Liu, Y-T; (2014) Genetics and pathogenesis of inherited neuropathies. Doctoral thesis , UCL (University College London).

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Abstract

Inherited neuropathies are a clinically and genetically heterogeneous group of diseases affecting the peripheral nervous system (PNS). More than 70 causative genes have been recognised, however, there are still patients whose disease-causing genes have not been identified, particularly those presenting with complex phenotypes which also involve the central nervous system (CNS) and other organs. The main objective of my PhD was to establish the genetic diagnosis in these patients through an integrated approach combining conventional Sanger sequencing and the next generation sequencing (NGS) technologies which include whole exome sequencing (WES) and targeted resequencing. Based on this integrated approach, mutations in several genes for inherited neuropathies and related disorders have been identified. My thesis focuses on: (1) screening studies in large cohorts of patients conducted by Sanger sequencing to define the frequency of the mutations in the NEFL gene in Charcot-Marie-Tooth disease (CMT), in the SPTLC2 gene in hereditary sensory neuropathy type I and in the PDYN gene in autosomal dominant cerebellar ataxia (ADCA) in British population; (2) WES studies to identify mutations in patients with inherited neuropathies or autosomal recessive cerebellar ataxia (ARCA), including a novel ADCK3 mutation in ARCA and two novel genes causing CMT, MARS and C12orf65; (3) the development of two targeted resequencing panels for CMT and hereditary spastic paraplegia (HSP) with axonal neuropathy to identify disease-causing mutations in two cohorts; (4) the broadening of the phenotypic spectrum of KIF5A in patients with HSP and CMT type 2. In this thesis functional studies for some of the identified mutations were also performed such as the impairment of the mitochondrial respiratory enzymes in the lymphoblasts of patients with the C12orf65 mutation and in fibroblasts of patients with the ADCK3 mutation. The challenges faced by the use of NGS in genetic diagnosis and how to address these challenges in the future are discussed.

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