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Diagnostic utility of telomere length testing in a hospital-based setting
Journal article   Open access   Peer reviewed

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

Jonathan K Alder, Vidya Sagar Hanumanthu, Margaret A Strong, Amy E DeZern, Susan E Stanley, Clifford M Takemoto, Ludmilla Danilova, Carolyn D Applegate, Stephen G Bolton, David W Mohr, …
Proceedings of the National Academy of Sciences - PNAS, Vol.115(10), pp.E2358-E2365
PNAS Plus
03/06/2018
DOI: 10.1073/pnas.1720427115
PMCID: PMC5877993
PMID: 29463756
url
https://doi.org/10.1073/pnas.1720427115View
Published (Version of record) Open Access

Abstract

This study defines clinical indications for using telomere length (TL) measurement as a diagnostic tool in a hospital setting. It shows that, in contrast to other methods, TL measurement by flow cytometry and FISH (flowFISH) can be standardized, and has reproducible and definable upper and lower normal boundaries. In telomerase mutation carriers and carriers of other mutant telomere maintenance genes, TL had prognostic value, correlating with the age of onset of short telomeres syndrome phenotypes, as well as the predominant complication. In a prospective study, TL results were actionable in one-fourth of cases with idiopathic bone marrow failure affecting the stem cell donor choice and/or treatment regimen. The data show that, for targeted clinical indications, and in a hospital setting, TL measurement by flowFISH informs patient care decisions. Telomere length (TL) predicts the onset of cellular senescence in vitro but the diagnostic utility of TL measurement in clinical settings is not fully known. We tested the value of TL measurement by flow cytometry and FISH (flowFISH) in patients with mutations in telomerase and telomere maintenance genes. TL had a discrete and reproducible normal range with definable upper and lower boundaries. While TL above the 50th age-adjusted percentile had a 100% negative predictive value for clinically relevant mutations, the lower threshold in mutation carriers was age-dependent, and adult mutation carriers often overlapped with the lowest decile of controls. The extent of telomere shortening correlated with the age at diagnosis as well as the short telomere syndrome phenotype. Extremely short TL caused bone marrow failure and immunodeficiency in children and young adults, while milder defects manifested as pulmonary fibrosis-emphysema in adults. We prospectively examined whether TL altered treatment decisions for newly diagnosed idiopathic bone marrow failure patients and found abnormally short TL enriched for patients with mutations in some inherited bone marrow failure genes, such as RUNX1 , in addition to telomerase and telomere maintenance genes. The result was actionable, altering the choice of treatment regimen and/or hematopoietic stem cell donor in one-fourth of the cases (9 of 38, 24%). We conclude that TL measurement by flowFISH, when used for targeted clinical indications and in limited settings, can influence treatment decisions in ways that improve outcome.
 Biological Sciences PNAS Plus liver disease interstitial lung disease aplastic anemia primary immunodeficiency precision medicine

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