Germline RTEL1 Variants in Telomere Biology Disorders

ABSTRACT Rare germline variation in regulator of telomere elongation helicase 1 (RTEL1) is associated with telomere biology disorders (TBDs). Biallelic RTEL1 variants result in childhood onset dyskeratosis congenita and Hoyeraal‐Hreidarsson syndrome whereas heterozygous individuals usually present later in life with pulmonary fibrosis or bone marrow failure. We compiled all TBD‐associated RTEL1 variants in the literature and assessed phenotypes and outcomes of 44 individuals from 14 families with mono‐ or biallelic RTEL1 variants enrolled in clinical trial NCT00027274. Variants were classified by adapting ACMG‐AMP guidelines using clinical information, telomere length, and variant allele frequency data. Compared with heterozygotes, individuals with biallelic RTEL1 variants had an earlier age at diagnosis (median age 35.5 vs. 5.1 years, p < 0.01) and worse overall survival (median age 66.5 vs. 22.9 years, p < 0.001). There were 257 unique RTEL1 variants reported in 47 publications, and 209 had a gnomAD minor allele frequency <1%. Only 38.3% (80/209) met pathogenic/likely pathogenic criteria. Notably, 8 of 209 reported disease‐associated variants were benign or likely benign and the rest were variants of uncertain significance. Given the considerable differences in outcomes of TBDs associated with RTEL1 germline variants and the extent of variation in the gene, systematic functional studies and standardization of variant curation are urgently needed to inform clinical management.