Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 10, Pages E2358-E2365Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1720427115
Keywords
aplastic anemia; interstitial lung disease; primary immunodeficiency; liver disease; precision medicine
Categories
Funding
- NIH [K99-R00 HL113105, K23 HL123601, R37 AG009383, R01 CA160433, R01 HL119476, T32 GM007309]
- Maryland Stem Cell Research
- Commonwealth Foundation
- Johns Hopkins inHealth initiative
- Flight Attendants Medical Research Institute
- Gary Williams Foundation
- NATIONAL CANCER INSTITUTE [R01CA160433] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R00HL113105, R01HL119476, K23HL123601] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007309] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R37AG009383] Funding Source: NIH RePORTER
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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 agedependent, 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.
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