Details

Autor(en) / Beteiligte

• Vis, Joanne J.
• Smagt, Jasper J.
• Batenburg, Aernoud A.
• Goldschmeding, Roel
• Es, H. Wouter
• Grutters, Jan C.
• Moorsel, Coline H. M.

Titel

Pulmonary fibrosis in non‐mutation carriers of families with short telomere syndrome gene mutations

Ist Teil von

• Respirology (Carlton, Vic.), 2021-12, Vol.26 (12), p.1160-1170

Ort / Verlag

Chichester, UK: John Wiley & Sons, Ltd

Erscheinungsjahr

2021

Quelle

Wiley-Blackwell Full Collection

Beschreibungen/Notizen

• Background and objective Diagnostic and predictive genetic testing for disease cause and risk estimation is common in many countries. For genetic diseases, predictive test results are commonly straightforward: presence of the mutation involves increased risk for disease and absence of the mutation involves no inherit risk for disease. Germline mutations in telomere‐related genes (TRGs) can lead to telomere shortening and are associated with short telomere syndrome (STS). Telomere length is heritable, and in families with STS due to a TRG mutation, progeny with and without the TRG mutation is known to have shorter than average telomeres. We hypothesize that progeny of TRG mutation carriers who did not inherit the TRG mutation may still develop pulmonary fibrosis. Methods A genetic screen of 99 unrelated families with familial pulmonary fibrosis revealed five patients with features of pulmonary fibrosis but without carrying the familial disease‐causing TRG mutation. Results Features of STS were present in each family, including short telomeres in blood and tissue of the non‐mutation carrying patients. Additional genetic, clinical or environmental risk factors for pulmonary fibrosis were present in each non‐mutation carrying patient. Conclusion Our study shows that non‐mutation carrying first‐degree relatives in families with STS are at increased risk for pulmonary fibrosis. Disease development may be triggered by inherited short telomeres and additional risk factors for disease. This observation has profound consequences for genetic counselling. Unlike any other genetic syndrome, absence of the mutation does not imply absence of disease risk. Therefore, clinical follow‐up is still urged for non‐mutation carrying first‐degree family members. We present five patients with familial pulmonary fibrosis without carrying the familial telomere‐related gene (TRG) mutation. This shows that increased risk for disease may be induced by inheritance of short telomeres. It implies that, in predictive genetic testing, absence of TRG mutation does not exclude the risk for disease. See related Editorial