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

Autor:	Groen K; Department of Pulmonology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands., van der Vis JJ; Department of Pulmonology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands.; Department of Clinical Chemistry, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands., van Batenburg AA; Department of Pulmonology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands., Kazemier KM; Department of Pulmonology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands.; Center of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands., de Bruijn MJW; Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, the Netherlands., Stadhouders R; Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, the Netherlands., Arp P; Department of Internal Medicine, Laboratory of Population Genomics, Erasmus Medical Center, Rotterdam, the Netherlands., Verkerk AJMH; Department of Internal Medicine, Laboratory of Population Genomics, Erasmus Medical Center, Rotterdam, the Netherlands., Schoemaker AE; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., de Bie CI; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., Massink MPG; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., van Beek FT; Department of Pulmonology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands., Grutters JC; Department of Pulmonology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands.; Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands., Vergouw LJM; Department of Internal Medicine, Laboratory of Population Genomics, Erasmus Medical Center, Rotterdam, the Netherlands., van Moorsel CHM; Department of Pulmonology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, the Netherlands.
Jazyk:	angličtina
Zdroj:	ERJ open research [ERJ Open Res] 2024 Feb 19; Vol. 10 (1). Date of Electronic Publication: 2024 Feb 19 (Print Publication: 2024).
DOI:	10.1183/23120541.00487-2023
Abstrakt:	Introduction: 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. Methods: 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. Results: 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 telomere-related 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. Discussion: 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. Competing Interests: Conflict of interest: C.I. de Bie received a one-time fee for a presentation from Boehringer Ingelheim. Conflict of interest: Leonie J.M. Vergouw received, via her insititution, a grant from the Longfibrose patiëntenvereniging/Pendersfonds. Conflict of interest: C.H.M. van Moorsel received, via her institution, funding from Boehringer Ingelheim for digital auscultation in pre-ILD and a lecture fee. Additionally, she is co-chair of the ClinGen ILD-GCEP. Conflict of interest: The remaining authors have nothing to disclose. (Copyright ©The authors 2024.)
Databáze:	MEDLINE
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