Telomere length in inherited bone marrow failure syndromes

Abstract

Telomeres are long DNA repeats and a protein complex at chromosome ends that are essential for genome integrity. Telomeres are very short in patients with dyskeratosis congenita due to germline mutations in telomere biology genes. We compared telomere length in patients with Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome with telomere length in dyskeratosis congenita. Telomere length was measured in six leukocyte subsets by automated multicolor flow fluorescence in situ hybridization, and age-adjusted using Z-scores (-2.326 = 1(st) percentile) were created. We examined individual data, and used canonical variate analysis for group comparisons and outlier detection. Most dyskeratosis congenita telomere lengths were below the 1(st) percentile, while only 2 Fanconi anemia and one each Diamond-Blackfan anemia and Shwachman-Diamond syndrome were that low. However, Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome clustered in the bottom half of the normal range. Canonical variate analysis separated dyskeratosis congenita widely from the other three syndromes by the first canonical variable (89.7% of the variance); the second variable (10.0%) separated Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and Fanconi anemia from each other. Overall, unlike in dyskeratosis congenita, telomere lengths in patients with non-dyskeratosis congenita inherited bone marrow failure syndromes were usually in the normal range, albeit shorter than in unaffected individuals. Clinicaltrials.gov identifier: 00027274.

Trial registration: ClinicalTrials.gov NCT00027274.

Copyright© Ferrata Storti Foundation.

Figures

Figure 1.

Telomere length according to age in patients with dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), Fanconi anemia (FA), and Shwachman-Diamond syndrome (SDS). The vertical axis represents telomere length in kilobases (kb). The curved lines in the figures indicate the 1st, 10th, 50th, 90th, and 99th percentiles of results from 400 normal controls. Symbols represent patients. (A) 34 DBA (red diamond), 25 non-mosaic FA (closed blue triangle), 5 mosaic FA (open blue triangle), 14 SDS (black circle). (Top panels) Granulocytes, lymphocytes, and CD45RA-positive/CD20-negative naïve T cells. (Bottom panels) CD45RA-negative memory T cells, CD20-positive B cells, and CD57-positive NK cells. (B) 100 patients with DC (red diamond).

Figure 2.

Telomere length Z-score individual data in patients with DC, FA, DBA, and SDS. Dashed lines represent the mean and +2.326 or −2.326 standard deviations (SD) from the mean (equivalent to the 1st percentile) for normal individuals.

Figure 3.

(A) Telomere length Z-scores of IBMFS groups analyzed by canonical variate analyses. Patients were included only if they had data for all six leukocyte subsets. There were 85 with DC, 23 with FA, 30 with DBA, and 14 with SDS. According to the first canonical variable, the DC group was distinct from the 3 non-DC patient groups, which were similar to normal (marked with *). According to the second canonical variable, FA and SDS were low, while DBA was the closest to normal. The stars are the means, and the circles represent the 95% confidence intervals. The first canonical variable accounted for 89.7% of the difference, while the second accounted for 10%. (B) Telomere length Z-scores of IBMFS individuals analyzed by canonical variate analyses. The stars are the group means (see Figure 3A). The symbols represent individuals and indicate how close they are to other types of IBMFS. (Top left) Position of DC patients compared with DC, FA, DBA, and SDS. (Top right) Position of FA patients. (Bottom left) Position of DBA patients. (Bottom right) Position of SDS patients. (All panels) blue: close to DC; gray: close to FA; red: close to DBA; yellow: close to SDS.