Mohamed, Mai Adel Abdulla; (2025) Deciphering the molecular genetic basis of motile cilia diseases. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Defective function of specialized motile cilia, responsible for vital fluid flow and particle transport in the upper and lower airway epithelia and other specialised epithelia, plays a pivotal role in primary ciliary dyskinesia (PCD). This debilitating motile ciliopathy, afflicting an estimated 1 in 7,500 individuals, arises from variants in genes governing motile cilia structure and function. PCD leads to muco-obstructive disease and pulmonary function deterioration. While about 50 established PCD genes account for most cases (70-80%), a significant subset (20-30%) remains genetically uncharacterized. To address this genetic knowledge gap, this study employed advanced sequencing techniques and tailored bioinformatics analyses to identify disease-causing variants within motile cilia-related genes comprising both the established PCD genes and a panel of PCD candidate genes. Identified genetic variants were assessed for likely pathogenicity using the American College of Medical Genetics and Genomics (ACMG) classification system. The investigation yielded a 78% diagnostic success rate, revealing a significant proportion of cases carrying homozygous variants in known PCD genes. Interestingly, a novel TTC12 variant with potential splicing implications was identified. In addition to identifying variants in established PCD genes, the study aimed to discover novel PCD genes. Fifteen unique variants were identified as putative disease-causing in 13 candidate genes. These candidate genes were selected based on their potential involvement with cilia, as supported by clinical records, published research, tissue expression profiles, and expression levels during cilia development. These novel variants' validity was corroborated through familial investigations and functional assessments of cilia in patient samples, coupled with data from model organism studies. Promising candidate genes such as DLEC1, SPATA17, DNAH1, KIAA0586, and RFX2 have been identified. Through increased genetic diagnosis and gene discovery, this research significantly contributes to the refinement of PCD genetic testing and enhances our understanding of the underlying biology of PCD, with potential clinical implications.

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