Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, P.O.BOX 281, FI-0029, Helsinki, Finland.
Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Building 6M, SE-901 87, Umeå, Sweden.
Orphanet J Rare Dis. 2018 Aug 17;13(1):139. doi: 10.1186/s13023-018-0864-9.
The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKC), the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs.
Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions.
In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients.
Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.
端粒生物学疾病（TBDs）包括一系列多系统疾病，其特征为黏膜皮肤症状和骨髓衰竭。在先天性角化不良症（DKC）中，TBD 的临床特征源于增殖组织中关键干细胞群体的耗竭，这是由于端粒酶功能异常所致。由于临床表现广泛且缺乏明确的实验室检测，临床诊断可能具有挑战性，特别是如果患者缺乏 TBD 的典型临床特征。
对一组表现出不同免疫表型且缺乏分子诊断的患者进行了临床测序。在缺乏明确诊断提示的情况下，对具有不同免疫和血液学状况的患者选择了无假设的全外显子组测序（WES）。
在属于三个家族的四名患者中，我们在已知导致 TBD 的基因（DKC1、TERT 和 RTEL1）中检测到五个新的变异体。除了分子发现外，他们的血细胞端粒都缩短了。这些发现与所显示的 TBD 表型一致，有助于对患者进行分子诊断和随后的临床随访。
我们的结果强烈支持基于 WES 的方法用于具有异质性或非典型临床表现的 TBD 患者的常规遗传诊断，否则这些患者可能仍未被诊断。
