Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

Abstract

Biallelic germline mutations in <i>RTEL1</i> (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of <i>RTEL1</i> mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic <i>RTEL1</i> mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three <i>RTEL1</i> variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic <i>RTEL1</i> variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, <i>RTEL1</i> variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3' telomeric overhangs were significantly eroded in 4. In summary, heterozygous <i>RTEL1</i> variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying <i>RTEL1</i> variants. Pathogenicity assessment of heterozygous <i>RTEL1</i> variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.