NHLBI GO-ESP Family Studies: Idiopathic Bronchiectasis of unknown etiology that is not related to cystic fibrosis or classic primary ciliary dyskinesia or immune deficiency or any other known causes

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO.

The major goal of this project is to apply next generation resequencing technology to identify disease-causing variants that cause bronchiectasis of unknown etiology (e.g. non cystic fibrosis (CF), classic primary ciliary dyskinesia (PCD), immune deficiency, or any other known cause of bronchiectasis), i.e., "idiopathic bronchiectasis."

As part of our ongoing efforts to define the genetic cause of rare lung diseases, we have also studied families in whom diagnosis of PCD or other known etiologies could not be confirmed. We have systematically collected and stored the DNA and phenotypic data on each of the families in our cohort. The phenotypic data includes age, gender, ethnicity information, clinical data pertaining to the airways disease, including neonatal respiratory distress, otitis media, sinusitis and bronchiectasis, ciliary ultrastructure analysis, and microbial colonization (status of nontuberculosis mycobacterium). During the course of our study, we have acquired 98 unrelated patients in whom bronchiectasis seemed to be of unknown causes. We will be using 11 unrelated patients, 5 unrelated affected sib-pairs, and 3 affected sibs from a family from this cohort, based on 1) development of bronchiectasis in the absence of smoking, 2) a good family pedigree with available DNA, and 3) a family history of bronchiectasis and/or occurrence of airways disease in a sibling. Classic CF, PCD and immune deficiency were ruled out, based on the tests described above. Alpha-1 antiprotease deficiency work up was negative and none of the patients were tobacco users or smokers.

• Study Weblinks:
  • NHLBI GO-ESP Project
• Study Design:
  • Prospective Longitudinal Cohort
• Study Type:
  • Cohort
• Total number of consented subjects: 24
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• Sequence Read Archive
• BioSample
• MeSH

Inclusion Criteria: Participants with bronchiectasis of unknown etiology (where common causes such as cystic fibrosis (CF), classic primary ciliary dyskinesia (PCD), immune deficiency or smoking have been ruled out).

Exclusion Criteria: Participants with bronchiectasis caused by common causes.

Bronchiectasis was a common disorder in the past, but its prevalence has declined due to the reduction in tuberculosis and the development of vaccines and antibiotics. Hence, by the elimination of non-genetic causes of bronchiectasis, the genetic causes have become more evident. The current estimated prevalence of bronchiectasis is 4.2 per 100,000 persons 18-34 years old and 272 per 100,000 persons 75 years or older. Approximately, 50% of patients have bronchiectasis due to cystic fibrosis (CF). From the remaining half, the etiology is still missing from 30-35% of the patients and it would be extremely important to define the gene(s) causing bronchiectasis in these patients.

The molecular mechanisms and signaling pathways for idiopathic bronchiectasis are not well defined, as it is a polygenic disorder with extensive locus heterogeneity. Due to an incomplete understanding of the genetic causes and locus heterogeneity, tracking down genetic variants in the candidate gene would be inadequate, labor-intensive and time-consuming; hence, it would be useful to simultaneously interrogate the human genome.

While studying the rare lung diseases, we have excluded the known causes of bronchiectasis, using specialized techniques in our patients and hence availability of well-characterized patient population presents a unique opportunity to define causative genes using exomic sequencing platform.

Exome resequencing of an affected individual with a family history of bronchiectasis of unknown etiology represents a cost-effective and robust strategy for the sensitive and specific identification of the pathogenic protein-coding or splice variants.

• Primary Phenotype: Bronchiectasis

• Principal Investigators
  • Michael Knowles, MD. University of North Carolina, Chapel Hill, NC, USA.
  • Maimoona Zariwala, PhD. University of North Carolina, Chapel Hill, NC, USA.
• Collaborators
  • Jonathan Berg, MD, PhD. University of North Carolina, Chapel Hill, NC, USA.
  • Kenneth Olivier, MD. NIAID, National Institute of Health, Bethesda, MD, USA.
  • Steven Holland, MD. NIAID, National Institute of Health, Bethesda, MD, USA.
• Funding Sources
  • U54 HL096458. National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
  • R01 HL071798. National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
  • RC2 HL102926. National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
  • RC2 HL102925. National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
• Sequencing Center
  • Deborah Nickerson, PhD. University of Washington, Seattle, WA, USA.
  • Stacey Gabriel, PhD. Broad Institute, Cambridge, MA, USA.