Gardiner, AR; (2016) A genetic investigation of the muscle and neuronal channelopathies: from Sanger to next-generation sequencing. Doctoral thesis , UCL (University College London).

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Abstract

The neurological channelopathies are a group of hereditary, episodic and frequently debilitating diseases often caused by dysfunction of voltage-gated ion channels. This thesis reports genetic studies of carefully clinically characterised patient cohorts with different episodic neurological and neuromuscular disorders including paroxysmal dyskinesias, episodic ataxia, periodic paralysis and episodic rhabdomyolysis. Genetic and clinical heterogeneity has in the past, using traditional Sanger sequencing methods, made genetic diagnosis difficult and time consuming. This has led to many patients and families being undiagnosed. Here, different sequencing technologies were employed to define the genetic architecture in the paroxysmal disorders. Initially, Sanger sequencing was employed to screen the three known paroxysmal dyskinesia genes in a large cohort of paroxysmal movement disorder patients and smaller mixed episodic phenotype cohort. A genetic diagnosis was achieved in 39% and 13% of the cohorts respectively, and the genetic and phenotypic overlap was highlighted. Subsequently, next-generation sequencing panels were developed, for the first time in our laboratory. Small custom-designed amplicon-based panels were used for the skeletal muscle and neuronal channelopathies. They offered considerable clinical and practical benefit over traditional Sanger sequencing and revealed further phenotypic overlap, however there were still problems to overcome with incomplete coverage. Large custom and non-custom pull-down panels were used to investigate patients with recurrent rhabdomyolysis patients. The contribution of genetic abnormalities was determined, and it was concluded that while the contribution of the RYR1 was substantial, it was minimal for the classic voltage-gated ion channels SCN4A and CACNA1S Lastly, whole-exome sequencing was applied to two large undiagnosed possible channelopathy families. One family was found to indeed harbour a channelopathy mutation, whilst the other did not. Overall, next-generation sequencing proved to be a more thorough and efficient method for channelopathy genetic diagnosis and several novel findings throughout the thesis expanded the current knowledge within the field.

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