The evolving genetic landscape of telomere biology disorder dyskeratosis congenita

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. Synopsis The evolving genetic landscape of inherited bone marrow failure syndrome dyskeratosis congenita reveals new pathogenic variants that broadens our understanding of current genetic and molecular mechanisms underlying this disorder. Several novel pathogenic variants within known susceptibility loci, as well as in the novel X-linked locus POLA1, are part of the evolving DC and DCL genetic landscape. Telomere maintenance is impacted by novel variants in POLA1 and POT1, while pervasive transcription and inflammation are caused by ZCCHC8 variants. Current knowledge on disease mechanisms beyond the regulation of long non-coding RNA TERC is extended by the clinical, genetic, and molecular similarity between DC and DCL cases. The evolving genetic landscape of inherited bone marrow failure syndrome dyskeratosis congenita reveals new pathogenic variants that broadens our understanding of current genetic and molecular mechanisms underlying this disorder.