Identifying hidden inherited metabolic diseases in the UK population

Inherited metabolic diseases are rare diseases associated with genetic variants that impair enzymes, leading to accumulation of substrates. Many of these are treatable, emphasising the crucial need for accurate diagnosis. In classical presentations, these manifest in childhood with features such as developmental delay, skeletal dysplasia and haematological problems. More recently, milder forms of these inherited metabolic diseases have been identified by genome sequencing in adult populations. Dr McNeill’s group has recently identified a small number of adults who were found to have an inherited metabolic disease only after research exome testing. This suggests that adults with mild presentations of inherited metabolic diseases will be present in general clinical populations; but only discoverable via genomic technology. 

The student will undertake a bioinformatics project to screen genomic datasets for variants in genes that cause inherited metabolic disorders. These datasets will include Dr McNeill’s Sheffield exome datasets, the 100 000 genomes project, UK biobank and the SOLVE-RD dataset. Identified variants will be classified using the American College of Medical Genetics - Association of Molecular Pathology criteria. The clinical phenotype of the research participants will be assessed to judge if it is compatible with an inherited metabolic disease. Where ethical permissions are in place, participants will be recalled for further clinical assessment. The student will then undertake cell biology studies to examine the functional impact of certain genomic variants on enzyme function to investigate why some gene variants cause mild adult onset forms of disease and others severe paediatric presentations. The student will receive full training in analysing genomic data, classifying gene variants, appropriate clinical phenotyping and functional studies. The skills will enable the PhD student to develop as an independent researcher or to progress to training in a diagnostics laboratory. 

Entry Requirements:

Candidates must have a first or upper second class honors degree or significant research experience. (add any additional requirements here)

How to apply:

Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select 'Neuroscience' as the department.

Enquiries:

Interested candidates should in the first instance contact Dr Alisdair McNeill, Senior Clinical Lecturer in Neurogenetics, a.mcneill@sheffield.ac.uk

Funding:

Self funded students only