About my research
Chromatin regulators play a crucial role in controlling how our genome functions, and disruptions in these genes are known to cause a group of neurodevelopmental disorders called chromatinopathies. However, until recently, we lacked a comprehensive view of how often potentially damaging variants appear in these genes across large rare-disease and general-population cohorts.
During my PhD, I analysed a curated list of 924 chromatin-regulator genes to understand the burden and inheritance of protein-truncating and protein-altering variants (PTVs/PAVs). My goal was to identify both new diagnoses and candidate genes that may represent previously unrecognised chromatinopathies.
Using publicly available gene-constraint metrics and de novo variant enrichment analyses, we found that chromatin regulators are highly depleted for pathogenic variants in the general population but significantly enriched for de novo PTVs/PAVs in rare-disease cohorts. This contrast highlights how essential proper chromatin regulation is for healthy development. We also observed that patients carrying PTVs in these genes often presented with multi-systemic neurodevelopmental phenotypes, suggesting broad biological impact. Overall, our analyses led to 510 potential diagnoses spanning known and novel chromatinopathies, including five genes showing reduced penetrance, which has important implications for clinical interpretation.
Beyond variant analyses, we also investigated molecular changes in neuronal models of Kabuki Syndrome type 1 (KS1). By integrating H3K4me1 ChIP-seq and RNA-seq data, we identified disrupted pathways and regulatory regions consistently affected in KS1. These findings highlight potential therapeutic targets and provide new insight into disease mechanisms.
Journey to the viva
My PhD journey, though challenging at times, was filled with memorable moments that reinforced my commitment to an academic career. I loved collaborating with colleagues from diverse scientific and clinical backgrounds, which broadened my knowledge in many directions. While the fast pace of academic life was difficult at first, it strengthened my time-management and decision-making skills. Ultimately, this experience showed me that a PhD is not only about gaining academic and technical expertise, but also about personal growth.
Reflections on the PhD experience
The PhD has been an incredible opportunity for me to develop academically and personally. I was fortunate to create life-long connections with my colleagues and collaborators, as well as to introduce myself to the academic scene. I am very grateful for the support provided by my supervisory team consisting of Prof. Siddharth Banka, Dr. Adam Stevens and Prof. Sue Kimber. Furthermore, I will always remember the opportunities that have been given to me to present my research at the international-level conference around the world.
Future directions
I am excited to join Dr. Adam Stevens’s lab at the University of Manchester as a postdoctoral researcher in evolutionary and genomic modelling. My postdoctoral work will focus on uncovering genetic pathomechanisms of complex conditions using evolutionary genomics and mathematical prediction methods. I am confident that this research will shed light on the mechanisms underlying both complex and rare diseases.