A new variant in the ZCCHC8 gene: diverse clinical phenotypes and expression in the lung

Karlijn Groen, Joanne J. van der Vis, Aernoud A. van Batenburg, Karin M. Kazemier, Marjolein J.W. de Bruijn, Ralph Stadhouders, Pascal Arp, Annemieke J.M.H. Verkerk, Angela E. Schoemaker, Charlotte I. de Bie, Maarten P.G. Massink, Frouke T. van Beek, Jan C. Grutters, Leonie J.M. Vergouw, Coline H.M. van Moorsel*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Downloads (Pure)



Pulmonary fibrosis is a severe disease which can be familial. A genetic cause can only be found in ∼40% of families. Searching for shared novel genetic variants may aid the discovery of new genetic causes of disease. 


Whole-exome sequencing was performed in 152 unrelated patients with a suspected genetic cause of pulmonary fibrosis from the St Antonius interstitial lung disease biobank. Variants of interest were selected by filtering for novel, potentially deleterious variants that were present in at least three unrelated pulmonary fibrosis patients. 


The novel c.586G>A p.(E196K) variant in the ZCCHC8 gene was observed in three unrelated patients: two familial patients and one sporadic patient, who was later genealogically linked to one of the families. The variant was identified in nine additional relatives with pulmonary fibrosis and other telomererelated phenotypes, such as pulmonary arterial venous malformations, emphysema, myelodysplastic syndrome, acute myeloid leukaemia and dyskeratosis congenita. One family showed incomplete segregation, with absence of the variant in one pulmonary fibrosis patient who carried a PARN variant. The majority of ZCCHC8 variant carriers showed short telomeres in blood. ZCCHC8 protein was located in different lung cell types, including alveolar type 2 (AT2) pneumocytes, the culprit cells in pulmonary fibrosis. AT2 cells showed telomere shortening and increased DNA damage, which was comparable to patients with sporadic pulmonary fibrosis and those with pulmonary fibrosis carrying a telomere-related gene variant, respectively. 


The ZCCHC8 c.586G>A variant confirms the involvement of ZCCHC8 in pulmonary fibrosis and short-telomere syndromes and underlines the importance of including the ZCCHC8 gene in diagnostic gene panels for these diseases.

Original languageEnglish
Article number00487-2023
JournalERJ Open Research
Issue number1
Publication statusPublished - 1 Jan 2024

Bibliographical note

Publisher Copyright:
© The authors 2024.


Dive into the research topics of 'A new variant in the ZCCHC8 gene: diverse clinical phenotypes and expression in the lung'. Together they form a unique fingerprint.

Cite this