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Title: Identification of novel disease-causing variants in rare diseases using trio exome sequencing
Author: Pepler, A.
ISNI:       0000 0004 7225 3074
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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The use of trio exome next-generation sequencing (NGS), an analysis of the entire complement of coding exons within an affected index patient and unaffected parents, is increasingly being utilised in the analysis of patients with congenital diseases. This thesis describes the use of trio exome sequencing in the analysis of three distinct circumstances. First, the analysis of a cohort of eight trios in which the index patients suffer from startle disease, characterized by dysfunction of inhibitory glycinergic synapses. This revealed a single case of allelic drop-out of a known GLRA1 p.Y307C variant in a novel de novo pattern of inheritance, three cases where known or expected pathogenic variants had been identified in genes known to cause a seizure phenotype (DOLK and DMD), and an association with variants in ATRN, a null mutant of which is associated with a seizure phenotype in Mus musculus. Second, whole exome analysis of three individual cases with rare diseases was performed; a case of hypomyelinating leukodystrophy with a homozygous NKX6-2 p.L54Qfs variant, a case of microcephaly and pontocerebellar hypoplasia with a MED14 de novo p.R1162C variant, and a case of syndromic intellectual disability with hypotonia and a homozygous DRG1 p.Y295* variant. None of these genes had yet been implicated in disease, but all show some functional implication in each of the respective disorders. Third, novel de novo GRIN1 p.M818R and GRIN2B p.M824V variants were identified in further cases with developmental delay and hypotonia, adding to recent publications expanding the phenotype of variants within the NMDA receptor subunits. In each of these cases, trio exome sequencing was requested due to unclear disease aetiology and the resulting data indicates, in the majority of these cases, novel or putative genotype-phenotype correlations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available