[Telomeres and lung]

Area of Science:

• Genetics
• Pulmonology
• Immunology

Background:

• Familial interstitial lung disease (ILD) is a significant clinical challenge.
• Genetic factors play a crucial role in the pathogenesis of ILD.
• Telomere-related gene (TRG) mutations have been identified as a cause of familial ILD.

Purpose of the Study:

• To investigate the prevalence and clinical implications of TRG mutations in familial ILD.
• To explore the association of TRG mutations with extra-pulmonary manifestations and disease prognosis.
• To highlight the importance of genetic counseling and testing in managing familial ILD.

Main Methods:

• Genetic analysis of familial ILD cohorts.
• Clinical data collection on ILD patients with and without TRG mutations.
• Assessment of extra-pulmonary manifestations and lung function decline.

Main Results:

• TRG mutations (TERT, TERC, RTEL1, PARN, DKC1, TINF2, NAF1, NOP10, NHP2, ACD, ZCCH8) identified in approximately 30% of familial ILD cases.
• Patients with TRG mutations exhibit extra-pulmonary manifestations (immune-hematological, hepatic, mucosal-cutaneous).
• TRG mutations are linked to both idiopathic pulmonary fibrosis (IPF) and non-IPF ILDs, including hypersensitivity pneumonitis (HP), and are associated with accelerated forced vital capacity (FVC) decline and poorer lung transplant outcomes.

Conclusions:

• TRG mutations are a significant genetic cause of familial ILD, associated with diverse clinical phenotypes.
• Early identification through genetic counseling and pre-symptomatic testing can aid in personalized management and risk assessment.
• Environmental exposure reduction and genetic counseling are crucial for patients and families affected by TRG-related ILD.