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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.