Heterozygous variants in bone marrow failure and myeloid neoplasms.

Biallelic germline mutations in (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic 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 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 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, 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 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying variants. Pathogenicity assessment of heterozygous variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.