Telomere length triggered genetic screening for telomeropathies in lung diseases: First data of the Aachen telomeropathy registry

Introduction:

Telomeropathies or Dyskeratosis Congenita (DKC) is a multisystem disorder caused by defective telomere maintenance. In adults, telomeropathies present clinically a heterogeneous picture with frequently observed mono/oligosymptomatic manifestations. In this study, we aim to analyze for the incidence of cryptic DKC in patients with idiopathic pulmonary fibrosis (IPF) and/or pulmonary arterial hypertension (PAH) using a telomere length (TL) triggered diagnostic approach.

Methods and Patients:

Patients from the outpatient clinic of the pneumology divison of the University Hospital Aachen were included into the Aachen telomere registry. TL screening was carried out by using fluorescence in situ hybridization and flow cytometry (flow-FISH) analysis of the peripheral blood granulocytes and lymphocytes. In a 2-step approach, patients with granulocyte or lymphocyte TL measured below the 10% percentile of age-adjusted healthy controls or absolute lymphocyte TL below 6.5 kb triggered further genetic work-up by next-generation-sequencing (NGS, Miseq sequencer, Illumina).

Results:

14% (2/14) of all patients were found to have TL below the 10% percentile. Additional 43% (6/14) showed absolute lymphocyte TL below 6.5 kb. In total, 57% (8/14) underwent NGS screening and typical mutations associated with altered telomere maintenance were identified in 14% (2/14) of all patients. One male 78y old patient with IPF showed a RTEL1 mutation 164R>H with granulocyte TL below 10% and lymphocyte TL below 6.5 kb. One 69y old female patient with PAH had lymphocyte TL below 6.5 kb and showed a RTEL1 mutation 437A>P. Mean lymphocyte TL was 5.0 ± 0.5 kb in patients with RTEL1 mutation and 6.3 ± 1.1 kb in patients without detected mutations. Mean granulocyte TL was 5.6 ± 0.8 kb in patients with RTEL1 mutation and 7.5 ± 1.0 kb in patients without detected mutations.

Conclusions:

We provide first data on the feasibility of routine screening for DKC in adults with rare lung diseases based on TL. 14% of our small patient cohort was identified to have known DKC causing mutation. Our study suggests that telomeropathies affecting the respiratory system occurs in a relevant percentage of patients and might be severely underdiagnosed particularly in old adults resulting in impaired prognosis and treatment.