My laboratory investigates the genetic basis of lung disease. We strive to leverage genetics to understand the molecular mechanism of disease and to integrate these discoveries into clinical practice.

Discovery of rare genetic mutations underlying adult-onset lung disease

We study kindreds with familial pulmonary fibrosis, a progressive disease typically affecting older adults. We have used genome linkage scans and next-generation sequencing to identify rare coding mutations in genes belonging to the surfactant (SFTPA2, SFTPC) and telomerase (TERT, TERC, RTEL1 and PARN) pathways. Each mutation is individually rare and generally private for the family in which it is discovered. Collectively, however, TERT mutations are the most common genetic defect associated with familial pulmonary fibrosis. Rare variants in all of these genes are found in about 25% of families. We find that approximately half of all patients with TERT, TERC, PARN and RTEL1 mutations have a diagnosis of Idiopathic pulmonary Fibrosis (IPF). The remainder have other interstitial lung disease diagnoses. More than 50% of individuals who have inherited these mutations may be asymptomatic, but have sub-clinical pulmonary, blood, and skin findings.

Exome Sequencing Links Mutations in PARN and RTEL1 with Familial Pulmonary Fibrosis and Telomere Shortening. Nat. Genet., 2015. [PMID: 25848748]

Genetic defects in surfactant protein A2 associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009. [PMID: 19100526]

Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A. 2007. [PMID: 17460043]

Telomere-Related Lung Fibrosis is Diagnostically Heterogeneous but Uniformly Progressive. Eur Respir J. 2016. [PMID: 27540018]

Adult-onset pulmonary fibrosis caused by mutations Subclinical Lung Disease, Macrocytosis and Premature Graying in Kindreds with Telomerase (TERT) Mutations. Chest 2011. [PMID: 21349926]

Understanding the molecular mechanisms of disease

About 5% of individuals of older adults with an inherited telomerase mutation also have somatic mutation(s) in the TERT promoter. Acquisition of these somatic mutations in white blood cells result in increased telomerase activity and cellular proliferation. Thus, for some people, telomerase activation is safely tolerated and advantageous for clonal expansion.

Almost all mutations linked to pulmonary fibrosis segregate in families with an autosomal dominant pattern with incomplete penetrance. Recently, we found evidence for autosomal recessive pattern of inheritance for a rare PARN missense variant (p.Arg444Cys) in one kindred.

Somatic mutations in telomerase promoter counterbalance germline loss-of-function mutations. J Clin Invest. 2017. [PMID: 28192371]

Homozygous rare PARN missense mutation in familial pulmonary fibrosis. Am. J. Resp. Crit. Care. 2019. [PMID: 30525901]

Using patient cohorts to translate genetic discoveries

Telomere lengths are associated with survival for patients with IPF, even after accounting for traditional risk factors. We have expanded these findings to other types of interstitial lung disease, such as chronic hypersensitivity pneumonitis and interstitial pneumonia with autoimmune features. Telomere lengths predict survival after lung transplantation, the rate of lung decline, and risk of adverse complications from immunosuppression. These findings suggest that telomere length can be used as a biomarker for personalizing patient treatments.

Telomere Length and Genetic Variant Associations with Interstitial Lung Disease Progression and Survival. Eur Respir J. 2019. [PMID: 30635297]

Telomere Length and Use of Immunosuppressive Medications in Idiopathic Pulmonary Fibrosis. Am. J. Respir Crit Care Med. 2019. [PMID: 30566847]

Effect of telomere length on survival in idiopathic pulmonary fibrosis: an observational study with independent validation. Lancet Respir Med. 2014. [PMID: 24948432]

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