The Mosaic Brain: a New Diagnostic Approach in Focal Epilepsies

Overall, this observational cohort study aims to:

1. Improve our understanding of the genetic architecture of childhood focal epilepsies.
2. Develop a liquid biopsy of cerebrospinal fluid (CSF) and assess feasibility to detect cerebral mosaicism using cell-free DNA (cfDNA) analysis and evaluate its performance against brain tissue on the panel testing.
3. Develop a methodology to use trace tissue from Stereoelectroencephalography (SEEG) DNA and assess feasibility to detect cerebral mosaicism and evaluate its performance against brain tissue on the panel testing.

3. Validate the use of the liquid biopsy and SEEG trace tissue for use in the English National Health Service clinical services and share with other Genomic Laboratory Hubs.

Study Overview

• Status: Not yet recruiting
• Conditions: Epilepsy Intractable; Epilepsy in Children

Detailed Description

Epilepsy is characterised by recurrent epileptic seizures, and is the most common brain disease affecting children, significantly reducing their quality of life. Understanding the cause of epilepsy is key, as it can help doctors to identify the most effective treatment. This is an urgent issue as 30% of all children with epilepsy do not respond to currently available treatments.

In some children, seizures can start in an area of abnormal brain structure which can be removed with epilepsy surgery.

We see 150 children a year with epilepsy suspected to be caused by a brain lesion. As part of their evaluation, we do genetic testing in blood, as we know that changes in their DNA (mutations) can cause epilepsy in 30-40% of children.

It is now known that mutations are found in some areas of brain responsible for seizures but these are not present in the blood. This is mosaicism, when genetic variation affects only a subgroup of cells or tissues in an individual. Understanding these genetic changes in the brain tissue will help us understand how epilepsy starts and may help us design new treatments. Recently, we designed a new genetic test to pick up these mosaic mutations in brain tissue. However, current methods to detect mosaicism require the use of brain tissue, which limits testing to those children who qualify for surgery.

To expand testing to more children, without the need for surgery, we want to focus our work in using alternative samples, such as cell-free DNA cerebrospinal fluid (CSF) and trace-tissue DNA from trace cells collected from Stereoelectroencephalography (SEEG) electrodes.

We aim to further our understanding of brain mosaicism in epilepsy, using the current available tests, as well as aim to increase access to testing by developing methods to use samples collected using less invasive and pre-surgical methods.

• Study Type: Observational
• Enrollment (Estimated): 40

Contacts and Locations

• Study Contact: Name: Flavia Matos Santo, MSc; Phone Number: 4944 020 7405 9200; Email: flavia.matossanto@gosh.nhs.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

- Children in the epilepsy surgery service at GOSH.

Description

Inclusion Criteria:

• Children in the epilepsy surgery pathway at Great Ormond Street Hospital (GOSH) with a clear or suspected MRI lesion.
• All children undergoing SEEG at GOSH. Children for which consent was obtained from themselves or, if appropriate, from their legal representatives.
• Children in whom there are no clinical contraindication to having a lumbar puncture procedure pre-surgery.
• Both sexes.
• Under the age of 18.

Exclusion Criteria:

• Children that although undergoing epilepsy treatment or testing for an ischaemic lesion.
• Children with malignant brain tumours.
• Children in whom there are contraindications to performing a lumbar puncture procedure.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Measure concordance of genetic results for brain mosaicism testing between brain tissue and alternative samples.	24 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Present and compare DNA quality metrics from the several samples types using different methodologies and select the methods yielding better sample quality.	24 months
Measure concordance between variant allele frequency (VAF) from brain tissue mosaic genetic testing and VAF calculated using alternative samples.	24 months
Present and compare mosaic genetic variability results between alternative samples (cell-free DNA and trace tissue DNA) and peripheral blood DNA.	24 months
Present descriptive statistics detailing changes to patient management and genetic counselling directly resulting from a genetic mosaic diagnosis.	24 months

Collaborators and Investigators

• Sponsor: Institute of Child Health
• Collaborators: Great Ormond Street Hospital for Children NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2024
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: September 17, 2024
• First Submitted That Met QC Criteria: September 17, 2024
• First Posted (Estimated): September 19, 2024

Study Record Updates

• Last Update Posted (Estimated): September 19, 2024
• Last Update Submitted That Met QC Criteria: September 17, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Epilepsies, Partial; Drug Resistant Epilepsy
• Other Study ID Numbers: 23BM09

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No