiser DI, Friez MJ, Tedder M, Lee JA, DuPont BR, Stevenson RE, Skinner SA, Schwartz CE, Genevieve D, Sadikovic B. Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders. Am J Hum Genet. 2020 Mar 5;106(3):356-370. doi: 10.1016/j.ajhg.2020.01.019. Epub 2020 Feb 27.

  PMID: 32109418 BACKGROUND

• Sadikovic B, Levy MA, Kerkhof J, Aref-Eshghi E, Schenkel L, Stuart A, McConkey H, Henneman P, Venema A, Schwartz CE, Stevenson RE, Skinner SA, DuPont BR, Fletcher RS, Balci TB, Siu VM, Granadillo JL, Masters J, Kadour M, Friez MJ, van Haelst MM, Mannens MMAM, Louie RJ, Lee JA, Tedder ML, Alders M. Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders. Genet Med. 2021 Jun;23(6):1065-1074. doi: 10.1038/s41436-020-01096-4. Epub 2021 Feb 5.

  PMID: 33547396 BACKGROUND

• Kerkhof J, Rastin C, Levy MA, Relator R, McConkey H, Demain L, Dominguez-Garrido E, Kaat LD, Houge SD, DuPont BR, Fee T, Fletcher RS, Gokhale D, Haukanes BI, Henneman P, Hilton S, Hilton BA, Jenkinson S, Lee JA, Louie RJ, Motazacker MM, Rzasa J, Stevenson RE, Plomp A, van der Laan L, van der Smagt J, Walden KK, Banka S, Mannens M, Skinner SA, Friez MJ, Campbell C, Tedder ML, Alders M, Sadikovic B. Diagnostic utility and reporting recommendations for clinical DNA methylation episignature testing in genetically undiagnosed rare diseases. Genet Med. 2024 May;26(5):101075. doi: 10.1016/j.gim.2024.101075. Epub 2024 Jan 18.

  PMID: 38251460 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Whole blood will be extracted and DNA extracted for EPIC array analysis. No blood will be retained.

MeSH Terms

Conditions

Rare Diseases; Undiagnosed Diseases; Genetic Diseases, Inborn; Congenital Abnormalities

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Siddharth Banka, MBBS, MRCPCH, CCT, PhD, Prof

  University of Manchester

  PRINCIPAL INVESTIGATOR

Central Study Contacts

James C McConnell, PhD

CONTACT

+441612765403; james.mcconnell@mft.nhs.uk

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Genomic Medicine and Rare Diseases

Study Record Dates

• First Submitted: September 4, 2026
• First Posted: September 24, 2026
• Study Start: October 1, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029
• Last Updated: September 24, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)