Sangam: A Confluence of Knowledge Streams

Clinical and molecular delineation of neurodevelopmental disorders within genetically isolated communities

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dc.contributor Baple, Emma
dc.contributor Crosby, Andrew
dc.contributor James, Unay
dc.creator Fasham, J
dc.date 2023-01-03T07:54:47Z
dc.date 2022-12-19
dc.date 2022-12-23T11:42:26Z
dc.date 2023-01-03T07:54:47Z
dc.date.accessioned 2023-02-23T12:18:54Z
dc.date.available 2023-02-23T12:18:54Z
dc.identifier ORCID: 0000-0002-7614-9202 (Fasham, James)
dc.identifier http://hdl.handle.net/10871/132103
dc.identifier.uri http://localhost:8080/xmlui/handle/CUHPOERS/258742
dc.description The unique genetic make-up of genetically isolated communities, where otherwise rare genetic founder variants may become enriched, allows the clinical relevance of these variants to be more precisely determined where this may not otherwise be possible. This thesis details clinical and genomic studies of inherited neurodevelopmental disorders identified within Amish and Palestinian communities to advance understanding of the pathomolecular basis of these diseases. Chapter 3 describes the discovery of a novel clinically recognisable syndromic microcephalic neuronal migration disorder with similarities to the “tubulinopathies”, resulting from biallelic variants in CAMSAP1, a microtubule-associated molecule. This finding, stemming from investigations in an extended Palestinian family, entailed collaborative clinical, genomic, cell and mouse studies. Four additional unrelated affected families were identified, highlighting the global relevance of such work. This chapter also documents preliminary studies identifying CAMSAP2 and CAMSAP3 variants as candidate causes of an overlapping phenotype. Chapter 4 describes the use of whole-genome sequencing to identify a homozygous SLC4A10 multi-exon deletion in two Palestinian children with microcephaly, abnormal slit-like lateral ventricles and features consistent with autistic spectrum disorder, closely mirroring findings in Slc4a10-/- mice. Eight affected individuals from four unrelated families were subsequently identified. Collaborative mouse and functional data determined that presynaptic inhibitory Abstract 4 GABAergic transmission is compromised, identifying a potential therapeutic approach involving GABAA receptor agonists. Chapter 5 illustrates how the serendipitous accumulation in a community setting of otherwise rare gene variants enables their clinical relevance to be correctly elucidated. Clinical and genetic studies of SCN9A gene variants in the Amish and UK Biobank conclusively refute previous associations between SCN9A and epilepsy, leading ClinGen to re-evaluate this incorrect disease-gene association. Together the work described in this thesis provides new insights into pathomolecular neurodevelopmental processes and improves scientific and clinical understanding of rare genetic variation, illustrating how community genomic research may expedite discovery of new rare diseases, improve clinical care and ultimately aid development of targeted treatments for these disorders.
dc.description GW4-CAT
dc.publisher University of Exeter
dc.publisher Health and Life Sciences
dc.rights 2024-06-20
dc.rights The work arising from this thesis will contribute to a number of high impact publications and the request for an embargo reflects the time it will take us to complete these studies and publish the findings.
dc.rights http://www.rioxx.net/licenses/all-rights-reserved
dc.subject Exome
dc.subject Genome
dc.subject GABA
dc.subject Neuronal migration disorder
dc.subject Palestinian
dc.subject Amish
dc.subject CAMSAP
dc.subject microtubule
dc.subject genetically isolated
dc.subject SCN9A
dc.subject SLC4A10
dc.subject epilepsy
dc.title Clinical and molecular delineation of neurodevelopmental disorders within genetically isolated communities
dc.type Thesis or dissertation
dc.type Doctor of Philosophy in Medical Studies
dc.type Doctoral
dc.type Doctoral Thesis


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