Salpietro Damiano, Vincenzo; (2024) Dissecting the Genetic Basis of Synaptic Transmission and Neurodevelopmental Disorders. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The understanding of synaptic transmission and its impact on human diseases has not yet been fully elucidated, especially in the case of neurodevelopmental disorders. In this work, I learnt two techniques that will help advance our understanding of these conditions: next-generation sequencing (NGS) technologies and functional studies aimed at validating rare disease-associated genetic variants. The goal of my work was to reach a genetic diagnosis in individuals affected by neuromuscular and neurodevelopmental conditions (Chapters 3 and 4), paroxysmal neurological disorders (Chapter 5), and genetic syndromes with associated severe neurodevelopmental impairment (Chapter 6). First, I describe the work performed to find the genetic cause of congenital myasthenic syndromes or neurodevelopmental disorders. My findings are: (i) VAMP1 (encoding synaptobrevin-1) is a gene causing congenital myasthenia; (ii) VAMP2 (encoding synaptobrevin-2) is a gene causing earlyinfantile neurodevelopmental impairment and seizures, and the disease mechanism involves abnormal fusion of synaptic vesicles. Second, I describe the work done on postsynaptic neurodevelopmental disorders with a focus on the AMPA receptor (AMPAR). My key findings are that GRIA2 (encoding the AMPAR GluA2 subunit) is a gene implicated in neurodevelopmental disorders that are frequently associated with epilepsy and behavioural problems, due to impaired GluA2 conductance. Third, I describe one of the largest cohorts of paroxysmal movement disorders with episodic ataxia (EA) to date, delineating the expanding EA-associated molecular and clinical spectrum and the work done on two novel genes, PDE2A and KCNA6, that were identified as a cause of different paroxysmal neurological disorders (i.e., paroxysmal dyskinesia and infantile seizures). Finally, I describe the work done to characterise ultra-rare genetic syndromes associated with neurodevelopmental impairment due to biallelic loss-of-function variants in DDX59 and GTPBP1/GTPBP2. I present my discoveries that will help me and my colleagues in the field to improve translational research for the benefit of patients and their families.

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