Telomere length is associated with disease severity and declines with age in dyskeratosis congenita
Telomere length is associated with disease severity and declines with age in dyskeratosis congenita
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DOI：
10.3324/haematol.2011.055269
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发表时间：
2012-03-01
期刊：
影响因子：
--
通讯作者：
Savage, Sharon A.
中科院分区：
文献类型：
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作者：
Alter, Blanche P.;Rosenberg, Philip S.;Savage, Sharon A.
Backgrounddyskeratosis congenita是一种癌症倾向的骨髓衰竭综合征所造成的染色体端粒biology.Design和MethodsWe研究了65例先天性角化不良和127名未受影响的亲属。应用荧光原位杂交技术检测外周血白细胞亚群端粒长度。我们年龄调整端粒长度使用Z-分数（标准差的平均年龄）。ResultsWe证实，端粒长度低于第一百分位数的年龄是非常敏感和特异性的先天性角化不良的诊断。我们提供的证据表明，淋巴细胞，而不是粒细胞可能足以用于临床筛选，而淋巴细胞亚群可能需要挑战性的情况下，包括沉默载体的识别。我们首次使用流式荧光原位杂交显示，最短的端粒与严重的变异（Hoyeraal-Hreidarsson和Revesz综合征），DKC 1，TINF 2或未知基因的突变以及中度或重度再生障碍性贫血相关。在第一个纵向随访的先天性角化不良患者，我们表明，端粒长度随年龄的增长而下降，在对比观察到的横截面data.ConclusionsTelomere长度的流动荧光原位杂交是一个重要的诊断测试先天性角化不良;年龄校正值提供了疾病严重程度的定量测量（临床亚群、突变基因和骨髓衰竭程度）。先天性角化不良患者端粒缩短加快。本研究注册于www.clinicaltrials.gov（标识符：NCT 00027274）。
BackgroundDyskeratosis congenita is a cancer-prone bone marrow failure syndrome caused by aberrations in telomere biology.Design and MethodsWe studied 65 patients with dyskeratosis congenita and 127 unaffected relatives. Telomere length was measured by automated multicolor flow fluorescence in situ hybridization in peripheral blood leukocyte subsets. We age-adjusted telomere length using Z-scores (standard deviations from the mean for age).ResultsWe confirmed that telomere lengths below the first percentile for age are very sensitive and specific for the diagnosis of dyskeratosis congenita. We provide evidence that lymphocytes alone and not granulocytes may suffice for clinical screening, while lymphocyte subsets may be required for challenging cases, including identification of silent carriers. We show for the first time using flow fluorescence in situ hybridization that the shortest telomeres are associated with severe variants (Hoyeraal-Hreidarsson and Revesz syndromes), mutations in DKC1, TINF2, or unknown genes, and moderate or severe aplastic anemia. In the first longitudinal follow up of dyskeratosis congenita patients, we demonstrate that telomere lengths decline with age, in contrast to the apparent stable telomere length observed in cross-sectional data.ConclusionsTelomere length by flow fluorescence in situ hybridization is an important diagnostic test for dyskeratosis congenita; age-adjusted values provide a quantitative measure of disease severity (clinical subset, mutated gene, and degree of bone marrow failure). Patients with dyskeratosis congenita have accelerated telomere shortening. This study is registered at www.clinicaltrials.gov (identifier: NCT00027274).