Respiratory GeCIP Domain


The Respiratory GeCIP domain is split into five subdomains each dealing with a specific disease group. These sub-domains are:

  1. primary ciliary dyskinesia (PCD)
  2. familial interstitial lung disease (ILD)
  3. non-CF bronchiectasis
  4. pulmonary arteriovenous malformations (PAVM)
  5. hereditary haemorrhagic telangiectasia (HHT).

Each subdomain will undertake research into two areas, i) linking the genes that are known to be disease-causing with the clinical effect it has on the patient, and ii) identifying genes that are expected to be disease-causing and confirming or refuting this in laboratory models.

The combination of both research areas will help to understand better the genetic cause of the diseases and their effects, allowing more tailored and effective screening and treatment for patients.

Below are the current subdomains for this domain. You can find the full details of the research proposed by this domain in the Respiratory GeCIP detailed research plan.

Primary Ciliary Dyskinesia (PCD)Claire HoggPrimary 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.
Familial Interstitial Lung Diseases (ILDs) Gisli JenkinsInterstitial 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.
Non-CF BronchiectasisAnthony De SoyzaBronchiectasis 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) Claire ShovlinHereditary 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) Claire ShovlinPulmonary 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.
Familial Spontaneous Pneumothorax (FSP)Stefan MarciniakPrimary spontaneous pneumothorax (PSP) occurs when the lung deflates in the absence of obvious underlying lung disease. This occurs in 20 males per 100,000 population; women are affected 5 times less often. In 10% of males affected by PSP and 25% of affected women, at least one first-degree family member has also been affected and in these instances the condition is called Familial Spontaneous Pneumothorax (FSP) (4).
Rather than being a single entity, FSP comprises an increasing number of genetic disorders often with severe extra-pulmonary manifestations ranging from renal cancer [FLCN1 mutation in Birt-Hogg-Dubé (BHD) syndrome] to aortic rupture [mutations affecting extracellular matrix formation including COL3A1, FBN1, or TGFBR2 etc. in vascular Ehlers Danlos, Marfan, and Loeys Dietz syndromes respectively] (5).
Despite the large heritable component in FSP, up to half of cases remain unclassifiable following thorough investigation in a specialist Pneumothorax Genetics service. By recruiting individuals with FSP who fulfil the following criteria, it is hoped that many of the remaining causative mutations will be identified: (i) primary spontaneous pneumothorax, (ii) one or more affected relatives, and (iii) prior testing for FLCN or FBN1 mutations if suggested by the clinical and radiological findings. In this way, we hope eventually to develop inexpensive, targeted gene panels for routine screening of FSP families.


1) G. Raghu et al., An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 183, 788 (Mar 15, 2011).

2) R. Wei et al., Association between MUC5B and TERT polymorphisms and different interstitial lung disease phenotypes. Transl Res, (Dec 17, 2013).

3) M.S. Devine, C.K.Garcia. Genetic Interstitial Lung Disease. Clin Chest Med 33, 95 (Mar, 2012).

4) Abolnik IZ, Lossos IS, Zlotogora J, Brauer R (1991) On the inheritance of primary spontaneous pneumothorax. Am J Med Genet 40: 155-158

5) Scott RM, Henske EP, Raby B, Boone PM, Rusk RA, Marciniak SJ (2018) Familial pneumothorax: towards precision medicine. Thorax 73: 270-276

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