The evolving genetic landscape of dyskeratosis congenita (DC) and DC-like (DCL) disorders

Dyskeratosis congenita (DC) is a complex inherited bone marrow failure syndrome which is principally a disorder of telomere maintenance. To date approximately 35% of cases remain uncharacterised at the genetic level. Whole exome sequencing on a large collection of uncharacterized DC and DC-like (DCL) families (n=167) has revealed several novel pathogenic variants within known susceptibility loci, POT1 and ZCCHC8, as well as the novel locus POLA1. Functional characterisation of identified POLA1 and POT1 pathogenic variants, uncovered their effect on protein-protein interactions that have critical implications for telomere maintenance. ZCCHC8 variants disrupt protein interactions that affect nuclear exosome targeting (NEXT) complex stoichiometry and its binding with the human silencing hub (HUSH) complex chromatin modifier MPP8. Global transcriptomic analysis revealed signatures of pervasive transcription that include several short (snRNA and snoRD) and long non-coding RNA (transposable elements; LINE-1) driving inflammation in ZCCHC8 patient blood cells. In summary, our studies inform the current genetic architecture of DC and DCL disorders, by revealing novel gene loci such as POLA1 and extend our current knowledge on disease mechanisms beyond the regulation of long non-coding RNA TERC.