Disruption during neurodevelopment can result in neurodevelopmental disorders (NDDs), which are characterised by a variety of clinical features, including intellectual disability and developmental delay. NDDs are often difficult to diagnose, owing to a large amount of phenotypic and genetic variability. As a result, many individuals do not have a genetic answer for their disorder.

To address this, the first part of this PhD involved analysing exome and genome sequencing to search for pathogenic variants in a cohort of patients who have microcephaly (reduced head size) and a combination of clinical phenotypes. This aim led to the identification of two variants in established disease genes, providing immediate answers for these families. A third variant was identified in a novel disease gene, MSL2, which encodes a subunit of the MSL complex, involved in chromatin modification and has now been published as part of an international collaboration.

The second part of this PhD involved investigating ELAV-Like 2 (ELAVL2), a gene previously identified for its crucial role in brain development. Currently, ELAVL2 has not yet been associated with NDDs. We have collated an international cohort of 15 patients who all have de novo variants in ELAVL2 and present with overlapping neurodevelopmental phenotypes. Six truncating variants and two larger-scale gene disruptions have been identified, confirming that haploinsufficiency for ELAVL2 is the likely disease mechanism. However, seven missense variants and a terminal exon frameshift required further molecular investigation. I hypothesised that these variants also act in a haploinsufficient manner, by disrupting the levels or function of ELAVL2. A cycloheximide chase assay was used to assess whether ELAVL2 variants reduce protein stability. Variants that did not decrease protein stability were studied for their impact on the ability of ELAVL2 to form a dimer, which is not well investigated.

My results support that variants in ELAVL2 cause a novel neurodevelopmental disorder, connecting this well-established neuronal protein with neurodevelopmental phenotypes in patients.

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Meeting ID: 977 5670 4741
Password: bioc