PULMONARY FIBROSIS AND A TERT FOUNDER MUTATION WITH A LATENCY PERIOD OF 300 YEARS.

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Germline mutations in the gene encoding telomerase reverse transcriptase (TERT) cause haploinsufficiency with subsequent telomere shortening. TERT mutations are associated with short telomere syndromes, such as pulmonary fibrosis, which is often the first manifestation of a short telomere syndrome. Telomere length is heritable, and progeny of telomerase mutation carriers are known to have shorter telomeres. In families with TERT mutations, genetic anticipation, the earlier onset of symptoms with successive generation, is described. Little is known on the number of generations that may pass before disease occurs in families with a TERT mutation.The objective of this study was to determine classification and origin of the new TERT c.2005T mutation from population genetics and from genealogical data and disease history of affected families.The TERT gene of 240 patients with familial pulmonary fibrosis was screened for mutations. Additionally, 1015 patients with pulmonary fibrosis, 1237 patients with an interstitial lung disease without pulmonary fibrosis (ILD-non PF) and 529 healthy controls were genotyped for the TERT c.2005C>T mutation. Genealogical research was performed on all patients who carried the TERT c.2005T mutation.We detected the TERT c.2005T (p.Arg669Trp) mutation in 13 out of 1255 patients with pulmonary fibrosis versus none of the ILD-non PF patients and healthy controls. Genealogical research connected four of the TERT c.2005T mutation carriers to a common ancestor who lived 7 generations back, spanning a period of 300 years.The TERT c.2005T mutation is a pathogenic mutation and associates with pulmonary fibrosis. This study learns that a latency period of over 300 years may pass before the cumulative effect of telomere shortening eventually leads to pulmonary fibrosis. This finding underlines the complexity of the clinical interpretation of TERT mutations, because not the presence of the mutation, but the result of genetic anticipation is associated with disease. Therefore, multidisciplinary discussion between pulmonary physicians, clinical geneticists and genetic laboratory experts is recommended.


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