A Multi-omics Investigation of Ring14

Awardee: Heather Mefford

Institution: St. Jude Children's Research Hospital

Grant Amount: $67,897.00

Funding Period: February 1, 2024 - January 31, 2025

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Summary:

Ring14 is an understudied and life-limiting rare chromosomal disorder with symptoms including severe and drug-resistant epilepsy, slow growth, low muscle tone, intellectual disability, and other multi-system health issues. For the last 10 years, the major hurdle in studying Ring14 has been the lack of a reliable model that accurately represents what is seen in individuals with Ring14 due to the unique structure and instability of the ring chromosome. Additionally, cellular models for neurological conditions do not always mirror the true biological state of the brain. Spatial transcriptomics is a new technology that combines brain imaging, gene sequencing, and cell characterization simultaneously to provide holistic biologic insight. In this collaborative study, we will perform spatial transcriptomics in brain tissue to directly and simultaneously study how Ring14 affects the cellular structure, organization, and gene expression in the brain. We will also study methylation – a biomarker for the regulation or turning on/off of genes – in multiple Ring14 patients and compare their methylation patterns with individuals with other chromosome 14 differences (i.e., deletions) and healthy individuals without epilepsy. Previous studies and karyotypes (chromosome genetic tests) have shown that the instability of the ring chromosome causes mosaicism in the body, meaning the ring chromosome is not present in all cells. So far, no study has been able to assess the extent of mosaicism in the most disease-relevant tissue, the brain. By evaluating the content of ring14 in brain tissue and integrating methylation and transcriptomic data, we will elucidate the unique biology and mechanisms of Ring14. Our study has the potential to inform future targeted therapeutic development for this devastating life-limiting condition.