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Background The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKC), the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs. Methods Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions. Results In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes ( DKC1 , TERT and RTEL1 ). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients. Conclusions Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.

Telomere length (TL) limits somatic cell replication. However, the shortest among the telomeres in each nucleus, not mean TL, is thought to induce replicative senescence. Researchers have relied on Southern blotting (SB), and techniques calibrated by SB, for precise measurements of TL in epidemiological studies. However, SB provides little information on the shortest telomeres among the 92 telomeres in the nucleus of human somatic cells. Therefore, little is known about the accumulation of short telomeres with age, or whether it limits the human lifespan. To fill this knowledge void, we used the Telomere‐Shortest‐Length‐Assay (TeSLA), a method that tallies and measures single telomeres of all chromosomes. We charted the age‐dependent buildup of short telomeres (<3 kb) in human hematopoietic cells from 334 individuals (birth‐89 years) from the general population, and 18 patients with dyskeratosis congenita‐telomere biology disorders (DC/TBDs), whose hematopoietic cells have presumably reached or are close to their replicative limit. For comparison, we also measured TL with SB. We found that in hematopoietic cells, the buildup of short telomeres occurs in parallel with the shortening with age of mean TL. However, the proportion of short telomeres was lower in octogenarians from the general population than in patients with DC/TBDs. At any age, mean TL was longer and the proportion of short telomeres lower in females than in males. We conclude that though converging to the TL‐mediated replicative limit, hematopoietic cell telomeres are unlikely to reach this limit during the lifespan of most contemporary humans. Population studies have principally focused on the role of mean telomere length in human health and longevity. The availability of new telomere length measurement techniques enables examining the relations between the shortest telomeres and human diseases.

Telomeres are the nucleoprotein complex at chromosome ends essential in genomic stability. Baseline telomere length (TL) is determined by rare and common germline genetic variants but shortens with age and is susceptible to certain environmental exposures. Cellular senescence or apoptosis are normally triggered when telomeres reach a critically short length, but cancer cells overcome these protective mechanisms and continue to divide despite chromosomal instability. Rare germline variants in telomere maintenance genes cause exceedingly short telomeres for age (< 1st percentile) and the telomere biology disorders, which are associated with elevated risks of bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, and squamous cell carcinoma of the head/neck and anogenital regions. Long telomeres due to rare germline variants in the same or different telomere maintenance genes are associated with elevated risks of other cancers, such as chronic lymphocytic leukemia or sarcoma. Early epidemiology studies of TL in the general population lacked reproducibility but new methods, including creation of a TL polygenic score using common variants, have found longer telomeres associated with excess risks of renal cell carcinoma, glioma, lung cancer, and others. It has become clear that when it comes to TL and cancer etiology, not too short, not too long, but “just right” telomeres are important in minimizing cancer risk.

The telomerase enzyme is essential for telomere maintenance. Pathogenic variants in telomere-associated genes have been associated with critical telomere shortening, resulting in telomere biology disorders (TBD) such as bone marrow failure, idiopathic pulmonary fibrosis, and dyskeratosis congenita. The TBDs are clinically heterogeneous and families with TBD often experience an earlier onset and increased symptom severity for each generation. Consensus guidelines have identified certain genetic variants as pathogenic or likely pathogenic, but many are classified as variants of uncertain significance (VUS) in the absence of additional supporting evidence. The pathogenicity of a VUS in genes encoding the telomerase complex could be evaluated by in vitro telomerase activity (TA) measurement. We have developed a functional TA assay in patient-derived T-cells based on the Telomeric Repeat Amplification Protocol (TRAP) combined with qPCR. TA was significantly lower in six TBD patients with a TERT or TERC variant compared to controls (0.11 versus 0.54, p  < 0.001). Four patients had a TA of more than three standard deviations below the mean of controls, strongly supporting pathogenicity of the variants. In summary, functional analysis of TA in patient-derived cells could support pathogenic evaluation in clinical diagnostics and reduce the number of reported VUS for TBD patients.

Telomeres are terminal protective chromosome structures. Genetic variants in genes coding for proteins required for telomere maintenance cause rare, life-threatening Telomere Biology Disorders (TBDs) such as dyskeratosis congenita, aplastic anemia or pulmonary fibrosis. The more frequently used mice strains have telomeres much longer than the human ones which question their use as in vivo models for TBDs. One mice model with shorter telomeres based on the CAST/EiJ mouse strain carrying a mutation in the Terc gene, coding for the telomerase RNA component, has been studied in comparison with C57BL/6J mice, carrying the same mutation and long telomeres. The possible alterations produced in lungs and the haematopoietic system, frequently affected in TBD patients, were determined at different ages of the mice. Homozygous mutant mice presented a very shortened life span, more notorious in the short-telomeres CAST/EiJ strain. The lungs of mutant mice presented a transitory increase in fibrosis and a significant decrease in the relative amount of the alveolar epithelial type 2 cells from six months of age. This decrease was larger in mutant homozygous animals but was also observed in heterozygous animals. On the contrary the expression of the senescence-related protein P21 increased from six months of age in mutant mice of both strains. The analysis of the haematopoietic system indicated a decrease in the number of megakaryocyte-erythroid progenitors in homozygous mutants and an increase in the clonogenic potential of bone marrow and LSK cells. Bone marrow cells from homozygous mutant animals presented decreasing in vitro expansion capacity. The alterations observed are compatible with precocious ageing of lung alveolar cells and the bone marrow cells that correlate with the alterations observed in TBD patients. The alterations seem to be more related to the genotype of the animals that to the basal telomere length of the strains although they are more pronounced in the short-telomere CAST/EiJ-derived strain than in C57BL/6J animals. Therefore, both animal models, at ages over 6–8 months, could represent valuable and convenient models for the study of TBDs and for the assay of new therapeutic products.

Telomeres are repetitive nucleotide sequences at the ends of chromosomes that preserve genomic integrity. Defects in telomere maintenance mechanisms lead to premature telomere shortening, resulting in cellular senescence, apoptosis, and organ dysfunction, collectively termed telomere biology disorders (TBDs). Short telomere length is associated with an increased risk of end-stage fibrotic disease of the lung and/or liver, which may necessitate lung or liver transplantation. Beyond pulmonary and hepatic involvement, TBDs can also affect cardiac and renal function. Importantly, the bone marrow function is often also compromised, which can significantly influence transplant outcomes. Although evidence remains scarce, particularly in non-lung solid organ transplant recipients, post-transplant immunosuppressive therapy, typically including corticosteroids, calcineurin inhibitors, and cell cycle inhibitors, may exacerbate the underlying hematopoietic fragility in TBD patients. Hematological complications may result from both the intrinsic TBD and the additive myelotoxic effects of immunosuppressive agents (e.g., azathioprine, mycophenolate mofetil) or anti-infectious prophylaxis (e.g., trimethoprim-sulfamethoxazole, valganciclovir). Early recognition of TBDs prior to transplantation is essential. Assessment of telomere length and genetic testing should be considered in at-risk candidates, particularly those with early-onset pulmonary fibrosis, unexplained cytopenia, cryptogenic liver disease, or a family history suggestive of TBD. A multidisciplinary approach involving pulmonology, hepatology, hematology, and transplant specialists is crucial to optimize patient selection, perioperative management, and post-transplant care. This review summarizes current knowledge on hematological complications following solid organ transplantation in TBD patients and describes expert-opinion strategies for the pre-transplant evaluation and post-transplant management of these high-risk individuals.

Purpose of Review Telomere biology disorders (TBD) are a group of genetic disorders characterized by premature shortening of telomeres, resulting in accelerated aging of somatic cells. This often leads to major multisystem organ dysfunction, and TBDs have become increasingly recognized as a significant contributor to numerous disease processes within the past 10–15 years. Both research and clinical practice in this field are rapidly evolving. Recent Findings A subset of patients with TBD suffers from interstitial lung disease, most commonly pulmonary fibrosis. Often, the clinical presentation is indistinguishable from other forms of lung fibrosis. There are no pathognomonic radiographic or histological features, and a high level of suspicion is therefore required. Telomere evaluation is thus crucial to establishing the diagnosis. Summary This review details the clinical presentation, objective evaluation, indicated genetic testing, and recommended management strategies for patients affected by interstitial lung disease associated with TBDs. Our goal is to empower pulmonologists and other healthcare professionals who care for these patients to provide appropriate and personalized care for this population.

Telomere Biology Disorders (TBDs) are a group of rare diseases characterized by the presence of short and/or dysfunctional telomeres. They comprise a group of bone marrow failure syndromes, idiopathic pulmonary fibrosis, and liver disease, among other diseases. Genetic alterations (variants) in the genes responsible for telomere homeostasis have been linked to TBDs. Despite the number of variants already identified as pathogenic, an even more significant number must be better understood. The study of TBDs is challenging since identifying these variants is difficult due to their rareness, it is hard to predict their impact on the disease onset, and there are not enough samples to study. Most of our knowledge about pathogenic variants comes from assessing telomerase activity from patients and their relatives affected by a TBD. However, we still lack a cell-based model to identify new variants and to study the long-term impact of such variants on the genes involved in TBDs. Herein, we present a cell-based model using CRISPR base editing to mutagenize the endogenous alleles of 21 genes involved in telomere biology. We identified key residues in the genes encoding 17 different proteins impacting cell growth. We provide functional evidence for variants of uncertain significance in patients with TBDs. We also identified variants resistant to telomerase inhibition that, similar to cells expressing wild-type telomerase, exhibited increased tumorigenic potential using an in vitro tumour growth assay. We believe that such cell-based approaches will significantly advance our understanding of the biology of TBDs and may contribute to the development of new therapies for this group of diseases.

Studies of rare and common illnesses have led to remarkable progress in the understanding of the role of telomeres (nucleoprotein complexes at chromosome ends essential for chromosomal integrity) in human disease. Telomere biology disorders encompass a growing spectrum of conditions caused by rare pathogenic germline variants in genes encoding essential aspects of telomere function. Dyskeratosis congenita, a disorder at the severe end of this spectrum, typically presents in childhood with the classic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia, accompanied by a very high risk of bone marrow failure, cancer, pulmonary fibrosis, and other medical problems. In contrast, the less severe end of the telomere biology disorder spectrum consists of middle-age or older adults with just one feature typically seen in dyskeratosis congenita, such as pulmonary fibrosis or bone marrow failure. In the common disease realm, large-scale molecular epidemiology studies have discovered novel associations between illnesses, such as cancer, heart disease, and mental health, and both telomere length and common genetic variants in telomere biology genes. This review highlights recent findings of telomere biology in human disease from both the rare and common disease perspectives. Multi-disciplinary collaborations between clinicians, basic scientists, and epidemiologist are essential as we seek to incorporate new telomere biology discoveries to improve health outcomes.

Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure. Patients with TBDs often experience bone marrow failure. NAD, an essential metabolic coenzyme, is decreased in models of DC. Herein, using telomerase reverse transcriptase null ( Tert −/− ) mice with critically short telomeres, we investigated the effect of NAD supplementation with the NAD precursor, nicotinamide riboside (NR), on features of health span disrupted by telomere impairment. Our results revealed that NR ameliorated body weight loss in Tert −/− mice and improved telomere integrity and telomere dysfunction-induced systemic inflammation. NR supplementation also mitigated myeloid skewing of Tert −/− hematopoietic stem cells. Furthermore, NR alleviated villous atrophy and inflammation in the small intestine of Tert −/− transplant recipient mice. Altogether, our findings support NAD intervention as a potential therapeutic strategy to enhance aspects of health span compromised by telomere attrition.