THESIS
2023
1 online resource (xi, 80 pages) : color illustrations
Abstract
Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive
stenosis of the internal carotid artery (ICA). Previous studies have found association of the gene
variant RNF213 p.R4859K in East Asian population. However, other genetic factors involved
in the disease and affected cell types remain to be discovered.
In this thesis, I conducted genetic characterization of moyamoya disease by whole exome sequencing.
In our cohort, 25 out of all patients were found to carry inherited RNF213 p.R4859K
variants. Further analysis suggests that STAT1 is a potential transcription factor of RNF213 in
endothelial cells. Analysis on rare germline SNPs suggests the involvement of the HLA system
in the disease. Taking advantage of trio blood samples of the patients and their pare...[
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Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive
stenosis of the internal carotid artery (ICA). Previous studies have found association of the gene
variant RNF213 p.R4859K in East Asian population. However, other genetic factors involved
in the disease and affected cell types remain to be discovered.
In this thesis, I conducted genetic characterization of moyamoya disease by whole exome sequencing.
In our cohort, 25 out of all patients were found to carry inherited RNF213 p.R4859K
variants. Further analysis suggests that STAT1 is a potential transcription factor of RNF213 in
endothelial cells. Analysis on rare germline SNPs suggests the involvement of the HLA system
in the disease. Taking advantage of trio blood samples of the patients and their parents, a total
of 106 de novo germline mutations were identified, with a validation rate of 91% by Sanger
sequencing. Next, an in-house cell type gene enrichment analysis pipeline based on single cell
RNA sequencing data from PanglaoDB was applied. It is found that red pulp macrophages
followed by endothelial cells are most likely affected by our list of detected DNMs in coding
regions. We also developed a network based pipeline for cell type enrichment analysis and
the result suggests phagocytes as most likely affected by the DNMs which is compatible with previous results. I also constructed a pipeline for identifying compound heterozygous variants
potentially contributing to the development of the disease. As a result, 5 genes were found to
be affected by potentially pathogenic compound heterozygous variants.
To summarize, this thesis studied genetic factors potentially associated with the disease.
Interestingly, cell type gene enrichment analysis revealed a potential role of immune cells. This
finding could revolutionize our understanding of MMD and the pipeline could help with studies
of diseases with unknown cell types.
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