Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as 'DC-like' (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients' blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.

中文翻译：

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端粒生物学疾病先天性角化不良的不断发展的遗传景观。


先天性角化不良 （DC） 是一种罕见的遗传性骨髓衰竭综合征，由主要影响端粒生物学的基因突变引起。大约 35% 的病例在基因水平上仍未确定特征。为了探索遗传景观，我们对大量临床诊断的 DC 病例以及表现出类似于 DC 特征的病例进行了遗传研究，称为“DC 样”（DCL）。这导致我们在已知遗传位点和新的 X 连锁基因 POLA1 中鉴定了几种新的致病性变异。此外，我们还在来自不同家族的多个病例中鉴定了 POT1 和 ZCCHC8 的几个新变异，扩展了 DC 和 DCL 表型的等位基因系列。新型 POLA1 和 POT1 变体的功能表征揭示了蛋白质与引物酶、CTC1-STN1-TEN1 （CST） 和 shelterin 亚基复合物相互作用的致病作用，这对端粒维持至关重要。ZCCHC8 变体表现出 ZCCHC8 缺陷和普遍转录的迹象，引发患者血液中的炎症。总之，我们的研究扩展了当前的遗传结构，并拓宽了我们对 DC 和 DCL 疾病的疾病机制的理解。