Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):E2358-E2365. doi: 10.1073/pnas.1720427115. Epub 2018 Feb 20.

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

Author information

1
Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
2
Telomere Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
3
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
4
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
5
Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
6
McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
7
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
8
Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287; cgreider@jhmi.edu marmani1@jhmi.edu.

Abstract

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.

KEYWORDS:

aplastic anemia; interstitial lung disease; liver disease; precision medicine; primary immunodeficiency

PMID:
29463756
PMCID:
PMC5877993
DOI:
10.1073/pnas.1720427115
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center