Respiratory

Primary Ciliary Dyskinesia (PCD) is a rare, complex and heterogeneous inherited disorder affecting primarily the motile respiratory cilia. The diagnostic pathway for PCD includes the assessment of clinical symptoms suggestive of PCD and where possible non-invasive measurement of nasal nitric oxide. If suggestive these investigations are followed by a nasal brush biopsy assessed by light and electron microscopy. Light microscopy assessment of cilia function is by high speed video analysis of the frequency and pattern (waveform) of cilia movement on live cells. Electron microscopy allows visualisation of the ultrastructure of cilia and can often provide a definitive diagnosis. In 15-30% of cases where ciliary ultrastructure is normal the expanding knowledge of PCD-associated gene mutations is furthering diagnostic capabilities. To date, more than 39 disease-associated mutations have been identified, which encode proteins involved in ciliary synthesis, structure and function, and are estimated to account for 72%of known PCD cases. A combination of genetics and downstream protein analysis using advanced techniques such as 3D electron tomography and immunofluorescent antibody staining has already confirmed an array of new disease causing mutations, and this area will be greatly enhanced by the whole genome data generated through this project.

Interstitial Lung Diseases (ILDs) are a heterogenous group of lung diseases characterised by inflammation and fibrosis of the alveolar interstitium. The commonest and most serious ILD is Idiopathic Pulmonary Fibrosis (IPF), which is characterised by progressive breathlessness and cough which ultimately leads to respiratory failure and death with a median survival of patients of approximately 3 years (1-2). TERT mutations are the most common single genetic defect found in FPF, and these variants have increasing penetrance in males, with increasing age and have positively associated with fibrogenic environmental exposures (3).
However, 65% of patients do not have known genetic variants explaining their disease. Similarly the genotype phenotype interactions for FPF remain unclear and importantly the effects of known mutations on disease progression and lung function are unknown. Therefore, these studies will determine the effect of different mutations on disease phenotype and progression. Initial genetic analysis will be followed up with functional genomic and proteomic analysis using tissues derived from patients with ILD and FPF.

Bronchiectasis is a life-limiting chronic infection and airway inflammation syndrome. To date no specifically licenced therapies are available for bronchiectasis reflecting the very limited understanding of the pathophysiology of bronchiectasis. It is highly likely that bronchiectasis is due to a number of tractable underlying defects including novel immunodeficiencies, ciliopathies and epithelial function/ sodium channelopathies. Understanding the frequency of genetic abnormalities within the more “extreme” phenotypes of bronchiectasis will allow further studies such as ex vivo new pathway analysis (novel target validation in patients cells), application of new therapies using personalised medicines/clinical stratification (biomarker directed therapies) and better inform prognosis. We will also aim to study how the novel genetic data discovered within more “extreme phenotypes” may apply to the wider bronchiectasis population.

Hereditary haemorrhagic telangiectasia (HHT) affects approximately 1 in 5,000 people, and is extremely challenging to manage. The hallmarks of HHT are arteriovenous malformations (AVMs), and nasal/gastrointestinal telangiectatic vessels. Once present, vascular abnormalities are usually too numerous to treat using conventional medical approaches, and patients require life-long management to reduce risks of major haemorrhage, pregnancy-related deaths, high output cardiac failure, and strokes. Disease-causing genes such as ENG, ACVRL1 and SMAD4 modify signalling by TGF-beta superfamily members, but at least 20% of HHT patients do not have disease-causing variants in the known and emerging genes. Despite significant advances since the HHT gene assignments of ENG in 1994, and ACVRL1 in 1996, molecular therapies are only now being developed for the HHT population.

Pulmonary arteriovenous malformations (PAVMs) are abnormal vascular communications between a pulmonary artery and a pulmonary vein leading to an intrapulmonary right-to-left shunt. They affect ~50% of people with hereditary haemorrhagic telangiectasia (HHT, usually due to ENG, ACVRL1 (encoding ALK-1) or SMAD4 sequence variants), and display other familial patterns, unrelated to HHT. PAVMs require interventional and medical management to prevent ischaemic stroke, brain abscess, severe hypoxaemia, and pulmonary haemorrhage which is the main cause of maternal death in pregnancy (maternal death rate 1% per pregnancy). Identification of new disease-causing genes and gene variants will improve understanding of pathophysiological mechanisms and consequences, leading to improved patient care.