The presence of germline pathogenic variants (GPVs) in genes involved in telomere length regulation or protection has been demonstrated to be a causative factor for telomere biology disorders (TBDs). TBDs are a group of rare diseases characterized by premature ageing, which exhibit remarkable clinical heterogeneity, with manifestations ranging from pulmonary fibrosis and liver disease in adulthood to bone marrow failure and mucocutaneous anomalies in infancy. To date, pathogenic variants in over 20 telomere-related genes (TRGs) have been implicated, each affecting telomere length or integrity through diverse molecular pathways. This review summarizes the genetic and clinical complexity of TBDs, highlighting challenges in diagnosis and genetic counselling.

Background:Mutations in telomere-related genes (TRGs) are the main cause of monogenic familial pulmonary fibrosis. Dyskerin, encoded by the X-localised gene DKC1, is involved in telomere maintenance. Methods:This retrospective study aimed to further characterise the pulmonary phenotype of DKC1-deficient patients with pulmonary fibrosis identified between 2010 and 2025 in our laboratory. Results:We reported eight, as yet undescribed, to our knowledge, probands affected by pulmonary fibrosis associated with X-linked DKC1 deficiency. The median age at interstitial lung disease (ILD) diagnosis was 47 years. Four had idiopathic pulmonary fibrosis, two unclassifiable fibrosis, one idiopathic nonspecific interstitial pneumonia and one unknown. All patients displayed ectodermal abnormalities (premature hair greying, nail dystrophies, reticulated hyper- or hypopigmentation, tooth abnormalities and oral leukoplasia). Haematological abnormalities were found in four patients. Seven patients died during follow-up and one patient received a transplant. Median survival after ILD diagnosis was 22 months (range 3-81 months). Conclusions:Compared with patients with pulmonary fibrosis associated with other TRG variants, those with pulmonary fibrosis associated with X-linked recessive DKC1 variants are younger and have a shorter survival time. Early identification and referral of these patients to an expert transplantation centre should be considered.

COPA syndrome is a rare monogenic autoinflammatory disease due to heterozygous mutations in COPA, encoding the coatomer subunit α. COPA syndrome demonstrates phenotypic overlap with STING-associated vasculopathy with onset in infancy (SAVI), the latter due to gain-of-function mutations in STING1. Indeed, STING activation is a key driver of the pathogenesis of COPA syndrome, and a recent report suggested that the presence of the common HAQ STING allele confers complete protection against the development of clinical disease in the context of pathogenic heterozygous mutations in COPA. Given the potential significance of this result for patient management, we investigated the STING HAQ haplotype status of a separate cohort of individuals segregating pathogenic mutations in COPA. In doing so, we ascertained five HAQ-negative, clinically asymptomatic individuals aged 30, 39, 39, 42, and 43 years at last evaluation, and an HAQ-positive male with kidney disease that we consider most likely attributable to the recurrent R233H mutation in COPA. Our findings challenge the suggestion that STING haplotype status is the sole determinant of clinical penetrance in COPA syndrome.

Telomere-related gene (TRG) pathogenic variants are detected in ∼30% of familial pulmonary fibrosis (PF) cases. Danazol, a synthetic sex hormone with androgenic properties, has been found associated with telomere elongation and hematologic response in patients with short telomeres. The objective of the ANDROTELO multicenter, prospective, open-label single-arm phase II clinical trial ( NCT03710356 ) was to evaluate the efficacy and safety of danazol in carriers of TRG mutations with PF or bone-marrow failure (BMF).Included patients were carriers of a pathogenic or likely pathogenic TRG variant and presented a PF lung involving ≥10% parenchymal involvement on chest CT (PF group) and/or severe BMF (BMF group). Treatment was danazol 400 mg twice a day for 12 months. We included 25 patients with PF (16 males) and 5 with BMF (2 males). One PF patient withdrew consent. At inclusion, the median age in the PF group was 62.5 years, FVC 69% (interquartile range 40;120) and DLCO 44% (29;84). Ten of 24 PF patients (42%) completed the 12-month treatment. Causes of premature treatment discontinuation were side effects (n=9), death (n=3), lung transplantation (n=1), and disease progression (n=1). Fourteen PF patients were evaluated at month 12: 8 showed a relative decline of FVC of <5%. The median relative decrease in FVC and DLCO was −10% (interquartile range −14;−2) and −10.3% (−22.7;4.2). The 5 patients in the BMF group completed the 12-month treatment and exhibited at least partial response. Danazol was poorly tolerated in patients with TRG-related PF in this study, thus precluding efficacy assessment.

Here we show that somatic genetic rescue is frequent in telomere biology disorders (TBDs) caused by germline ZCCHC8 variants. Our results highlight the critical intrinsic role of ZCCHC8 in human hematopoiesis and a potential mechanism for disease modification in TBDs.

Background:Chronic lung allograft dysfunction (CLAD) is the main cause of death following lung transplantation (LT). Its pathophysiology and risk factors remain poorly understood. Donor or recipient genetic characteristics could be involved. MUC5B promoter rs35705950 polymorphism is one of the major genetic factors associated with pulmonary fibrosis. We aimed to correlate the MUC5B genotype of recipients and donors with LT outcomes. Methods:Recipient and donor blood samples from the Cohort in Lung Transplantation biobank were used. MUC5B status was determined by quantitative PCR using probes for rs35705950 polymorphism. CLAD occurrence and phenotype were blindly adjudicated. Results:210 recipient-donor pairs were analysed. At 5 years, 68 patients (32.4%) had CLAD. The MUC5B rs35705950 polymorphism, whether in the donor or the recipient, was not associated with CLAD at 5 years (OR 1.07 (95% CI 0.53-2.11), p=0.8, and OR 0.79 (95% CI 0.37-1.60), p=0.5, respectively), CLAD-free survival or CLAD phenotype. The prevalence of the recipients' T allele differed among underlying respiratory diseases (20.0% in interstitial lung disease, 8.4% in emphysema, 13.4% in cystic fibrosis and 5.6% for others, p=0.03). Risk of antibody-mediated rejection (AMR) was independent of the donor MUC5B polymorphism genotype, whereas the presence of the T allele in the recipient was associated with a reduced occurrence of AMR (OR 0.26 (95% CI 0.08-0.69), p=0.015). Conclusion:MUC5B rs35705950 polymorphism in the donor or the recipient does not affect LT outcomes. The significant association between the recipients' polymorphism and reduced AMR occurrence has yet to be confirmed.

BACKGROUND:Shorter leukocyte telomere length (LTL) has been reported in patients with rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) and linked to increased disease severity and mortality in idiopathic pulmonary fibrosis, which shares similarities with RA-ILD. We aimed to evaluate the impact of short LTL on baseline respiratory disease severity, disease progression and survival in patients with RA-ILD. METHODS:Patients diagnosed with RA-ILD following multidisciplinary assessment were enrolled in a prospective French observational study. LTL was measured at enrolment using qPCR. Short LTL was defined as age-adjusted LTL <10th percentile. Lung disease progression was defined as death, lung transplantation or functional respiratory decline (absolute decrease in forced vital capacity (FVC) ≥5% predicted or diffusing capacity of the lung for carbon monoxide (D LCO) ≥10% predicted). RESULTS:Among 101 patients with RA-ILD, 46% were male, mean±sd age at enrolment was 66±10 years and 43 (43%) had short LTL. Patients with short LTL had lower FVC % predicted (82% versus 93%) and D LCO % predicted (49% versus 63%) at enrolment, and greater 12-month decline in FVC % predicted and D LCO % predicted in mixed effects models (-7.7% (95% CI -11.6- -3.8%); p<0.001 and -4.5 (95% CI -7.2- -1.8%); p=0.001, respectively), although transplant-free survival was similar over a median (interquartile range) follow-up of 3.6 (1.8-7.0) years. Lung disease progression was observed within 12 months of enrolment in 33 (33%) patients, more frequently in patients with short LTL (47% versus 22%; univariate p=0.011) and lower FVC at enrolment. Multivariate logistic regression identified lower FVC and short LTL as predictors of 12-month progression (OR 0.97 (95% CI 0.94-1.00); p=0.031 and OR 2.80 (95% CI 0.99-8.29); p=0.056, respectively). CONCLUSION:Short LTL is associated with baseline severity and 12-month progression in RA-ILD.

BACKGROUND AND OBJECTIVE:Interstitial lung diseases (ILDs) are rare and severe respiratory conditions that may ultimately result in pulmonary fibrosis (PF). The objective of this study was to present the results of molecular diagnosis of early-onset ILD (from neonates to young adults < 50 years) in a reference genetic diagnostic laboratory. METHODS:DNAs from 699 index cases and 190 relatives were studied over 6 years by Sanger and/or targeted next generation sequencing of surfactant-related genes and other genes involved in early-onset ILD. RESULTS:Pathogenic/likely pathogenic variants were evidenced for 62 patients (8.9%). The genes most frequently involved were SFTPA2 (13/62), followed by ABCA3 (12/62) and SFTPC (10/62). Among index cases for whom precise clinical data were available (n = 542), indications associated with a high molecular diagnostic yield were pulmonary alveolar proteinosis (61.5%, 8/13; p < 0.0007); family history of ILD/PF and lung cancer (36.8%, 7/19; p = 0.0132) and newborns > 32 weeks gestation with neonatal respiratory distress (14.8%, 9/61). The proportion of positive molecular investigations culminated in two age groups over the lifespan: 23.3% (7/30) in children aged 1 to 10 years, and 18.3% (15/82) in adults aged 30 to 40 years. Over the 6-year period, 190 relatives were subjected to testing in order to perform segregation studies (n = 123) and/or predictive testing (n = 79). CONCLUSION:This study highlights the specific patient's characteristics associated with a high or low molecular diagnostic yield in clinical practice. Furthermore, it emphasises the importance of establishing a molecular diagnosis in order to provide genetic counselling to the family.

Telomeres, repetitive DNA sequences at the ends of chromosomes, play a crucial role in maintaining genomic stability. In recent years, their significance in lung transplantation has gained growing attention. Shortened telomeres—whether due to inherited telomeropathies or acquired attrition—have emerged as a risk factor for various pulmonary diseases, particularly pulmonary fibrosis, which is a leading indication for lung transplantation.This review provides a comprehensive overview of current knowledge on the impact of short telomeres in lung transplant recipients, encompassing pre-transplant assessment and post-transplant outcomes. Patients with telomere-biology disorder present unique clinical challenges. Before transplantation, they may exhibit extra-pulmonary manifestations such as bone marrow dysfunction, hepatic abnormalities, precipitation to develop cancer, all of which necessitate a tailored evaluation and multidisciplinary management. After transplantation, these patients appear to be at increased risk of complications, including drug-related hematologic toxicity, bone marrow failure, and heightened susceptibility to infections.The review emphasizes the importance of identifying patients with telomere biology disorders early in the transplant process and supports the incorporation of telomere length testing in selected populations. Furthermore, it highlights the need for adjusted immunosuppressive strategies and closer surveillance in this vulnerable population. Ultimately, the authors advocate for prospective, multicenter studies aimed at refining the prognostic value of telomere length and guiding evidence-based, individualized transplant strategies for patients with telomere biology disorders related interstitial lung diseases.

Approximately 30% of individuals diagnosed with familial pulmonary fibrosis (FPF) exhibit a pathogenic variant upon genetic analysis. We established a genetic Multidisciplinary Discussion (geneMDD) aimed to enhance expertise in diagnosing and managing FPF. This study aimed at prospectively evaluating the impact of geneMDD on diagnosis and treatment in patients referred to geneMDD. In this prospective study, we enrolled all consecutive patients referred to the geneMDD. At each meeting, the impact of the meeting was questioned on the genetic conclusion, the pulmonary diagnosis, and the treatment. A total of 115 patients were included. Before geneMDD, rare variants were detected in 82 out of 107 patients, among which 65 variants were classified as pathogenic/likely pathogenic. Following geneMDD, 2 pathogenic variants (3%) were reclassified as variants of uncertain significance (VUS) (n = 1) or benign (n = 1). Among the 17 variants initially classified as VUS, 2 (11.8%) were reclassified as likely pathogenic/pathogenic. The pulmonary diagnosis was confirmed for all patients (unclassifiable lung fibrosis was the more frequent diagnosis, n = 38, 33.0%). The therapeutic regimen was changed after geneMDD in 30 patients. Factors associated with therapeutic changes included the pulmonary diagnosis and presence of a pathogenic/likely pathogenic variant. In addition, the French health system allows offering whole genome sequencing (WGS) in patients with a first negative genetic analysis by NGS panel after discussion in geneMDD, but in total, since September 1st, 2021, WGS was negative for the four analysed families. This study suggests that geneMDD could influence the treatment of FPF patients.

BACKGROUND:Several rare surfactant-related gene (SRG) variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing. We aimed to study the epidemiology and phenotype of lung cancer in an international cohort of SRG variant carriers. METHODS:We conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomere-related gene (TRG) variant carriers. RESULTS:We identified 99 SRG adult variant carriers (SFTPA1 (n=18), SFTPA2 (n=31), SFTPC (n=24), ABCA3 (n=14) and NKX2-1 (n=12)), including 20 (20.2%) with lung cancer (SFTPA1 (n=7), SFTPA2 (n=8), SFTPC (n=3), NKX2-1 (n=2) and ABCA3 (n=0)). Among SRG variant carriers, the odds of lung cancer was associated with age (OR 1.04, 95% CI 1.01-1.08), smoking (OR 20.7, 95% CI 6.60-76.2) and SFTPA1/SFTPA2 variants (OR 3.97, 95% CI 1.39-13.2). Adenocarcinoma was the only histological type reported, with programmed death ligand-1 expression ≥1% in tumour cells in three samples. Cancer staging was localised (I/II) in eight (40%) individuals, locally advanced (III) in two (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and three received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patients versus TRG patients was 18.1 (95% CI 7.1-44.7). CONCLUSIONS:The high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular computed tomography scan follow-up should be evaluated.

Premature telomere shortening or telomere instability is associated with a group of rare and heterogeneous diseases collectively known as telomere biology disorders (TBDs). Here we identified two unrelated individuals with clinical manifestations of TBDs and short telomeres associated with the identical monoallelic variant c.767A>G; Y256C inRPA2. Although the replication protein A2 (RPA2) mutant did not affect ssDNA binding and G-quadruplex-unfolding properties of RPA, the mutation reduced the affinity of RPA2 with the ubiquitin ligase RFWD3 and reduced RPA ubiquitination. Using engineered knock-in cell lines, we found an accumulation of RPA at telomeres that did not trigger ATR activation but caused short and dysfunctional telomeres. Finally, both patients acquired, in a subset of blood cells, somatic genetic rescue events in eitherPOT1genes orTERTpromoters known to counteract the accelerated telomere shortening. Collectively, our study indicates that variants inRPA2represent a novel genetic cause of TBDs. Our results further support the fundamental role of the RPA complex in regulating telomere length and stability in humans.