Investigating the Genetic Basis of the Spastic-Ataxias using Next Generation Sequencing and a Mutation Database

Abstract

Introduction: “Spastic-ataxias” are a group of conditions that are characterised by spasticity as well as ataxia. They are usually hereditary in nature, and demonstrate widespread genetic heterogeneity and phenotypical variance. In this thesis, I seek to draw meaningful genotype-phenotype relationship in two disorders – Hereditary Cerebellar Ataxia (HCA) and Hereditary Spastic Paraplegia (HSP).

Method: We undertook separate studies for each disorder. The first study is a retrospective review of HCA cases referred to the Neurogenetics Clinic at Royal North Shore Hospital over a 15-year period. Here, the patient’s signs and symptoms are analysed with their mode of genetic investigation. The second study is a systemic review of all published HSP cases in the PubMed database until April 2018. For this study, the cases of HSP are limited to patients with mutations in ATL1, SPAST, and REEP1, the most common autosomal dominant variants of HSP. The signs and symptoms of these cases were analysed along with the genetic and mutational data.

Results: For the HCA study, we reviewed 87 cases, and found routine repeat expansion panels have a detection rate of 13.8%, with next-generation sequencing (NGS) yielded a further 34.4% (11/32). NGS and whole genome sequencing together improve the overall diagnostic rate to 28.8%, and detected several novel variants. For the HSP study, we reviewed 1642 cases, and found several key phenotypic differences amongst the three variants. We found loss-of-function variants to be more frequent in SPAST and REEP1, and is associated with more severe disease in SPAST.

Discussion: Our studies highlight the genetic and phenotypic heterogeneity of HCA and HSP. In HCA, we support the use of NGS approaches for individuals who were negative on repeat expansion testing. In HSP, we found several key differences amongst the variants to have implication for clinical diagnosis. These studies have contributed key findings to the literature of “spastic-ataxia”.