Balkan Journal of Medical Genetics

ULTRA-EARLY DIFFUSE LUNG DISEASE IN AN INFANT WITH PATHOGENIC VARIANT IN TELOMERASE REVERSE TRANSCRIPTASE (TERT) GENE
Visekruna J, Basa M, Grba T, Andjelkovic M, Pavlovic S, Nathan N, Sovtic A
*Corresponding Author: Ass. Prof. Aleksandar Sovtic, Department of Pulmonology, Mother and Child Health Institute of Serbia, Belgrade, Serbia, School of Medicine, University of Belgrade, Serbia; Email: aleksandar.sovtic@med.bg.ac.rs; Address: 6 Radoja Dakica, 11070 Belgrade, Serbia; Phone: +381 11 3108 158
page: 59

DISCUSSION

The proposed mechanism of pulmonary involvement emphasises the importance of triggers such as smoking, stress, obesity, and inflammation [8]. CMV infection could be the trigger, as it has been described as a presenting fea- ture in some TERT-variant associated disorders, such as dyskeratosis congenita (DC) [6]. The propensity of patients with confirmed pathogenic variants in the TERT gene to develop pneumonitis has been previously demonstrated [9]. Additional evidence suggests an impaired T cell immu- nologic response to CMV in lung transplant recipients with short telomere syndromes [10]. Although the relationship between viral infection and pulmonary fibrosis in adults is not fully understood, direct damage caused by a virus and immune-mediated injury are proposed mechanisms [11]. However, in this case, the reason for the early onset of the disease remains unclear since ventilation-induced lung injury or CMV-associated acute respiratory distress syndrome could have similar consequences. The typical clinical course in adults diagnosed with TERT mutation-associated conditions is insidious, with typical onset after the fourth decade of life [4,12]. Al- though the phenomenon of genetic anticipation based on the progressive shortening of telomeres is a characteristic of TERT gene mutations, no childhood presentation has currently been reported [4,13]. According to the literature and databases, each of the TERT mutations is referred to as “private mutations”, and a total of 2625 clinically known and classified variants with- in the coding region of the TERT gene, of which only 9% are classified as pathogenic/likely pathogenic (Fig. 2B). Within the coding region of the TERT gene, loss of function (LOF) variants are very rare and have been detected only in the heterozygous state, thus indicating that the TERT gene is almost completely intolerant to LOF variants [14]. The detected heterozygous variant, c.280A>T (p.Lys94Ter) in the patient, was an LOF variant. The results of in silico modelling of wild-type and mutated TERT demonstrated that amino acid changes and consequential downstream introduction of the STOP codon led to protein truncation and consequent removal of protein-binding sites (Fig. 2C). Since TERT interacts with 122 different interactors (Fig. 2D) in cells, its function is further disrupted due to the absence of accurate amino acids for protein-protein in- teractions. Zaug et al. described families suffering from pulmonary fibrosis due to TERT mutations with a highly variable degree of telomerase functional impairment. The results of their study showed that the degree of functional impairment of telomerase was highly variable and many TERT mutations were shown to retain high—near nor- mal—telomerase enzyme activity [15]. A limitation of this study was the absence of telomere length measurements or telomerase enzyme activity, which could have provided insights into the association between the detected germline variants, telomere length, and unusual early onset diseases. In conclusion, the identification of a pathogenic vari- ant in the TERT gene underlines the importance of genetic testing in paediatric patients presenting with respiratory failure, especially when confronted with atypical clini- cal features. The association between CMV infection and TERT mutations sheds light on potential disease mecha- nisms involving impaired telomerase function and immune response dysregulation and may lead to extremely rare early onset lung disease with chronic respiratory insufficiency and an unfavourable final outcome.

Number 27 VOL. 27 (2), 2024	Number 27 VOL. 27 (1), 2024
Number 26 Number 26 VOL. 26(2), 2023 All in one	Number 26 VOL. 26(2), 2023
Number 26 VOL. 26, 2023 Supplement	Number 26 VOL. 26(1), 2023
Number 25 VOL. 25(2), 2022	Number 25 VOL. 25 (1), 2022
Number 24 VOL. 24(2), 2021	Number 24 VOL. 24(1), 2021
Number 23 VOL. 23(2), 2020	Number 22 VOL. 22(2), 2019
Number 22 VOL. 22(1), 2019	Number 22 VOL. 22, 2019 Supplement
Number 21 VOL. 21(2), 2018	Number 21 VOL. 21 (1), 2018
Number 21 VOL. 21, 2018 Supplement	Number 20 VOL. 20 (2), 2017
Number 20 VOL. 20 (1), 2017	Number 19 VOL. 19 (2), 2016
Number 19 VOL. 19 (1), 2016	Number 18 VOL. 18 (2), 2015
Number 18 VOL. 18 (1), 2015	Number 17 VOL. 17 (2), 2014
Number 17 VOL. 17 (1), 2014	Number 16 VOL. 16 (2), 2013
Number 16 VOL. 16 (1), 2013	Number 15 VOL. 15 (2), 2012
Number 15 VOL. 15, 2012 Supplement	Number 15 Vol. 15 (1), 2012
Number 14 14 - Vol. 14 (2), 2011	Number 14 The 9th Balkan Congress of Medical Genetics
Number 14 14 - Vol. 14 (1), 2011	Number 13 Vol. 13 (2), 2010
Number 13 Vol.13 (1), 2010	Number 12 Vol.12 (2), 2009
Number 12 Vol.12 (1), 2009	Number 11 Vol.11 (2),2008
Number 11 Vol.11 (1),2008	Number 10 Vol.10 (2), 2007
Number 10 10 (1),2007	Number 9 1&2, 2006
Number 9 3&4, 2006	Number 8 1&2, 2005
Number 8 3&4, 2004	Number 7 1&2, 2004
Number 6 3&4, 2003	Number 6 1&2, 2003
Number 5 3&4, 2002	Number 5 1&2, 2002
Number 4 Vol.3 (4), 2000	Number 4 Vol.2 (4), 1999
Number 4 Vol.1 (4), 1998	Number 4 3&4, 2001
Number 4 1&2, 2001	Number 3 Vol.3 (3), 2000
Number 3 Vol.2 (3), 1999	Number 3 Vol.1 (3), 1998
Number 2 Vol.3(2), 2000	Number 2 Vol.1 (2), 1998
Number 2 Vol.2 (2), 1999	Number 1 Vol.3 (1), 2000
Number 1 Vol.2 (1), 1999	Number 1 Vol.1 (1), 1998

About the journal ::: Editorial ::: Subscription ::: Information for authors ::: Contact