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Title: Novel gene discovery in primary ciliary dyskinesia
Author: Fassad, Mahmoud Raafat
ISNI:       0000 0004 7659 8774
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Primary Ciliary Dyskinesia (PCD) is one of the 'ciliopathies', genetic disorders affecting either cilia structure or function. PCD is a rare recessive disease caused by defective motile cilia. Affected individuals manifest with neonatal respiratory distress, chronic wet cough, upper respiratory tract problems, progressive lung disease resulting in bronchiectasis, laterality problems including heart defects and adult infertility. Early diagnosis and management are essential for better respiratory disease prognosis. PCD is a highly genetically heterogeneous disorder with causal mutations identified in 36 genes that account for the disease in about 70% of PCD cases, suggesting that additional genes remain to be discovered. Targeted next generation sequencing was used for genetic screening of a cohort of patients with confirmed or suggestive PCD diagnosis. The use of multi-gene panel sequencing yielded a high diagnostic output (> 70%) with mutations identified in known PCD genes. Over half of these mutations were novel alleles, expanding the mutation spectrum in PCD genes. The inclusion of patients from various ethnic backgrounds revealed a striking impact of ethnicity on the composition of disease alleles uncovering a significant genetic stratification of PCD in different populations. Pathogenic mutations were also identified in several new candidate genes not previously linked to PCD. Molecular and cell biology techniques were coupled with model organism studies to characterize the involvement of the new candidate genes in cilia motility and PCD. Paramecium was proven to be a good model for functional characterization of PCD potential candidate genes. The previously uncharacterized C11orf70 was identified to play a highly conserved role in dynein assembly and intraflagellar transport (IFT)-related cilia cargo trafficking. Mutations identified in DNAH9 resulted in a distinct motile cilia defect with mild respiratory symptoms, unusual in PCD. Mutations identified in two intraflagellar transport genes, IFT74 and WDR19, linked together primary and motile ciliopathy phenotypes observed in the affected individuals.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available