端粒生物学失调症（TBD）由与端粒维持相关基因的致病性生殖细胞变异导致的早期端粒缩短所致。在成人中，TBD的特征为单/少症状临床表现（隐性TBD），这导致其被严重低估。我们呈现了一项前瞻性的多机构队列研究，在该研究中对新诊断出的再生障碍性贫血（AA）患者或临床医生怀疑存在TBD的患者进行了端粒长度（TL）筛查。通过流式荧光原位杂交（FISH）测量了262个样本的TL，并将TL视为可疑，一旦低于正常个体的第10百分位（标准筛查）或在40岁以上的患者中低于6.5 kb（扩展筛查）。在TL缩短的情况下，进行TBD相关基因的下一代测序（NGS）。被介绍的患者分为6个不同的筛查类别：（1）AA / 原发性夜间血红蛋白尿，（2）未解释的细胞减少症，（3）角化不良症，（4）骨髓增生异常综合征/急性髓性白血病，（5）间质性肺病，以及（6）其他疾病。总的来说，在120名患者中（n = 86标准筛查和n = 34扩展筛查），发现TL缩短。在76名标准患者中，17名有足够材料进行NGS，并确定了一种致病/可能致病的TBD相关基因变异。在76名标准和29名扩展筛查的患者中，检测到17名不确定意义的变异（22.4%的标准和20.7%的扩展筛查）。意料之中的是，突变主要发现在TERT和TERC中。总之，由流式FISH测量的TL代表了一种强大的体内功能筛查工具，用于筛查潜在的TBD，并且应该在每个新诊断的AA患者以及有临床怀疑存在潜在TBD的儿童和成人中进行。版权所有©2023作者。 Wolters Kluwer Health， Inc.代表欧洲血液学会发布。

Telomere biology disorders (TBD) result from premature telomere shortening due to pathogenic germline variants in telomere maintenance-associated genes. In adults, TBD are characterized by mono/oligosymptomatic clinical manifestations (cryptic TBD) contributing to severe underdiagnosis. We present a prospective multi-institutional cohort study where telomere length (TL) screening was performed in either newly diagnosed patients with aplastic anemia (AA) or if TBD was clinically suspected by the treating physician. TL of 262 samples was measured via flow-fluorescence in situ hybridization (FISH). TL was considered suspicious once below the 10th percentile of normal individuals (standard screening) or if below 6.5 kb in patients >40 years (extended screening). In cases with shortened TL, next generation sequencing (NGS) for TBD-associated genes was performed. The patients referred fell into 6 different screening categories: (1) AA/paroxysmal nocturnal hemoglobinuria, (2) unexplained cytopenia, (3) dyskeratosis congenita, (4) myelodysplastic syndrome/acute myeloid leukemia, (5) interstitial lung disease, and (6) others. Overall, TL was found to be shortened in 120 patients (n = 86 standard and n = 34 extended screening). In 17 of the 76 (22.4%) standard patients with sufficient material for NGS, a pathogenic/likely pathogenic TBD-associated gene variant was identified. Variants of uncertain significance were detected in 17 of 76 (22.4%) standard and 6 of 29 (20.7%) extended screened patients. Expectedly, mutations were mainly found in TERT and TERC. In conclusion, TL measured by flow-FISH represents a powerful functional in vivo screening for an underlying TBD and should be performed in every newly diagnosed patient with AA as well as other patients with clinical suspicion for an underlying TBD in both children and adults.Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.