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Definition of endophenotypic features indicative of genetic variants that cause congenital heart disease, through cardiac organoid (cardioid) modelling


   Faculty of Biology, Medicine and Health

  ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Recent advances in cardiac organoid modelling may yield novel approaches to generating “disease in a dish” models that will provide opportunities to dissect variant-specific mechanisms in congenital heart disease (CHD). But, genotype/phenotype relationships in cardiac organoids (cardioids) are very little characterised thus far.

The project will model known pathogenic variants (using ACMG criteria) in heart developmental genes from the Genomics England PanelApp “green gene” list for congenital heart disease, in cardioids. We will use CRISPR modification of hESC cell lines and compare variant-carrying with isogenic non-mutagenised controls. Cardioid phenotypes – gene expression, epigenetic, ultrastructural, microscopic, and functional – will be studied to evaluate the phenotypic manifestations of the introduced variants, and determine the presence and robustness of such genotype/phenotype relationships. The project will study variants that are disease-causing in different cell lineages – first heart field, second heart field, neural crest, and endothelial cells – to establish the capacity of the cardioid system to correctly identify known pathogenic variants in these lineages.

For those cell lineages in which robust genotype/phenotype relationships can be defined for known pathogenic variants, the project will then utilise the assays developed in the setting of possibly, rather than definitely, pathogenic variants. We will excerpt these from our own and others’ whole-exome and whole-genome sequencing studies in CHD. The ultimate aim of the project is to develop an organoid based assay system that will enable the characterisation of variants of unknown significance found in sequencing studies of CHD. 

1.     Candidates are required to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject.  Having completed a Master’s degree in a related area/subject is highly recommended. The envisaged course of study will be particularly suitable for candidates with experience in human genetics, functional genomics and bioinformatics. Interest in applying these approaches to the cardiovascular system will be an advantage.

2.     For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the PhD title.

3.     For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit www.internationalphd.manchester.ac.uk


Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website View Website
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website View Website

References

1. Page, D. J. et al. Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot. Circ Res 124, 553-563, doi:10.1161/CIRCRESAHA.118.313250 (2019).
2. Liu, Y. et al. Global prevalence of congenital heart disease in school-age children: a meta-analysis and systematic review. BMC Cardiovasc Disord 20, 488, doi:10.1186/s12872-020-01781-x (2020).
3. Williams, S. G., Byrne, D. J. F. & Keavney, B. D. Rare GATA6 variants associated with risk of congenital heart disease phenotypes in 200,000 UK Biobank exomes. J Hum Genet, doi:10.1038/s10038-021-00976-0 (2021).
4. Lahm, H. et al. Congenital heart disease risk loci identified by genome-wide association study in European patients. J Clin Invest 131, doi:10.1172/JCI141837 (2021).
5. McGurk, K. A. et al. Heritability and family-based GWAS analyses of the N-acyl ethanolamine and ceramide plasma lipidome. Hum Mol Genet 30, 500-513, doi:10.1093/hmg/ddab002 (2021).

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