Myelodysplasia and liver disease extend the spectrum of RTEL1 related telomeropathies.

Regulator of telomere elongation helicase 1 (RTEL1) is a DNA helicase involved in telomere maintenance.1,2 Germline biallelic RTEL1 variants have been previously reported in a subset of patients with dyskeratosis congenita (DC) and its severe variant Hoyeraal-Hreidarsson syndrome (HH).3–6 Furthermore, germline heterozygous RTEL1 variants have been linked to a subset of patients with pulmonary fibrosis.2,7,8 We have undertaken sequencing analysis (whole exome and targeted9) of RTEL1, using genomic DNA extracted from peripheral blood of 429 patients from our international bone marrow failure registry which includes DC, HH, aplastic anemia (AA), and familial myelodysplasia/leukemia (MDS/AML). This has revealed that 35 out of the 429 patients have RTEL1 variants (Table 1). Based on the minor allele frequency in the population reported on the Exome Aggregation Consortium database (ExAC – http://exac.broadinstitute.org/), the type of variant (missense, nonsense and indels), telomere length, the Combined Annotation Depletion (CADD) score,10 and segregation as well as information found in literature, we classified these variants into four different groups: (1) biallelic variants, (2) heterozygous loss of function (LOF) variants, (3) heterozygous missense variants of unknown significance (VUS) and (4) heterozygous missense bystander variants