scholarly journals The age of heterozygous telomerase mutant parents influences the adult phenotype of their offspring irrespective of genotype in zebrafish

2017 ◽  
Vol 2 ◽  
pp. 77
Author(s):  
Catherine M. Scahill ◽  
Zsofia Digby ◽  
Ian M. Sealy ◽  
Richard J. White ◽  
John E. Collins ◽  
...  
Keyword(s):  
Telomere Length ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Sex Bias ◽  
Whole Genome Sequencing Data ◽  
Dependent Manner ◽  
Sequencing Data ◽  
Older Parents ◽  
Male Sex ◽  
Length Analysis

Background: Mutations in proteins involved in telomere maintenance lead to a range of human diseases, including dyskeratosis congenita, idiopathic pulmonary fibrosis and cancer. Telomerase functions to add telomeric repeats back onto the ends of chromosomes, however non-canonical roles of components of telomerase have recently been suggested. Methods: Here we use a zebrafish telomerase mutant which harbours a nonsense mutation in tert to investigate the adult phenotypes of fish derived from heterozygous parents of different ages. Furthermore we use whole genome sequencing data to estimate average telomere lengths. Results: We show that homozygous offspring from older heterozygotes exhibit signs of body wasting at a younger age than those of younger parents, and that offspring of older heterozygous parents weigh less irrespective of genotype. We also demonstrate that tert homozygous mutant fish have a male sex bias, and that clutches from older parents also have a male sex bias in the heterozygous and wild-type populations. Telomere length analysis reveals that the telomeres of younger heterozygous parents are shorter than those of older heterozygous parents. Conclusions: These data indicate that the phenotypes observed in offspring from older parents cannot be explained by telomere length. Instead we propose that Tert functions outside of telomere length maintenance in an age-dependent manner to influence the adult phenotypes of the next generation.

scholarly journals The age of heterozygous telomerase mutant parents influences the adult phenotype of their offspring irrespective of genotype in zebrafish

2018 ◽  
Vol 2 ◽  
pp. 77
Author(s):  
Catherine M. Scahill ◽  
Zsofia Digby ◽  
Ian M. Sealy ◽  
Richard J. White ◽  
Neha Wali ◽  
...  
Keyword(s):  
Telomere Length ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Sex Bias ◽  
Whole Genome Sequencing Data ◽  
Dependent Manner ◽  
Sequencing Data ◽  
Older Parents ◽  
Male Sex ◽  
Length Analysis

Background: Mutations in proteins involved in telomere maintenance lead to a range of human diseases, including dyskeratosis congenita, idiopathic pulmonary fibrosis and cancer. Telomerase functions to add telomeric repeats back onto the ends of chromosomes, however non-canonical roles of components of telomerase have recently been suggested. Methods: Here we use a zebrafish telomerase mutant which harbours a nonsense mutation in tert to investigate the adult phenotypes of fish derived from heterozygous parents of different ages. Furthermore we use whole genome sequencing data to estimate average telomere lengths. Results: We show that homozygous offspring from older heterozygotes exhibit signs of body wasting at a younger age than those of younger parents, and that offspring of older heterozygous parents weigh less irrespective of genotype. We also demonstrate that tert homozygous mutant fish have a male sex bias, and that clutches from older parents also have a male sex bias in the heterozygous and wild-type populations. Telomere length analysis reveals that the telomeres of younger heterozygous parents are shorter than those of older heterozygous parents. Conclusions: These data indicate that the phenotypes observed in offspring from older parents cannot be explained by telomere length. Instead we propose that Tert functions outside of telomere length maintenance in an age-dependent manner to influence the adult phenotypes of the next generation.

scholarly journals WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Lilit Nersisyan ◽  
◽  
Maria Nikoghosyan ◽  
Arsen Arakelyan
Keyword(s):  
Telomere Length ◽  
Telomere Maintenance ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Association Analyses ◽  
Relative Contribution ◽  
Age Related ◽  
Small Influence ◽  
Ribonuclease Reductase ◽  
Length Analysis

AbstractTelomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother’s, and, to a lesser extent, with father’s TL having the strongest influence on the offspring. In this cohort, mother’s, but not father’s age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait.

scholarly journals Dyskerin Is a Component of the Arabidopsis Telomerase RNP Required for Telomere Maintenance

2008 ◽  
Vol 28 (7) ◽  
pp. 2332-2341 ◽  
Author(s):  
Kalpana Kannan ◽  
Andrew D. L. Nelson ◽  
Dorothy E. Shippen
Keyword(s):  
Telomere Length ◽  
Bone Marrow Failure ◽  
Telomerase Activity ◽  
Dyskeratosis Congenita ◽  
Dominant Negative ◽  
Telomere Maintenance ◽  
Dependent Manner ◽  
Missense Mutations

ABSTRACT Dyskerin binds the H/ACA box of human telomerase RNA and is a core telomerase subunit required for RNP biogenesis and enzyme function in vivo. Missense mutations in dyskerin result in dyskeratosis congenita, a complex syndrome characterized by bone marrow failure, telomerase enzyme deficiency, and progressive telomere shortening. Here we demonstrate that dyskerin also contributes to telomere maintenance in Arabidopsis thaliana. We report that both AtNAP57, the Arabidopsis dyskerin homolog, and AtTERT, the telomerase catalytic subunit, accumulate in the plant nucleolus, and AtNAP57 associates with active telomerase RNP particles in an RNA-dependent manner. Furthermore, AtNAP57 interacts in vitro with AtPOT1a, a novel component of Arabidopsis telomerase. Although a null mutation in AtNAP57 is lethal, AtNAP57, like AtTERT, is not haploinsufficient for telomere maintenance in Arabidopsis. However, introduction of an AtNAP57 allele containing a T66A mutation decreased telomerase activity in vitro, disrupted telomere length regulation on individual chromosome ends in vivo, and established a new, shorter telomere length set point. These results imply that T66A NAP57 behaves as a dominant-negative inhibitor of telomerase. We conclude that dyskerin is a conserved component of the telomerase RNP complex in higher eukaryotes that is required for maximal enzyme activity in vivo.

Non-canonical Functions of Telomerase Reverse Transcriptase: Emerging Roles and Biological Relevance

2020 ◽  
Vol 20 (6) ◽  
pp. 498-507 ◽  
Author(s):  
Connor A.H. Thompson ◽  
Judy M.Y. Wong
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Reverse Transcriptase ◽  
Cancer Cells ◽  
Telomere Length ◽  
Telomere Maintenance ◽  
Telomerase Reverse Transcriptase ◽  
Alternative Mechanism ◽  
Dependent Manner ◽  
Mitochondrial Integrity

Increasing evidence from research on telomerase suggests that in addition to its catalytic telomere repeat synthesis activity, telomerase may have other biologically important functions. The canonical roles of telomerase are at the telomere ends where they elongate telomeres and maintain genomic stability and cellular lifespan. The catalytic protein component Telomerase Reverse Transcriptase (TERT) is preferentially expressed at high levels in cancer cells despite the existence of an alternative mechanism for telomere maintenance (alternative lengthening of telomeres or ALT). TERT is also expressed at higher levels than necessary for maintaining functional telomere length, suggesting other possible adaptive functions. Emerging non-canonical roles of TERT include regulation of non-telomeric DNA damage responses, promotion of cell growth and proliferation, acceleration of cell cycle kinetics, and control of mitochondrial integrity following oxidative stress. Non-canonical activities of TERT primarily show cellular protective effects, and nuclear TERT has been shown to protect against cell death following double-stranded DNA damage, independent of its role in telomere length maintenance. TERT has been suggested to act as a chromatin modulator and participate in the transcriptional regulation of gene expression. TERT has also been reported to regulate transcript levels through an RNA-dependent RNA Polymerase (RdRP) activity and produce siRNAs in a Dicer-dependent manner. At the mitochondria, TERT is suggested to protect against oxidative stress-induced mtDNA damage and promote mitochondrial integrity. These extra-telomeric functions of TERT may be advantageous in the context of increased proliferation and metabolic stress often found in rapidly-dividing cancer cells. Understanding the spectrum of non-canonical functions of telomerase may have important implications for the rational design of anti-cancer chemotherapeutic drugs.

scholarly journals The effects of development and chronic oxidative stress on telomere length in an agricultural pest moth, Helicoverpa armigera

2020 ◽  
Author(s):  
Nonthakorn (Beatrice) Apirajkamol ◽  
Tom K Walsh ◽  
Angela McGaughran
Keyword(s):  
Oxidative Stress ◽  
Telomere Length ◽  
Helicoverpa Armigera ◽  
Developmental Stages ◽  
Repetitive Sequences ◽  
Telomere Maintenance ◽  
Cell Replication ◽  
Sequencing Data ◽  
Replication Process ◽  
Helicoverpa Armígera

Telomeres are repetitive sequences located at the end of chromosomes in eukaryotes that protect against loss of important sequences during the cell replication process. Telomere length (TL) shortens with every round of cell division. When a telomere becomes too short, cells can no longer proliferate and this triggers the cell apoptosis process. Apart from cell replication, the length of telomeres can be affected by factors such as sex, genetics, and stress levels. Oxidative stress in particular can cause damage to telomeres and telomere maintenance processes, resulting in TL shortening. This phenomenon occurs in humans and many vertebrates, especially endothermic species. However, the ways in which various stress types affect the TL of invertebrate species remains ambiguous. Here, we examined the effects of development and oxidative stress on TL in the invertebrate pest moth, Helicoverpa armigera . In the former case, we extracted genomic DNA from three developmental stages (1-day old egg, 4th instar, and first-day emerged moths) and measured TL by qPCR . In the latter, we chronically expos ed individuals to paraquat – an organic herbicide that induces oxidative stress - and then measured TL as per our development methodology . In addition, we examined TL in a subset of published whole genome short-read sequencing data of caterpillars and moths using the software, Computel. In our experimental work, we found that TL in H. armigera was significantly longer at the early stages of development and shortens in later stages. However, oxidative stress does not appear to shorten TL in H. armigera following chronic exposure to paraquat. In our Computel analysis, we found that caterpillars had longer mean TL than moths but this difference was not significant due to the high variation among samples. Collectively, our research provides new data on TL in an underrepresented group, adding new insights into the progression of TL shortening with development and the effects of oxidative stress on TL, while also more generally highlighting the value of applying complementary approaches to TL measurement.

Accelerated Shortening of Long Telomeres and Accumulation of Short Telomeres in Dyskeratosis Congenita.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1053-1053
Author(s):  
Monica Bessler ◽  
Rachida Bouharich ◽  
Shashikant Kulkarni ◽  
Sara Freeman ◽  
Hong-Yan Du ◽  
...  
Keyword(s):  
Telomere Length ◽  
Gene Mutation ◽  
Gene Deletion ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Parental Origin ◽  
Telomere Shortening ◽  
Genetic Components ◽  
Affected Parent ◽  
Normal Controls

Abstract Dyskeratosis congenita (DC) is the first human disease whose pathogenesis has been directly linked to an impairment of telomere maintenance. Telomeres protect chromosome ends from end to end fusion and degradation. Loss of telomere function causes cell cycle arrest or cell death. Telomeres are maintained by the telomerase ribonucloprotein complex whose integral RNA component, the telomerase RNA or TERC RNA, contains the sequences that act as a template for the synthesis of telomeric repeats. Autosomal dominant DC (AD DC), a rare inherited bone marrow failure syndrome, is caused by mutations in TERC, the RNA component of telomerase. Patients with AD DC have very short telomeres. Haploinsufficiency has been proposed to be the mechanism for telomere shortening in TERC gene mutation carriers. Individuals with AD DC not only inherited the TERC gene mutation but also the shortened telomeres from the affected parent. Here we studied the telomere dynamics over 3 generations in a 32-member extended family with AD DC due to a TERC gene deletion. The investigation of telomere length within a single family has the advantage that the molecular lesion responsible for telomere shortening is uniform and that the contribution of other genetic components influencing telomere length is similar. Our analysis shows that peripheral blood cells from family members haploinsufficient for TERC have very short telomeres (6.68 kb, range 5.53–8.45, SD 1.13, normal controls: 9.15 kb rage 8.56–10.77, SD 1.22). In contrast to normal controls, whose telomere lengths shorten with age, the telomere lengths in all individuals carrying the TERC gene deletion are equally short irrespective of their age. To study the inheritance of short telomeres and the effect of TERC haploinsufficiency on specific telomere lengths in affected individuals and their relatives we carried out Q-FISH analysis using polymorphic subtelomeric probes on chromosomes 11p, 7p, and 1p, which are able to distinguish the parental origin of telomeres in this family. Our analysis showed that in children of affected parents who have inherited the gene deletion, paternal and maternal telomeres are similarly short, and similar in length to those of the affected parent. In children of affected parents who have normal TERC genes paternal and maternal telomeres are again similar in length, and similar to those of the unaffected parent. These results are consistent with a model in which telomerase preferentially acts on the shortest telomeres. When TERC is limiting this leads to the accelerated shortening of longer telomeres and the accumulation of short telomeres. The limited amount of active telomerase in TERC RNA haploinsufficiency may not be able to maintain the minimal length of the increasing number of short telomeres. Thus, the number of critically short telomeres and the degree of residual telomerase activity may determine the onset of disease in patients with DC.

Significance of Telomere Length Measurement in the Diagnosis of Dyskeratosis Congenita.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 836-836
Author(s):  
Hong-Yan Du ◽  
Elena Pumbo ◽  
Akiko Shimamura ◽  
Adrianna Vlachos ◽  
Jeffrey M. Lipton ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Telomere Length ◽  
Bone Marrow Failure ◽  
Skin Pigmentation ◽  
Screening Method ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Healthy Controls ◽  
Mutation Carriers

Abstract Dyskeratosis congenita (DC) is a rare inherited bone marrow failure (BMF) syndrome. The classical features of DC include nail dystrophy, abnormal skin pigmentation, and mucosal leukoplakia. The diagnosis of DC can be difficult. Originally, the diagnosis was based on the presence of the classical mucocutaneous features. However, the identification of four genes responsible for DC (DKC1, TERC, TERT, and NOP10) showed that these mucocutaneous features are only present in a proportion of patients with DC. Additionally, screening for mutations in the affected genes is expensive and is negative in about 50% of patients with classical features of DC. The products of the genes mutated in DC are the components of the telomerase ribonucleoprotein complex, which is essential for telomere maintenance. Therefore it has been postulated that DC is a disease arising from excessive telomere shortening. Here we examined whether the measurement of telomeres could be used as a screening test to identify individuals with DC. For this purpose we examined telomere length in peripheral blood mononuclear cells from 169 patients who presented with bone marrow failure including 17 patients with DC, diagnosed by the presence of classical cutaneous features or the identification of mutations in DKC1, TERC or TERT, 28 patients with paroxysmal nocturnal hemoglobinuria, 25 patients with Diamond Blackfan anemia, 5 patients with Shwachman-Diamond syndrome, 8 patients with myelodysplastic syndrome, and 74 patients with aplastic anemia of unknown cause classified as idiopathic aplastic anemia. In addition we measured telomere length in 12 patients with idiopathic pulmonary fibrosis and in 45 individuals with a de novo deletion of chromosome 5p including the TERT gene. Their telomere lengths were compared with those of 202 age-matched healthy controls. Moreover, mutations were screened in the genes associated with DC. In cases where a mutation was identified, telomere length and mutations were also examined in all the family members. Our results show that all patients with DC and bone marrow failure have very short telomeres far below the first percentile of healthy controls. Not all mutation carriers, including some carriers of apparently dominant mutations, have very short telomeres. What is more, very short telomeres could be found in healthy individuals in these families, some of whom were not mutation carriers. These findings indicate that in patients with BMF the measurement of telomere length is a sensitive screening method for DC, whether very short telomeres in this setting are also specific for DC remains to be determined. However, in contrast to a previous study, we find that telomere length does not always identify mutation carriers in the families of DC.

TERT Mutations in Patients with Squamous Cell Carcinoma of the Tongue and Refractory Anemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3096-3096
Author(s):  
Geraldine Aubert ◽  
Mark Hills ◽  
Carol Cremin ◽  
Irma Vulto ◽  
Barbara McGillivray ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Pulmonary Fibrosis ◽  
Cell Carcinoma ◽  
Telomere Length ◽  
Squamous Cell ◽  
Peripheral Blood ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Refractory Anemia ◽  
Normal Cells

Abstract Dyskeratosis Congenita (DC) is a marrow failure syndrome characterized by skin and nail abnormalities, oral leukoplakia and very short telomeres in circulating leukocytes. Heritable defects in telomere maintenance have been directly implicated in DC by the discovery of mutations in genes encoding components of the telomerase complex: DKC1, TERT, and TERC as well as mutations in the gene encoding the telomere binding protein TINF2. Defective telomeres in DC result in impaired hematopoiesis and predispose to myeloproliferative disorders. Heritable mutations in TERT and TERC have also been implicated in patients presenting with aplastic anemia (AA) and idiopathic pulmonary fibrosis (IPF) without clinical signs of DC. Because short telomeres appear to be associated with increased risks for various human cancers, including head and neck cancer, we sequenced TERT and TERC in two patients with oral carcinoma and anemia. The first patient presented at age 47 with invasive squamous cell carcinoma (SCC) of the tongue. The patient had a male sibling said to be also suffering from SCC which was not available for analysis and his mother died at age 37 from lymphoma. The patient displayed mild macrocytic anemia and oral leukoplakia. The telomere lengths of peripheral blood cells from the patient, determined by flow-FISH, were found to be below the first percentile expected for his age. In contrast, the leukocyte telomere lengths for the patient’s father and a female sibling were within the normal range. Bi-directional sequence analysis of TERT and TERC was conducted on DNA isolated from whole blood for the three family members. A novel mutation in exon 9 of TERT, C842T, situated within the reverse transcriptase domain of the telomerase enzyme catalytic component was identified in the patient but not in the 2 unaffected relatives. This suggested inheritance of a TERT mutation from the mother. The function of TERT C842T was compared to wildtype (WT) TERT by transfecting WT and mutant TERT cDNA into clonal Jurkat T cells and measuring telomere elongation by flow-FISH following 4 weeks of culture. TERT C842T showed 30% of the elongation obtained with WT TERT (p=0.0034). The second patient is a 60 yr old male with SCC of the tongue and refractory anemia with ring sideroblasts. The leukocyte telomere length was around the 1st percentile expected for his age. TERT sequencing revealed a three nucleotide deletion resulting in loss of 441E while retaining frame that is expected to impair telomerase activity. Our data support the concept that mutations in TERT can cause defective telomere maintenance and thereby compromise the proliferation of hematopoietic as well as epithelial cells. The resulting loss of normal cells selects for cells with defective DNA damage checkpoints that are triggered by chromosome ends without telomere repeats. Such cells are at high risk of becoming malignant because their proliferation will be stimulated by the loss of normal cells and their genome is very unstable as telomere function is compromised. Together these factors facilitate and enable clonal evolution of abnormal cells by DNA repair defects and cycles of chromosome fusions/bridge/breakage. Hematological and pathological findings consistent with Dyskeratosis Congenita together with peripheral blood telomere length measurements appear useful parameters to screen for telomere defects in patients and facilitate the discovery of mutations in “telomere maintenance” genes. The TERT mutations in patients with oral carcinomas illustrate that disease manifestations of telomere dysfunction in humans can be very diverse and range from DC, to defective hematopoiesis, pulmonary fibrosis and cancer predisposition.

Telomere Elongation in Dyskeratosis Congenita Induced Pluripotent Stem Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 497-497
Author(s):  
Suneet Agarwal ◽  
Yuin-Han Loh ◽  
Erin M McLoughlin ◽  
Junjiu Huang ◽  
In-Hyun Park ◽  
...  
Keyword(s):  
Telomere Length ◽  
Autosomal Dominant ◽  
Somatic Cells ◽  
Ips Cells ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Patient Specific ◽  
Self Renewal ◽  
Induced Pluripotent

Abstract Abstract 497 Patients with dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer premature degeneration of multiple tissues. Bone marrow failure is the principal cause of mortality, and allogeneic stem cell transplantation is limited by increased treatment-related mortality. Somatic cells can be reprogrammed using defined genetic and chemical factors, yielding “induced pluripotent stem” (iPS) cell lines which have the capacity to differentiate into any tissue. Patient-specific iPS cells therefore hold promise as therapeutic agents and disease models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, and we have found that telomere length is increased in human iPS cells relative to the normal primary somatic cells from which they are derived. Here we investigated whether defects in telomerase function would limit derivation or self-renewal of iPS cells from patients with DC. We reprogrammed primary fibroblasts from patients with X-linked and autosomal dominant DC, caused by mutations in the genes encoding dyskerin and telomerase RNA component (TERC), respectively. We were able to establish multiple DC-specific iPS lines showing all hallmarks of pluripotency, including the formation of hematopoietic progenitors in vitro. Unexpectedly, DC-specific iPS cells were able to sustain continual proliferation in vitro, in contrast to the premature senescence displayed by the DC fibroblasts. Although early passage DC iPS cells had shorter telomeres than donor fibroblasts, we found that telomere length in DC iPS cells increased with continued passage in culture. To explain this finding, we discovered that steady state levels of TERC, which are critically limiting in several forms of DC, are upregulated in normal and DC iPS cells. We found that TERC upregulation is a feature of the pluripotent state, that the TERC locus is a target of pluripotency-associated transcription factors, and that transcriptional silencing accompanies a 3' deletion at the TERC locus in autosomal dominant DC. Our results demonstrate that reprogramming restores self-renewal capacity in DC cells despite genetic lesions affecting telomerase, and suggest that strategies to enhance endogenous TERC expression may be feasible and therapeutically beneficial in DC patients. The studies demonstrate the value of patient-specific iPS cells for basic and translational discovery, and further the rationale for autologous iPS based cellular therapy of genetic hematologic disorders. Disclosures: Daley: MPM Capital: Consultancy; Solasia: Consultancy; Epizyme: Consultancy; iPierian: Consultancy, Equity Ownership.

scholarly journals Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita

Blood ◽  
2007 ◽  
Vol 110 (5) ◽  
pp. 1439-1447 ◽  
Author(s):  
Blanche P. Alter ◽  
Gabriela M. Baerlocher ◽  
Sharon A. Savage ◽  
Stephen J. Chanock ◽  
Babette B. Weksler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Telomere Length ◽  
Bone Marrow Failure ◽  
Correct Diagnosis ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance

Abstract Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome in which the known susceptibility genes (DKC1, TERC, and TERT) belong to the telomere maintenance pathway; patients with DC have very short telomeres. We used multicolor flow fluorescence in situ hybridization analysis of median telomere length in total blood leukocytes, granulocytes, lymphocytes, and several lymphocyte subsets to confirm the diagnosis of DC, distinguish patients with DC from unaffected family members, identify clinically silent DC carriers, and discriminate between patients with DC and those with other bone marrow failure disorders. We defined “very short” telomeres as below the first percentile measured among 400 healthy control subjects over the entire age range. Diagnostic sensitivity and specificity of very short telomeres for DC were more than 90% for total lymphocytes, CD45RA+/CD20− naive T cells, and CD20+ B cells. Granulocyte and total leukocyte assays were not specific; CD45RA− memory T cells and CD57+ NK/NKT were not sensitive. We observed very short telomeres in a clinically normal family member who subsequently developed DC. We propose adding leukocyte subset flow fluorescence in situ hybridization telomere length measurement to the evaluation of patients and families suspected to have DC, because the correct diagnosis will substantially affect patient management.

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