Expanding the understanding of telomere biology disorder with reports from two families harboring variants in ZCCHC8 and TERC

This pattern implies that in these patients, it is not the telomerase mutation itself but the short telomeres that determine the severity of the disease.14,24,26

The most common cause of death in patients with dyskeratosis congenita is bone marrow failure due to aplastic anemia. Pulmonary disease is present in 20% of patients and is the second most common cause of death.16–18

Telomerase Mutations in Families with Idiopathic Pulmonary Fibrosis

Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase

mice have short life spans (~2–3 years), residual Tert expression in many adult tissues (discussed below)8, and, in the common Mus musculus laboratory strain, long telomeres (~20–65 kb)9

Genetic anticipation has been observed in some families with pulmonary fibrosis carrying monoallelic variants in several TBD-causing genes including TERC, TERT, PARN, RTEL1 and POT1 (refs.100,187,188,189,190,191,192

Genetics of human telomere biology disorders

This is substantiated by the observation that, similarly to some types of SGR that affect the RNA decay machinery (for example, DIS3 or MTREX; Fig. 4c) and likely increase the level of functional hTR, an inhibitor of the hTR poly(A) polymerase PAPD5 increases the level of mature hTR and improves the potential of haematopoietic stem and progenitor cells in the context of PARN or dyskerin deficiency59,237,238,239.

Since then, 16 additional TBD-causing genes have been identified (Table 1)

Telomerase Mutations and the Pulmonary Fibrosis–Bone Marrow Failure Syndrome Complex

Telomerase and Idiopathic Pulmonary Fibrosis

The consequences of telomerase deficiency were studied in model organisms before telomerase mutations were discovered in the setting of human disease[18, 19]

The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita

Association between aplastic anaemia and mutations in telomerase RNA

Short telomeres are a risk factor for idiopathic pulmonary fibrosis