Audiology and Speech Pathology - Theses
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ItemExploring the aetiology of child speech and language disorders: Genes, brain and behaviour( 2020)Background Speech and language disorders are exceptionally common, affecting 1 in 20 children, yet we understand little about their aetiology. Advances in genetic analysis and brain imaging have increased our ability to unravel genetic contributions and brain-behaviour explanations for speech and language disorders. This PhD is focused on elucidating gene-brain-behaviour relationships, by refining the speech and language phenotypes of children with genetic and neural pathologies. Aims There were three main aims of the thesis, each forming a sub-study: Study 1. To conduct speech and language phenotyping of individuals and families, to drive targeted sequencing and identification of known and novel genes that cause speech and language disorders; Study 2. To conduct speech and language phenotyping of a cohort of individuals with pathogenic variants in FOXP1, a gene implicated in impaired communication; Study 3. To describe brain-behaviour associations between topography and severity of polymicrogyria (PMG) and speech and language ability. Methods Participants were recruited through research databases, clinical collaborators and online parent support groups. Speech and oral motor function, receptive and expressive language, non-verbal cognition and adaptive behaviour were assessed using a protocol of standardised tests. Clinical history, MRI data (Study 3) and cognitive assessments were analysed to interpret speech and language findings in the context of broader neurodevelopmental phenotypes. Results Study 1. 25 probands with severe or persistent speech disorder were referred to the study and 16 were included in the final analysis. Speech and language were characterised in all probands and 49 family members. DNA samples for these 16 probands were sent for whole exome or whole genome sequencing. Study 2. Speech and language assessments were completed in 29 individuals with pathogenic FOXP1 variants. All verbal individuals had a complex speech phenotype including dysarthria and broader motor planning and programming impairments and 88% had phonological errors. Language impairments affected nearly all participants, though abilities varied across the cohort. Study 3. 52 individuals with PMG were assessed and MRIs analysed. All verbal participants (regardless of their PMG pattern) had dysarthria, which ranged in severity from mild cases with subclinical features only, to more severe cases with no verbal speech. Developmental speech errors and language impairments were frequent, and profiles were more severe in individuals with perisylvian PMG and bilateral distribution of PMG. Discussion This PhD has important clinical implications for diagnosis, prognosis and clinical management of children with severe speech and language disorders. The detailed speech and language phenotyping here can assist clinicians in identifying individuals with severe speech disorders who may warrant genetic testing or brain imaging (e.g. to detect PMG) to elucidate the cause of their speech disorder. Novel information I have provided about the exact nature of speech and language phenotypes will also assist clinicians and families with prognostic counselling, and to understand the implications these conditions have for learning support and educational placement. Results can also be used to inform development of targeted therapy approaches for children with these genetic and neurological conditions. The discovery that very few patients were receiving targeted therapy (e.g. for dysarthria), highlights the urgent need for early referrals for evidence-based speech therapy.