RTEL1 mutation modifies dyskeratosis congenita caused by a telomerase RNA template mutation.

Vertebrate telomeres, the sequences protecting the end of linear chromosomes, are composed of conserved hexameric GGTTAG repeats. Here we present a C50>A telomerase RNA template mutation that results in the incorporation of the variant telomeric repeat GTTTAG in a family with dyskeratosis congenita primarily presenting as idiopathic pulmonary fibrosis. The mutant telomerase shows reduced processivity, as demonstrated in direct activity assays and corroborated in vivo by Illumina whole-genome sequencing and Oxford Nanopore long-read telomere sequencing. The latter provides positional mutant repeat information that reveals the inheritance and maintenance of proximal mutant repeats in individuals who did not inherit the template mutation. Additionally, we describe an RTEL1 nonsense mutation that is associated with very short telomeres in progeny harboring wild-type telomerase and inherited mutant telomeric repeats in the absence of overt clinical phenotypes. In contrast, co-inheritance of the RTEL1 nonsense and TERC r.C50>A mutations coincide with severe early-onset DC phenotypes in two individuals.