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dc.contributor.authorRawlins, L
dc.date.accessioned2022-07-29T17:40:06Z
dc.date.issued2022-08-01
dc.date.updated2022-07-28T18:45:55Z
dc.description.abstractInherited neurodevelopmental disorders are a large group of clinically and genetically heterogeneous conditions affecting the development, structure and functioning of the central nervous system, and are frequently associated with extremes of brain growth. Whilst specific neurodevelopmental disorders are typically individually rare, as a group these conditions comprise a significant healthcare burden globally. A significant contribution to our understanding of neurodevelopmental disorders has been made by the study of autosomal recessive conditions, which are rare in the general population but occur at increased frequency in certain genetically isolated communities due to founder gene variants. The studies described in this thesis entail clinical, genetic and functional studies of inherited single gene disorders of brain growth identified in North American Amish and rural Pakistani communities, leading to investigations in other families globally. Chapter three describes the identification of a microcephalic neurodevelopmental disorder resulting from biallelic variants in the TRAPPC10 gene, encoding a transport protein particle (TRAPP) complex subunit involved in membrane trafficking and other cellular processes. This study, stemming from genetic findings in two Pakistani families harbouring distinct TRAPPC10 variants, entailed comprehensive clinical, genomic, mouse and functional studies to confirm TRAPPC10-related disorder as a novel TRAPPopathy. This chapter also describes preliminary clinical and genetic studies identifying or consolidating five further TRAPPopathy disorders. KPTN-related megalencephalic neurodevelopmental disorder was first identified by our research group in 2014. Chapter four documents the most detailed phenotypic description of the condition to date, alongside genetic findings of 36 affected individuals identified through international collaboration. This work enabled preliminary genotype-phenotype correlations to be drawn and patient management guidelines to be developed. Additionally, detailed comparisons with a Kptn-/- knock-out mouse model that closely recapitulates the human disease, alongside cell studies, provided fundamental new insights into the condition. Together, this enabled KPTN-related disorder to be confirmed as a new mTORopathy, highlighting the potential of mTOR inhibitors as a candidate therapeutic option for the condition. Chapter five details extensive clinical and genetic datasets to consolidate and more comprehensively define two previously poorly described causes of autosomal recessive disorders of brain growth and development. These involve variants in CEP55 associated with a severe lethal fetal disorder characterised by a variable spectrum of brain and kidney abnormalities, and INPP4A associated with a variable neurodevelopmental disorder with features of severe cognitive impairment, seizures, muscle weakness, cerebellar signs, spasticity and behavioural abnormalities. The clinical, genetic and molecular delineation of rare neurodevelopmental disorders facilitates accurate diagnosis and management of these conditions. The work described in this thesis also provides invaluable insights into disease pathogenesis and improves the scientific understanding of the subcellular processes underlying neurodevelopment. This knowledge is crucial to ultimately enable the discovery and delivery of potential new therapeutic avenues to treat these disorders.en_GB
dc.identifier.urihttp://hdl.handle.net/10871/130451
dc.language.isoenen_GB
dc.publisherUniversity of Exeteren_GB
dc.rights.embargoreasonThis thesis is embargoed until 31/Jan/2024 as it includes unpublished work that has been submitted for peer review or is being prepared for submission.en_GB
dc.subjectneurodevelopmental disorderen_GB
dc.subjectwhole exome sequencingen_GB
dc.subjectrare diseaseen_GB
dc.subjectAmishen_GB
dc.subjectPakistanen_GB
dc.subjectCEP55en_GB
dc.subjectINPP4Aen_GB
dc.subjectKPTNen_GB
dc.subjectTRAPPC10en_GB
dc.titleDelineating the clinical, genetic and molecular characteristics of neurodevelopmental disorders in a community settingen_GB
dc.typeThesis or dissertationen_GB
dc.date.available2022-07-29T17:40:06Z
dc.contributor.advisorEmma, Baple
dc.contributor.advisorCrosby, Andrew
dc.publisher.departmentCollege of Medicine and Health
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_GB
dc.type.degreetitlePhD in Medical Studies
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctoral Thesis
rioxxterms.versionNAen_GB
rioxxterms.licenseref.startdate2022-08-01
rioxxterms.typeThesisen_GB


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