Telomere Biology Disorders Research Articles

Different phenotypes with different endings-Telomere biology disorders and cancer predisposition with long telomeres.

Rare germline pathogenic variants (GPVs) in genes essential in telomere length maintenance and function have been implicated in two broad classes of human disease. The telomere biology disorders (TBDs) are a spectrum of life-threatening conditions, including bone marrow failure, liver and lung disease, cancer and other complications caused by GPVs in telomere maintenance genes that result in short and/or dysfunctional telomeres and reduced cellular replicative capacity. In contrast, cancer predisposition with long telomeres (CPLT) is a disorder associated with elevated risk of a variety of cancers, primarily melanoma, thyroid cancer, sarcoma, glioma and lymphoproliferative neoplasms caused by GPVs in shelterin complex genes that lead to excessive telomere elongation and increased cellular replicative capacity. While telomeres are at the root of both disorders, the term TBD is used to convey the clinical phenotypes driven by critically short or otherwise dysfunctional telomeres and their biological consequences.

A “rotating menu” of medical uncertainty for families affected by telomere biology disorders: A qualitative interview study

BackgroundMedical uncertainty may cause distress and challenge medical decision-making for patients with rare diseases and their caregivers. Few studies have examined the experience and management of medical uncertainty in rare disease and the dynamics of multiple medical uncertainty sources, issues, and management strategies. ObjectiveWe explored the experience and management of uncertainty in individuals with telomere biology disorders (TBDs), a set of rare cancer-prone bone marrow failure syndromes, and their caregivers. DesignParticipants (N = 32) in this qualitative-descriptive study were individuals with a TBD (n = 17) and/or their caregivers (n = 15). We thematically analyzed transcripts to describe the presence and dynamics of medical uncertainty in TBDs using categories from a previously published taxonomy. ResultsIndividuals with TBDs and caregivers described medical uncertainty as a chronic burden embodied amidst a range of interrelated sources and issues. Scientific uncertainty included diagnostic and prognostic ambiguity. Practical uncertainty focused on logistical challenges of building and maintaining medical care teams. Personal uncertainty included difficulty realigning self-identity, goals, and relationship expectations post-diagnosis. Scientific, practical, and personal uncertainty issues were entangled. The rarity of TBDs resulted in limited scientific knowledge, which gave rise to practical and personal uncertainties affecting medical decision-making and relationship formation (e.g., creating trusted care teams where patient knowledge of TBDs may exceed that of clinicians). Participants used multiple strategies for uncertainty management, particularly information-seeking and community-building. However, these management strategies could intensify, rather than resolve, participants’ medical uncertainty. ConclusionIn TBDs, medical uncertainty manifests as a network of multiple, interrelated, sources and issues, which require evolving management strategies. Researchers must be mindful that complex, synergistic uncertainty networks contribute to psychosocial challenges in TBDs. Additional research is warranted to address scientific uncertainty in TBDs, including clinical manifestations and underlying biology, and to develop psychosocial interventions that recognize and anticipate evolving uncertainty.

Inherited Predispositions to Myeloid Neoplasms: Pathogenesis and Clinical Implications.

Myeloid neoplasms with and without preexisting platelet disorders frequently develop in association with an underlying germline predisposition. Germline alterations affecting ANKRD26, CEBPA, DDX41, ETV6, and RUNX1 are associated with nonsyndromic predisposition to the development of myeloid neoplasms including acute myeloid leukemia and myelodysplastic syndrome. However, germline predisposition to myeloid neoplasms is also associated with a wide range of other syndromes, including SAMD9/9L associated predisposition, GATA2 deficiency, RASopathies, ribosomopathies, telomere biology disorders, Fanconi anemia, severe congenital neutropenia, Down syndrome, and others. In the fifth edition of the World Health Organization (WHO) series on the classification of tumors of hematopoietic and lymphoid tissues, myeloid neoplasms associated with germline predisposition have been recognized as a separate entity. Here, we review several disorders from this WHO entity as well as other related conditions with an emphasis on the molecular pathogenesis of disease and accompanying somatic alterations. Finally, we provide an overview of establishing the molecular diagnosis of these germline genetic conditions and general recommendations for screening and management of the associated hematologic conditions.

Defining the complex needs of families with rare diseases-the example of telomere biology disorders.

Families with rare diseases, such as telomere biology disorders (TBDs), may have extensive unmet needs given the heterogeneity, chronicity, and potential severity of illness. TBDs are rare inherited syndromes associated with high risk of bone marrow failure, cancer, pulmonary fibrosis, and other severe, chronic complications. To identify gaps in clinical care, we aimed to ascertain the perceived unmet needs of adults and family caregivers, current or bereaved, of individuals with TBDs. Participants were aged ≥18 years with a self-reported TBD diagnosis and/or ever caregivers to one or more family members with a TBD. Participants completed an online survey (N = 35) and/or an audio-recorded telephone interview (N = 32). We calculated descriptive statistics in SPSS and thematically analyzed interview transcripts. Quantitative and qualitative data were analyzed concurrently. Most participants were aged ≥35 years, female, highly educated, and medically insured. Survey respondents reported numerous unmet needs in psychosocial, medical, financial, and daily activity domains. In interviews, participant descriptions validated and contextualized the salience of these unmet needs. Both qualitative and quantitative data identified critical shortfalls in addressing chronic family distress and specialty care coordination. Adults and caregivers of individuals with TBDs have a high risk of adverse psychosocial sequelae given extensive unmet needs. These findings provide a foundation for understanding the range and extent of gaps in care for families with rare diseases, especially TBDs but that are likely applicable to others. Tailored multi-disciplinary interventions involving patients, families, clinicians, researchers, and patient advocacy communities are required to appropriately address care needs for all rare diseases.

Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders.

Genomic instability disorders are characterized by DNA or chromosomal instability resulting in various clinical manifestations including developmental anomalies, immunodeficiency, and increased risk to develop cancers beginning in childhood. Many of these genomic instability disorders also present with exquisite sensitivity to anticancer treatments such as ionizing radiation and chemotherapy, which may further increase the risk of second cancers. In July 2023, the American Association of Cancer Research held the second Childhood Cancer Predisposition Workshop where multidisciplinary international experts discussed, reviewed, and updated recommendations for children with cancer predisposition syndromes. This article will discuss childhood cancer risks and surveillance recommendations for the group of genomic instability disorders with predominantly recessive inheritance, including the DNA repair disorders ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia, Xeroderma Pigmentosum, Bloom syndrome, and Rothmund-Thomson syndrome, as well as the telomere biology disorders and mosaic variegated aneuploidy. Recognition of children with genomic instability disorders is important in order to make the proper diagnosis, enable genetic counseling, and inform cancer screening, cancer risk reduction, and choice of anti-cancer therapy.

Clonal landscape and clinical outcomes of telomere biology disorders: somatic rescue and cancer mutations

AbstractTelomere biology disorders (TBDs), caused by pathogenic germ line variants in telomere-related genes, present with multiorgan disease and a predisposition to cancer. Clonal hematopoiesis (CH) as a marker of cancer development and survival in TBDs is poorly understood. Here, we characterized the clonal landscape of a large cohort of 207 patients with TBD with a broad range of age and phenotype. CH occurred predominantly in symptomatic patients and in signature genes typically associated with cancers: PPM1D, POT1, TERT promoter (TERTp), U2AF1S34, and/or TP53. Chromosome 1q gain (Chr1q+) was the commonest karyotypic abnormality. Clinically, multiorgan involvement and CH in TERTp, TP53, and splicing factor genes were associated with poorer overall survival. Chr1q+ and splicing factor or TP53 mutations significantly increased the risk of hematologic malignancies, regardless of clonal burden. Chr1q+ and U2AF1S34 mutated clones were premalignant events associated with the secondary acquisition of mutations in genes related to hematologic malignancies. Similar to the known effects of Chr1q+ and TP53-CH, functional studies demonstrated that U2AF1S34 mutations primarily compensated for aberrant upregulation of TP53 and interferon pathways in telomere-dysfunctional hematopoietic stem cells, highlighting the TP53 pathway as a canonical route of malignancy in TBD. In contrast, somatic POT1/PPM1D/TERTp mutations had distinct trajectories unrelated to cancer development. With implications beyond TBD, our data show that telomere dysfunction is a strong selective pressure for CH. In TBD, CH is a poor prognostic marker associated with worse overall survival. The identification of key regulatory pathways that drive clonal transformation in TBD allows for the identification of patients at a higher risk of cancer development.

Germline RTEL1 Variants in Telomere Biology Disorders.

Rare germline variation in regulator of telomere elongation helicase 1 (RTEL1) is associated with telomere biology disorders (TBDs). Biallelic RTEL1 variants result in childhood onset dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome whereas heterozygous individuals usually present later in life with pulmonary fibrosis or bone marrow failure. We compiled all TBD-associated RTEL1 variants in the literature and assessed phenotypes and outcomes of 44 individuals from 14 families with mono- or biallelic RTEL1 variants enrolled in clinical trial NCT00027274. Variants were classified by adapting ACMG-AMP guidelines using clinical information, telomere length, and variant allele frequency data. Compared with heterozygotes, individuals with biallelic RTEL1 variants had an earlier age at diagnosis (median age 35.5 vs. 5.1 years, p < 0.01) and worse overall survival (median age 66.5 vs. 22.9 years, p < 0.001). There were 257 unique RTEL1 variants reported in 47 publications, and 209 had a gnomAD minor allele frequency <1%. Only 38.3% (80/209) met pathogenic/likely pathogenic criteria. Notably, 8 of 209 reported disease-associated variants were benign or likely benign and the rest were variants of uncertain significance. Given the considerable differences in outcomes of TBDs associated with RTEL1 germline variants and the extent of variation in the gene, systematic functional studies and standardization of variant curation are urgently needed to inform clinical management.

Haematological features of telomere biology disorders diagnosed in adulthood: A French nationwide study of 127 patients.

Data on haematological features of telomere biology disorders (TBD) remain scarce. We describe haematological, extra-haematological characteristics and prognosis of 127 genetically confirmed TBD patients diagnosed after the age of 15. Ninety-three index cases and 34 affected relatives were included. At diagnosis of TBD, 76.3% of index cases had haematological features, half pulmonary features and a third liver features. At diagnosis, bone marrow failure (BMF) was present in 59 (46.5%), myelodysplastic syndrome (MDS) in 22 (17.3%) and acute myeloid leukaemia (AML) in 2 (1.6%) while 13 (10.2%) developed or worsened bone marrow involvement during follow-up. At diagnosis, compared to MDS/AML patients, BMF patients were younger (median 23.1 years vs. 43.8, p= 0.007), and had a better outcome (4-year overall survival 76.3% vs. 31.8%, p < 0.001). While frequencies and burden of cytogenetical and somatic mutations increased significantly in myeloid malignancies, some abnormalities were also observed in patients with normal blood counts and BMF, notably somatic spliceosome variants. Solid cancers developed in 8.7% patients, mainly human papillomavirus-related cancers and hepatocellular carcinomas. TBD is a multiorgan progressive disease. While BMF is the main haematological disorder, high-risk myeloid malignancies are common, and are, together with age, the only factors associated with a worse outcome.

Telomere Biology Disorders: Report on Clinical and Angiographic Findings

PurposeTo evaluate the retinal vasculature in pediatric patients with telomere biology disorders (TBD). DesignRetrospective consecutive case series. SubjectsPediatric patients with a diagnosis of TBD who underwent widefield fluorescein angiography (FA). MethodsElectronic medical records of pediatric patients with TBD at a tertiary referral eye center were reviewed from January 2019 to July 2023. Vascular phenotype was assessed by reviewing FA images. Main outcomes measuresIncomplete peripheral vascularization, aneurysmal dilatation, terminal arborization, anastomotic loops, capillary dropout, neovascularization, tortuosity, leakage from tractional membranes, and blockage from hemorrhage. ResultsFourteen eyes from 7 patients were included. All patients were genetically confirmed for TBD. The most common genetic variants were in CTC1 (5 patients; 71.4%), ACD (1 patient; 14.3%), and RTEL1 (1 patient; 14.3%). On FA, the most common findings were incomplete peripheral vascularization (14 eyes, 100%), aneurysmal dilatation (12 eyes, 85.7%), terminal arborization (12 eyes, 85.7%), anastomotic loops (12 eyes, 85.7%), capillary dropout (10 eyes, 71.4%), and neovascularization (9 eyes, 64.3%). Regarding treatment, laser photocoagulation (14 eyes, 100%), intravitreal bevacizumab injection (13 eyes, 92.6%), and sub-tenon’s Kenalog (11 eyes, 78.6%) were utilized. All patients managed with laser photocoagulation and/or bevacizumab required multiple treatments. ConclusionOur study describes a spectrum of vascular changes evidenced by widefield FA in pediatric patients with genetically confirmed TBD. Although further research is warranted to fully understand the etiology of these subtle vascular anomalies, widefield FA should be conducted in patients with genetically confirmed or suspected TBD.

Genetic predisposition to myelodysplastic syndrome: Genetic counseling and transplant implications

The development of myelodysplastic syndromes (MDS) is influenced by various genetic predispositions. Several important genes contribute to disease susceptibility. This paper explores common genetic predisposition genes in MDS, including DDX41, CEBPA, and SAMD9/SAMD9L, which are linked to hereditary conditions presenting diagnostic and clinical challenges. It delves into hereditary conditions that affect platelet production and count, such as RUNX1, ETV6, and ANKRD26, detailing their clinical features and how they contribute to an increased risk of MDS. The discussion extends to additional genetic syndromes like GATA2 deficiency, telomere biology disorders, Fanconi anemia, and Li-Fraumeni syndrome, along with new findings on genes like ERG that offer new insights into disease etiology. The importance of genetic counseling in MDS is underscored, outlining its goals, methods for evaluating family history, risk assessment, and the ethical considerations involved. Furthermore, the role of hematopoietic cell transplantation in managing MDS, particularly in patients with germline syndromes, is reviewed, emphasizing the need for optimal donor selection and personalized treatment approaches. This comprehensive overview illustrates the critical role of genetic factors in MDS and highlights the need for continued research and tailored clinical practices to improve patient outcomes.

Telomere biology disorders: from dyskeratosis congenita and beyond.

Defective telomerase function or telomere maintenance causes genomic instability. Alterations in telomere length and/or attrition are the primary features of rare diseases known as telomere biology disorders or telomeropathies. Recent advances in the molecular basis of these disorders and cutting-edge methods assessing telomere length have increased our understanding of this topic. Multiorgan manifestations and different phenotypes have been reported even in carriers within the same family. In this context, apart from dyskeratosis congenita, disorders formerly considered idiopathic (i.e. pulmonary fibrosis, liver cirrhosis) frequently correlate with underlying defective telomere maintenance mechanisms. Moreover, these patients are prone to developing specific cancer types and exhibit exceptional sensitivity and toxicity in standard chemotherapy regimens. The current review describes the diverse spectrum of clinical manifestations of telomere biology disorders in pediatric and adult patients, their correlation with pathogenic variants, and considerations during their management to increase awareness and improve a multidisciplinary approach.

RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening

Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.

Genetic Testing for Rare Retinal Diseases in Telomere Biology Disorders

Genetic Testing for Rare Retinal Diseases in Telomere Biology Disorders

Reduced anti-Müllerian hormone levels in males with inherited bone marrow failure syndromes.

Fanconi anemia (FA), dyskeratosis congenita-related telomere biology disorders (DC/TBD), and Diamond-Blackfan anemia (DBA) are inherited bone marrow failure syndromes (IBMFS) with high risks of bone marrow failure, leukemia, and solid tumors. Individuals with FA have reduced fertility. Previously, we showed low levels of anti-Müllerian hormone (AMH), a circulating marker of ovarian reserve, in females with IBMFS. In males, AMH may be a direct marker of Sertoli cell function and an indirect marker of spermatogenesis. In this study, we assessed serum AMH levels in pubertal and postpubertal males with FA, DC/TBD, or DBA and compared this with their unaffected male relatives and unrelated healthy male volunteers. Males with FA had significantly lower levels of AMH (median: 5 ng/mL, range: 1.18-6.75) compared with unaffected male relatives (median: 7.31 ng/mL, range: 3.46-18.82, P = 0.03) or healthy male volunteers (median: 7.66 ng/mL, range: 3.3-14.67, P = 0.008). Males with DC/TBD had lower levels of AMH (median: 3.76 ng/mL, range: 0-8.9) compared with unaffected relatives (median: 5.31 ng/mL, range: 1.2-17.77, P = 0.01) or healthy volunteers (median: 5.995 ng/mL, range: 1.57-14.67, P < 0.001). Males with DBA had similar levels of AMH (median: 3.46 ng/mL, range: 2.32-11.85) as unaffected relatives (median: 4.66 ng/mL, range: 0.09-13.51, P = 0.56) and healthy volunteers (median: 5.81 ng/mL, range: 1.57-14.67, P = 0.10). Our findings suggest a defect in the production of AMH in postpubertal males with FA and DC/TBD, similar to that observed in females. These findings warrant confirmation in larger prospective studies.

“Crying in the wilderness” the use of online support in telomere biology disorders: thematic analysis (Preprint)

“Crying in the wilderness” the use of online support in telomere biology disorders: thematic analysis (Preprint)

Liver disease and transplantation in telomere biology disorders: An international multicenter cohort.

Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes. Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study. Group A ("Advanced") included 40 patients with advanced liver disease. Of these, 20 underwent LT (Group AT). Group M ("Mild") included 43 patients not warranting LT evaluation, none of whom were felt to be medically unfit for liver transplantation. Supplemental oxygen requirement, pulmonary arteriovenous malformation, hepatopulmonary syndrome, and higher bilirubin and international normalized ratio values were associated with Group A. Other demographics, clinical manifestations, and laboratory findings were similar between groups. Six group A patients were declined for LT; 3 died on the waitlist. Median follow-up post-LT was 2.9 years (range 0.6-13.2y). One-year survival post-LT was 73%. Median survival post-LT has not been reached. Group AT patients had improved survival by age compared to all nontransplant patients (log-rank test p = 0.02). Of 14 patients with pretransplant hypoxemia, 8 (57%) had improved oxygenation after transplant. LT recipients with TBD do not exhibit excessive posttransplant mortality, and LT improved respiratory status in 57%. A TBD diagnosis should not exclude LT consideration.

At the end, it is POT1 again: Phosphorylation allows human telomeric protein POT1 to recruit the C-rich strand end replication machinery

Recently in Cell, Cai etal.1 reported how phosphorylation of human shelterin protein POT1 allows it to recruit the telomeric C-rich strand replication machinery, providing mechanistic insights into an understudied area of telomere biology with implications for telomere biology disorders.

Genetic predisposition to porto-sinusoidal vascular disorder.

Porto-sinusoidal vascular disorder is a rare liver disease. The pathophysiological mechanisms underlying the development of porto-sinusoidal vascular disorder are unknown. Isolated cases of porto-sinusoidal vascular disorder associated with gene mutations have been reported, but no overview is available. Therefore, we performed an extensive literature search to provide a comprehensive overview of gene mutations associated with porto-sinusoidal vascular disorder. We identified 34 genes and one chromosomal abnormality associated with porto-sinusoidal vascular disorder in the literature, and we describe here one additional gene mutation (TBL1XR1 mutation, leading to Pierpont syndrome). These gene mutations are associated either with extrahepatic organ involvement as part of syndromes (Adams Oliver, telomere biology disorders, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, immune deficiencies, cystic fibrosis, cystinosis, Williams Beuren, Turner, Pierpont) or with isolated porto-sinusoidal vascular disorder (KCNN3, DGUOK, FOPV, GIMAP5, FCHSD1, TRMT5, HRG gene mutations). Most of the cases were revealed by signs or complications of portal hypertension. When analysing the cell types in which these genes are expressed, we found that these genes are predominantly expressed in immune cells, suggesting that these cells may play a more important role in the development of porto-sinusoidal vascular disorder than previously thought. In addition, pathway analyses suggested that there may be 2 types of porto-sinusoidal vascular disorder associated with gene mutations: those resulting directly from morphogenetic abnormalities and those secondary to immune changes.

Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease

Telomere length is an important biomarker of organismal aging and cellular replicative potential, but existing measurement methods are limited in resolution and accuracy. Here, we deploy digital telomere measurement (DTM) by nanopore sequencing to understand how distributions of human telomere length change with age and disease. We measure telomere attrition and de novo elongation with up to 30 bp resolution in genetically defined populations of human cells, in blood cells from healthy donors and in blood cells from patients with genetic defects in telomere maintenance. We find that human aging is accompanied by a progressive loss of long telomeres and an accumulation of shorter telomeres. In patients with defects in telomere maintenance, the accumulation of short telomeres is more pronounced and correlates with phenotypic severity. We apply machine learning to train a binary classification model that distinguishes healthy individuals from those with telomere biology disorders. This sequencing and bioinformatic pipeline will advance our understanding of telomere maintenance mechanisms and the use of telomere length as a clinical biomarker of aging and disease.

POT1 recruits and regulates CST-Polα/primase at human telomeres

Telomere maintenance requires the extension of the G-rich telomeric repeat strand by telomerase and the fill-in synthesis of the C-rich strand by Polα/primase. At telomeres, Polα/primase is bound to Ctc1/Stn1/Ten1 (CST), a single-stranded DNA-binding complex. Like mutations in telomerase, mutations affecting CST-Polα/primase result in pathological telomere shortening and cause a telomere biology disorder, Coats plus (CP). We determined cryogenic electron microscopy structures of human CST bound to the shelterin heterodimer POT1/TPP1 that reveal how CST is recruited to telomeres by POT1. Our findings suggest that POT1 hinge phosphorylation is required for CST recruitment, and the complex is formed through conserved interactions involving several residues mutated in CP. Our structural and biochemical data suggest that phosphorylated POT1 holds CST-Polα/primase in an inactive, autoinhibited state until telomerase has extended the telomere ends. We propose that dephosphorylation of POT1 releases CST-Polα/primase into an active state that completes telomere replication through fill-in synthesis.