Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

Abstract

Key Points• RTEL1 variants associate with AA, idiopathic cytopenias, and hypocellular myelodysplastic syndromes.• Detailed clinical/family history, functional assays, and in silico tools are critical for interpreting the pathogenicity of RTEL1 variants.Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 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 5 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n 5 59). Twenty-three RTEL1 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 RTEL1 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, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 39 telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants.Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.

Germline variants in predisposition genes in children with Down syndrome and acute lymphoblastic leukemia

“…This variant, classed "likely pathogenic" in ClinVar, was identified in 3 unrelated patients with autosomal-recessive dyskeratosis congenita (a disease of telomere attrition), in compound heterozygosity with another RTEL1 variant. 19 Heterozygous RTEL1 variants are associated with bone marrow failure and myeloid neoplasms, 20 although the effects on DS-ALL risk have not been reported. Common genetic variants in the region are associated with interindividual variation in telomere length and confer risk of pediatric cancers, including ALL.…”

Aplastic anemia: Etiology, molecular pathogenesis, and emerging concepts

“…49 Biallelic mutations in regulator of telomere elongation helicase 1 (RTEL1), which encodes a protein critical to telomere homeostasis, is a known cause of congenital bone marrow failure, but has been identified in 1%-2% of AA cases; most RTEL1 variants, however, are felt not to be pathogenic in the latter condition. 50 The degree of telomere length shortening or erosion has been shown to correlate with the severity of AA, risk of relapse, overall survival, and risk of clonal evolution (via acquisition of new cytogenetic aberrancy) to conditions such as myelodysplastic syndrome (MDS), which will be discussed in more detail later. 51 Telomere length shortening in cases of AA is likely insufficient to lead to AA and ultimately calls into question the distinction between acquired and inherited bone marrow failure syndromes such as AA given it frequently occurs in adult patients without a clear family history of such.…”

Diagnostic algorithm for lower-risk myelodysplastic syndromes

“…Biallelic germline mutations have been identified that clinically manifest with the dyskeratosis congenita phenotype and Hoyeraal-Hreidarsson syndrome [106]. Of relevance to this diagnostic workup, Marsh et al [107] have recently reported that heterozygous RTEL1 variants classified as likely pathogenic can be associated with unexplained cytopenias, AA, and hMDS, seen both at an early age and in adulthood. These variants had variable penetrance, and it was noted that telomere length analysis alone may not detect all primary telomere defects, as RTEL1 variants were detected that were associated with eroded 3′ overhangs only.…”

“…Analyses of GATA2 mutational status are also highly relevant given the well-documented predisposition to MDS [109][110][111]. Lastly, a range of other germline mutations may present with late-onset MDS and these should always be considered dependent on phenotype and history (Table 6) [103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121].…”