Exome Sequencing Identifies Mutant TINF2 in a Family With Pulmonary Fibrosis

Abstract

BACKGROUND: Short telomeres are a common defect in idiopathic pulmonary fi brosis, yet mutations in the telomerase genes account for only a subset of these cases.

Management of suspected monogenic lung fibrosis in a specialised centre

“…Mutations in DKC1, NAF1 and TINF2 are much rarer (figure 1) [9,23,[28][29][30][31][32][33][34][35]. TERT or TERC mutations may be found in about 1-3% of sporadic IPF cases [28].…”

“…Other manifestations: Other manifestations linked to telomere disease include cellular or humoral immunodeficiency, exudative retinopathies, central neurological involvement with cerebral calcifications, gastrointestinal bleeding, radiation sensitivity or infertility [31,74,75]. These manifestations have mainly been described in children and never or very rarely associated with adult pulmonary fibrosis [76].…”

Hepatopulmonary Syndrome Is a Frequent Cause of Dyspnea in the Short Telomere Disorders

“…IPF is the fi rst presentation in adults with moderate telomere shortening, and mutations in six telomerase and telomere genes account for one-third of familial pulmonary fi brosis cases. [3][4][5][6][7][8] In smokers, emphysema, alone or combined with fi brosis, may be a fi rst manifestation and the frequency of mutations in telomerase rivals a 1 -antitrypsin defi ciency as a risk factor for severe emphysema. 9 Some patients may show other premature aging features, including early hair graying and osteoporosis.…”

What the Genetics “RTEL”ing Us about Telomeres and Pulmonary Fibrosis

“…Telomerase has two essential components, and mutations in TERT, the telomerase reverse transcriptase, and TR, the telomerase RNA, explain the inheritance in the largest subset of cases. Mutations in the telomerase component, DKC1, and the telomere binding protein, TINF2, account for another 1 to 2% of cases ( Figure 1A) (3,4). Relevant to clinical practice, patients with telomere-mediated lung disease are at risk for syndromic comorbidities such as bone marrow failure, liver disease, and enteropathy (2).…”

“…The levels of fine particulate matter (PM2.5) and the larger coarse particle (PM10) have both declined by a third nationally, going from 2000 to 2013 (2). Because these pollutants have been implicated in respiratory and cardiac diseases, this is thought to have resulted in significant health benefits, with more than one study associating reduced air pollution with increased life expectancy (3,4). Despite these improvements, more than 46 million people still live in areas where the annual average level of particle pollution is considered unhealthful (5).…”