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

CASE PRESENTATION

The data of the patient were collected at the Depart- ment of Pulmonology at the Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”. This is a tertiary- level institution, recognized as the reference centre for rare diseases. This study was approved by the Ethics Commit- tee of the Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic” in Belgrade, Serbia (Decision 8/106). Written informed consent was obtained for publication. A full-term male infant was born to healthy non- consanguineous parents. His birth weight was 4020 g, and his APGAR score was 9. The patient met early develop- mental milestones. At the age of five months, the child was admitted to a regional hospital with fever, cough, tachyp- noea, cyanosis, and increased breathing work. A chest ra- diography revealed diffusely decreased lung transparency with diffuse alveolar opacification. Therefore, a course of parenteral antibiotics and systemic corticosteroids as well as inhaled bronchodilators was administered. The respira- tory viral PCR panel of the nasopharyngeal swab tested negative. A few days later, the patient was intubated due to clinical deterioration and transferred to our hospital. Upon admission, bilateral late inspiratory crackles were observed. A chest CT showed bilateral consolidation of the lung parenchyma with coarse intralobular thickening, minor ground-glass areas, and volume loss (Fig. 1A). The genetic results for primary immunodeficiency, cystic fibrosis, and metabolic disorders were negative. Flexible bronchoscopy revealed bronchomalacia. Bron- choalveolar fluid (BAL) analysis revealed significant lym- phocytosis (12%) and neutrophilia (20%), while PCR was positive for cytomegalovirus (CMV). Therefore, parenteral ganciclovir was initiated. Immunophenotypic analysis of BAL showed <1% CD1+ cells with a normal CD4/CD8 ratio. The complete blood count and liver function test re- sults were normal. The immunophenotype of lymphocytes in the peripheral blood showed a slightly decreased CD4 count and a CD4:CD8 ratio of 1.2. One week later, the child developed life-threatening cardiac dysrhythmias requiring a pacemaker implantation. Echocardiographic findings were normal without pulmo- nary hypertension. A combination of respiratory insuf- ficiency and cardiac arrhythmias arose clinical suspicion for central congenital hypoventilation syndrome. Genetic analysis for the PHOX2B gene mutations was negative. Considering the possible connection between CMV pneumonitis and early-onset respiratory failure, clini- cal exome sequencing (CES) was performed using the TruSight One (TSO) panel (Illumina, San Diego, CA, USA). This panel includes all known disease-associated genes described in the OMIM database as of 2013 and is designed to cover all exons and flanking intronic regions of 4,813 genes (~62,000 exons). All genes in the TSO panel where pathogenic, likely pathogenic, or variants of uncertain significance (VUS) were detected were further analysed. Variant Interpreter (Illumina) software was used for systematic interpretation of detected variants, and the variants were classified according to the recommenda- tions of the American College of Medical Genetics and Genomics (ACMG) [7]. A novel heterozygous nonsense variant, c.280A>T, p.Lys94Ter (p.K94*), was detected in the TERT gene (NM_198253.3). This variant introduces a premature STOP codon in the second of the 16 exons in the gene (Fig. 2A), leading to protein truncation and degradation via nonsense-mediated mRNA decay. The variant was classified as “likely pathogenic” according to the ACMG classification recommendations based on the following criteria: PVS1 (Very Strong): Loss-of-function (LOF) variants in the TERT gene are a known mechanism of disease, with 76 reported pathogenic LOF variants; PM2 (Supporting): The variant has not been previously recorded in the GnomAD Exomes or GnomAD Genomes population databases, indicating it is rare. The results of the segregation analysis showed that neither parent was a carrier of the detected variant, indicating its de novo origin. Pulse doses of methylprednisolone were initiated, with prednisone between doses and hydroxychloroquine and azithromycin, showing modest clinical benefits. Un- fortunately, failure to wean off MV in a further course led to a tracheotomy, and MV was continued at home. An open lung biopsy was not performed. A control chest CT scan six months later revealed progression of the lung disease (Fig. 1B). Head CT, performed before steroid therapy com- menced, showed supratentorial parenchymal volume loss with compensatory enlargement of CSF spaces. Eighteen months after the initial presentation, a new severe bilat- eral pneumonia led to multi-organ failure and death. The parents did not provide consent for autopsy.

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