Subclinical Lung Disease, Macrocytosis, and Premature Graying in Kindreds With Telomerase ( TERT ) Mutations

Background Mutations in the human gene encoding the protein component of telomerase ( TERT ) are the most common genetic defect in patients with familial idiopathic pulmonary fibrosis (IPF). The subclinical phenotypes of asymptomatic members of these families have not been evaluated with respect to TERT mutation status or telomere length. Methods We measured a variety of pulmonary, blood, skin, and bone parameters for 20 subjects with heterozygous TERT mutations (carriers) and 20 family members who had not inherited a TERT mutation (noncarriers) to identify the spectrum of phenotypes associated with mutations in this gene. The two groups were matched for sex, age, and cigarette smoking. Three TERT mutation carriers had IPF (IPF carriers). The rest of the carriers were apparently healthy (asymptomatic carriers) and were compared with the noncarriers. Results Asymptomatic carriers exhibited significantly lower diffusing capacity of lung for carbon monoxide (D lco ), impaired recruitment of D lco with exercise, radiographic signs of lung fibrosis, and increased fractional lung tissue volume quantified by high-resolution chest CT scan than noncarriers. RBC and platelet counts were significantly lower, and the mean corpuscular volume and mean corpuscular hemoglobin concentration were significantly higher in carriers than in noncarriers. Carriers reported significantly earlier graying of hair than noncarriers. TERT mutation status is more accurately predicted by short telomere lengths than any of these measured phenotypes. Conclusions TERT mutation carriers exhibit early preclinical signs of lung fibrosis, bone marrow dysfunction, and premature graying. These clinical features and short telomere lengths characterize patients with germline TERT mutations.