Wedatilake, YNG; (2017) Clinical and genetic studies in paediatric mitochondrial disease. Doctoral thesis , UCL (University College London).

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Abstract

Paediatric mitochondrial disease is a clinically and genetically heterogeneous group of disorders. Prior to the advent of next generation sequencing, many patients did not receive a genetic diagnosis. Genetic diagnosis is important for prognostication and prenatal diagnosis. The aim of this thesis was to study the genetic aetiology of paediatric mitochondrial disease. Paediatric patients with suspected mitochondrial disease were grouped to facilitate studying the genetic aetiology. This included grouping patients by respiratory chain enzyme deficiency, by affected end- organ type (cardiomyopathy) or by collectively investigating patients presenting with a similar, genetically undefined clinical syndrome. Whole exome sequencing (WES) was used to investigate genetic causes in patients with suspected mitochondrial disease associated with cytochrome c oxidase (COX) deficiency. In another paediatric cohort with mitochondrial cardiomyopathy, mitochondrial DNA sequencing, candidate gene sequencing or WES were used to identify genetic causes. Two families with a unique syndrome (febrile episodes, sideroblastic anaemia and immunodeficiency) were investigated using WES or homozygosity mapping. Candidate genes were functionally evaluated including the use of animal models. Furthermore a natural history study was performed in a monogenic mitochondrial disease (SURF1 deficiency) using clinical data from 12 centres. WES in COX - deficient patients revealed candidate genes for 14/30, including genes not targeted to the mitochondrion. In a mitochondrial cardiomyopathy (n=30) cohort, 18 genetic causes were identified. ATAD3A and MDH2 were identified as novel causes of human disease. Novel AARS2 and VARS2 mutations were found in patients with new clinical presentations. Tubular aggregates were identified in SERAC1 deficiency, as a novel histological finding in this disease. TRNT1 mutations were identified as causing a unique clinical syndrome. Two candidate genes (IGHMBP2 and SCYL1) were investigated as the cause for a mitochondrial DNA depletion syndrome. WES is a powerful tool for gene identification in mitochondrial disease leading to discovery of previously unrecognised, novel genetic causes.

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