Rocca, Clarissa; (2025) Molecular and Computational Biology of Neurogenetic Disorders: Exploring Repeat Expansions, Voltage-Gated Calcium Channels, and SIRT6 Through Bioinformatic and Experimental Approaches. Doctoral thesis (Ph.D), UCL (University College London).

Text Clarissa Rocca - PhD Thesis - noSignatures.pdf - Accepted Version Access restricted to UCL open access staff until 1 August 2026. Download (23MB)

Abstract

Studying rare Mendelian disorders helps unravelling the genetic complexities of neurological diseases. In my work, I have focused on distinct genes and mechanisms, causing either neurodevelopmental or neurodegenerative disorders. Firstly, I explore short tandem repeats expansions, which are a major cause of neurological disease, using next generation sequencing databases, to help raise the diag- nostic yield of patients with genetically undiagnosed neurogenetic conditions. I analyse known disease-causing repeats in a cohort of neurological cases in an exome database, then I screen the Genomics England database for the repeat in NOP56, which causes spinocerebellar ataxia type 36, and identify the first British cohort affected by this condition. Then, I compare the diagnostic yield in research projects to standard diagnostic testing in the National Health Service leveraging the Genomics England database. This resource includes whole genome sequencing testing (including indications and outcomes) from patients with rare disease tests performed in research through the 100,000 Genomes Project, and in standard healthcare through the new Genomic Medicine Service. Here I highlight how learning from the 100,000 Genomes Project has informed the Genomic Medicine Service, resulting in higher diagnostic yields and earlier age at testing. Secondly, I functionally characterise variants found in CACNA1G and CACNA2D3, two genes that encode for voltage-gated calcium channels involved in the pathophysiology of cluster headache and neurodevelopmental delay. By using patch clamping on HEK-293 cells, I validate the function of missense variants, thereby expanding the clinical and functional spectrum of voltage-gated calcium channels. Thirdly, I study Drosophila melanogaster as an animal model to characterise biallelic mutations in the SIRT6 gene, in individuals presenting with neurodevelopmental delay seizures and intellectual disability. This model organism was used to investigate the role of the SIRT6 gene in neurodevelopment, and specifically the tissues that might have a higher requirement for this protein. The diverse methods used here advance our understanding of a group of neurological disorders caused by an array of gene defects that include point mutations, as well as repeat expansion defects.

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