Paediatrics (RCH) - Theses

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Author: Coleman, Matthew John × Subject: Paediatric ×

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    Investigating the molecular basis of brain malformations causing severe infantile epilepsies
    Coleman, Matthew John ( 2023-08)
    Malformations of cortical development (MCD) encompass a wide spectrum of conditions that result from abnormal brain development, including polymicrogyria, periventricular nodular heterotopia and focal cortical dysplasia. MCD affect ~1 in 2,500 children and can result in epilepsy, developmental delay and cerebral palsy. Infantile epileptic spasms syndrome (IESS) is one of the most common forms of severe epilepsy of infancy and MCD are observed in ~50% of children with IESS. It is thought that the majority of cases of IESS and MCD have an underlying genetic cause. Although multiple molecular pathways have been identified, ~60% of cases still lack a genetic diagnosis after standard clinical diagnostic testing. Genetic diagnoses are important for prognosis, diagnostic testing, genetic counselling and precision medicine. Recent advances in genetic technologies allow for rapid, in-depth interrogation of the molecular mechanisms underlying MCD formation. The hypotheses of this thesis are that the application of high-resolution genomic technologies will facilitate a better understanding of the genetic causes of IESS with MCD and that functional characterisation of genes of interest will assist to identify crucial molecular pathways in the normal development and function of the developing brain. The primary research aims of this project are: to investigate the genetic landscape of IESS due to MCD by utilising brain tissue studies; to develop a deeper understanding of the molecular basis and phenotypic classifiers involved in the pathogenesis of brain somatic SLC35A2 variation and its relationship to mild malformation of oligodendroglial hyperplasia in epilepsy (MOGHE); and to identify molecular mechanisms and biomarkers of MOGHE. The genetic basis of IESS due to MCD was identified in 47/59 (80%) individuals. Germline pathogenic variants were identified in 27/59 (46%) individuals in TSC2 (n=19), DEPDC5 (2), CDKL5 (2), COL4A1 and 6p25.2 deletion (1), NPRL3 (1), FGFR1 (1) and TSC1 (1). Pathogenic brain somatic variants were identified in 21/59 (36%) cases, in SLC35A2 (n=9), PIK3CA (3), MTOR (2), TSC2 (2), AKT3 (2), OFD1 (1), TSC1 (1) and DEPDC5 (1). This included one individual with a two-hit DEPDC5 diagnosis, with a germline DEPDC5 variant and a somatic DEPDC5 variant. Multidisciplinary tools and integrated diagnosis review identified all nine individuals with SLC35A2 variants as having mild malformation of cortical development with oligodendroglial hypoplasia in epilepsy (MOGHE). Multi-omic analysis of MOGHE tissue using single nuclei RNA-sequencing (snRNA-seq) and Tandem Mass Tag 16pro liquid chromatography–mass spectrometry (LC-MS/MS) showed that neurogenesis, neuron projection development, axo-dendritic development and neuron differentiation are dysregulated in MOGHE. snRNA-seq analysis identified oligodendrocyte progenitor cells (OPCs) and dividing oligodendrocyte progenitor cells (cOPCs) as the primary cells exhibiting aberrant expression profiles in lesional MOGHE tissues. ACTB, GNG7, MAP4, NEFL, SEMA3E and SOD1 were identified as potential biomarkers in MOGHE and may serve as disease biomarkers or druggable targets in the future. The findings of this thesis contribute to the knowledge of the genetic landscape of paediatric brain malformations and severe epilepsies of infancy and broaden the understanding of cortical malformation development and epileptogenesis.