Diagnostic utility of telomere length testing in a hospital-based setting

Alder, Jonathan K.; Hanumanthu, Vidya Sagar; Strong, Margaret A.; DeZern, Amy E.; Stanley, Susan E.; Takemoto, Clifford M.; Danilova, L.; Applegate, Carolyn D.; Bolton, Stephen G.; Mohr, David; Brodsky, Robert A.; Casella, James F.; Greider, Carol W.; Jackson, J. Brooks; Armanios, Mary

doi:10.1073/pnas.1720427115

Cited by 162 publications

(201 citation statements)

References 43 publications

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“…In contrast, all patients tested in our cohort had at least one subpopulation at or below the 1st percentile, with most between 1st and 10th percentile, which is consistent with some level of telomere maintenance defect. Indeed, previous reports showed that defining normal telomere length as above the 1st percentile would miss children with telomeropathies, 9 considering that up to one in 7 are in the 1st to 10th percentile range. 8 In contrast to Dhanraj's report, 3 although 2 individuals in our cohort had pancreatic hyperechogenicity (Patients 1 and 2), none showed clear evidence of pancreatic insufficiency (Table S1).…”

Section: Current Reportmentioning

confidence: 99%

Refining the phenotype associated with biallelic DNAJC21 mutations

et al. 2018

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Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes involved in genomic stability. Although they may be recognized by the association of typical clinical features, variable penetrance and expressivity are common, and clinical diagnosis is often challenging. DNAJC21, which is involved in ribosome biogenesis, was recently linked to bone marrow failure. However, the specific phenotype and natural history remain to be defined. We correlate molecular data, phenotype, and clinical history of 5 unreported affected children and all individuals reported in the literature. All patients present features consistent with IBMFS: bone marrow failure, growth retardation, failure to thrive, developmental delay, recurrent infections, and skin, teeth or hair abnormalities. Additional features present in some individuals include retinal abnormalities, pancreatic insufficiency, liver cirrhosis, skeletal abnormalities, congenital hip dysplasia, joint hypermobility, and cryptorchidism. We suggest that DNAJC21-related diseases constitute a distinct IBMFS, with features overlapping Shwachman-Diamond syndrome and Dyskeratosis congenita, and additional characteristics that are specific to DNAJC21 mutations. The full phenotypic spectrum, natural history, and optimal management will require more reports. Considering the aplastic anemia, the possible increased risk for leukemia, and the multisystemic features, we provide a checklist for clinical evaluation at diagnosis and regular follow-up.

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Section: Current Reportmentioning

confidence: 99%

Refining the phenotype associated with biallelic DNAJC21 mutations

et al. 2018

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“…Evidence collected during the past decade has established impaired telomere maintenance as a causative effect in a number of different conditions, ranging from bone marrow failure to pulmonary fibrosis and liver disease 2 . Interestingly, telomere shortening affects different tissues at different ages, and telomere length measurement in hospital settings has recently been proposed as a diagnostic tool in targeted indications, with the potential to inform treatment decisions and influence morbidity 3 .…”

Section: Introductionmentioning

confidence: 99%

“…While mutations in these genes were initially found in children suffering from the bone marrow failure syndrome dyskeratosis congenita (DC), adult-onset phenotypes, such as pulmonary fibrosis and liver disease now represent the most common presentation in patients harboring mutations in telomerase. Interestingly, patients with liver disease usually come to clinical attention at an earlier age and with longer telomeres when compared to patients with pulmonary fibrosis 3 , indicating that liver cells might be more susceptible to telomere dysfunction than the lung epithelia. Liver abnormalities have recently been shown to be common in patients with telomere syndromes, with liver disease carrying important implications for morbidity and mortality in these patients 5 .…”

Section: Introductionmentioning

confidence: 99%

Telomere dysfunction represses HNF4α leading to impaired hepatocyte development and function

Niero

Fok

Vessoni

et al. 2019

Preprint

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Telomere attrition is a risk factor for end-stage liver disease. Due to a lack of adequate models and intrinsic difficulties in studying telomerase in physiologically relevant cells, the molecular mechanisms responsible for liver disease in patients with telomere syndromes remain elusive.To circumvent that, we used genome editing to generate isogenic human embryonic stem cell lines (hESCs) harboring a clinically relevant mutation in telomerase (DKC1_A353V) and subjected them to an in vitro, stage-specific hepatocyte differentiation protocol, that resembles hepatocyte development in vivo. Our results show that while telomerase is highly expressed in hESCs, it is quickly silenced, due to TERT down-regulation, after endoderm differentiation, and completely absent in in vitro derived hepatocytes, similarly to what is observed in primary hepatocytes. While endoderm derivation is not impacted by telomere shortening, progressive telomere dysfunction impaired hepatic endoderm formation. Consequently, hepatocytederivation, as measured by expression of specific markers, as well by albumin expression and secretion, is severely compromised in telomerase mutant cells with short telomeres.Interestingly, this phenotype was not caused by cell death induction or senescence. Rather, telomere shortening induces down regulation of the human hepatocyte nuclear factor 4α (HNF4α), in a p53 dependent manner. Telomerase reactivation, as well as p53 silencing, rescued hepatocyte formation in telomerase mutants. Likewise, conditional expression of HNF4α, even in cells that retained short telomeres, accrued DNA damage, and p53 stabilization, successfully restored hepatocyte formation from hESCS. Conclusions:Combined, our data shows that telomere dysfunction acts a major regulator of HNF4α during hepatocyte development and function, pointing to a potential novel target for the clinical management of liver disease in telomere-syndrome patients.

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“…Clearly LKM had nothing to do with the extent of TL shrinkage in the control group, and why the control group's TL decreased so much is ignored in the paper. More generally, there are many problems with using TL as a proxy for biological aging (Alder et al, 2018). Even if this paper's basic logic is accepted, there are many problems with how the paper's data are handled.…”

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confidence: 99%