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Novel Gene Discovery in Primary Ciliary Dyskinesia

Fassad, Mahmoud Raafat; (2018) Novel Gene Discovery in Primary Ciliary Dyskinesia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

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.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Novel Gene Discovery in Primary Ciliary Dyskinesia
Event: University College London
Language: English
Additional information: Copyright © The Author 2018. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10063629
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