Clinical and Molecular Heterogeneity of RTEL1 Deficiency

Abstract

Typical features of dyskeratosis congenita (DC) resulting from excessive telomere shortening include bone marrow failure (BMF), mucosal fragility, and pulmonary or liver fibrosis. In more severe cases, immune deficiency and recurring infections can add to disease severity. RTEL1 deficiency has recently been described as a major genetic etiology, but the molecular basis and clinical consequences of RTEL1-associated DC are incompletely characterized. We report our observations in a cohort of six patients: five with novel biallelic RTEL1 mutations p.Trp456Cys, p.Ile425Thr, p.Cys1244ProfsX17, p.Pro884_Gln885ins53X13, and one with novel heterozygous mutation p.Val796AlafsX4. The most unifying features were hypocellular BMF in 6/6 and B-/NK-cell lymphopenia in 5/6 patients. In addition, three patients with homozygous mutations p.Trp456Cys or p.Ile425Thr also suffered from immunodeficiency, cerebellar hypoplasia, and enteropathy, consistent with Hoyeraal-Hreidarsson syndrome. Chromosomal breakage resembling a homologous recombination defect was detected in patient-derived fibroblasts but not in hematopoietic compartment. Notably, in both cellular compartments, differential expression of 1243aa and 1219/1300aa RTEL1 isoforms was observed. In fibroblasts, response to ionizing irradiation and non-homologous end joining were not impaired. Telomeric circles did not accumulate in patient-derived primary cells and lymphoblastoid cell lines, implying alternative pathomechanisms for telomeric loss. Overall, RTEL1-deficient cells exhibited a phenotype of replicative exhaustion, spontaneous apoptosis and senescence. Specifically, CD34+ cells failed to expand in vitro, B-cell development was compromised, and T-cells did not proliferate in long-term culture. Finally, we report on the natural history and outcome of our patients. While two patients died from infections, hematopoietic stem cell transplantation (HSCT) resulted in sustained engraftment in two patients. Whether chemotherapy negatively impacts on the course and onset of other DC-related symptoms remains open at present. Early-onset lung disease occurred in one of our patients after HSCT. In conclusion, RTEL deficiency can show a heterogeneous clinical picture ranging from mild hypocellular BMF with B/NK cell lymphopenia to early-onset, very severe, and rapidly progressing cellular deficiency.

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

“…RTEL1 encodes the regulator of telomere elongation helicase 1, which is essential for telomere maintenance and regulation of homologous recombination. Germline biallelic RTEL1 variants are responsible for dyskeratosis congenita and its severe variant Hoyeraal-Hreidarsson syndrome, 39 while heterozygous carriers with pulmonary fibrosis, [40][41][42] myelodysplasia and liver disease have been described. 43 Thus, our findings on FANCI, MAST1, POLH and RTEL1 would warrant further investigation in other large-scale studies on familial BC and the setup of functional studies to assess the impact of the variants.…”

Nonsense Suppression Therapy: New Hypothesis for the Treatment of Inherited Bone Marrow Failure Syndromes

“…Unfortunately, TINF2-mutated patients generally display poor outcome due to the severity of the disease, regardless of cancer [124]. RTEL1 mutations account for 5% of DC cases and are associated with heterogeneous clinical manifestations ranging from mild hypocellular bone marrow with B/NK cell lymphopenia to early, very severe cellular deficiency [57]. In addition, other pathological manifestations may be displayed by patients carrying nonsense mutations in RTEL1 gene such as early onset of thrombocytopenia, anemia, microcephaly, developmental delay, and cerebellar hypoplasia [62].…”

Regulator of telomere length 1 (RTEL1) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes

“…The patients reported by STUART et al [15] were considered to be extensively reported by NEWTON et al [7]. Five articles with clinical data and the present cohort were finally conserved for analysis [7,10,14,17].…”

“…RTEL1 is a DNA helicase playing roles in DNA replication, genome stability, DNA repair and telomere maintenance [8]. Bi-allelic mutations in RTEL1 have been reported in patients with Hoyeraal-Hreidarsson syndrome (see the Online Mendelian Inheritance in Man (OMIM) Catalogue; entry #305000, www.omim.org/), a severe variant of short telomere syndrome characterised by early-onset bone marrow failure, immunodeficiency and developmental defects associated with abnormally short telomeres, as well as myelodysplasia and liver disease [9][10][11][12][13][14]. Heterozygous RTEL1 mutations are also detected in 5-9% of patients with familial forms of ILD [15][16][17][18].…”