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Clinical and Molecular Heterogeneity of RTEL1 Deficiency
Carsten Speckmann1,2, Sushree Sangita Sahoo1,3, Marta Rizzi2,4
1Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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.
Insights
RTEL1 deficiency causes dyskeratosis congenita (DC) with bone marrow failure and immune deficiency. This study characterizes novel RTEL1 mutations and their varied clinical impacts, highlighting potential therapeutic targets.
Area of Science:
- Genetics and Molecular Biology
- Hematology
- Immunology
Background:
- Dyskeratosis congenita (DC) is characterized by bone marrow failure (BMF), mucosal fragility, and fibrosis, often linked to telomere shortening.
- RTEL1 deficiency is an emerging genetic cause of DC, but its molecular mechanisms and clinical spectrum require further elucidation.
- Understanding RTEL1-associated DC is crucial for diagnosing and managing this rare genetic disorder.
Purpose of the Study:
- To characterize the molecular basis and clinical consequences of RTEL1 deficiency in a cohort of six patients with dyskeratosis congenita.
- To investigate the cellular and molecular phenotypes associated with novel RTEL1 mutations.
- To describe the natural history and outcomes of patients with RTEL1-deficient DC.
Main Methods:
- Clinical evaluation and genetic analysis of six patients with suspected RTEL1-associated DC, identifying novel biallelic and heterozygous RTEL1 mutations.
- Assessment of cellular phenotypes, including chromosomal breakage, cell proliferation, apoptosis, and senescence in patient-derived cells.
- Analysis of RTEL1 isoform expression and telomere maintenance mechanisms.
- Longitudinal follow-up of patient natural history and treatment outcomes, including hematopoietic stem cell transplantation (HSCT).
Main Results:
- Six patients presented with hypocellular BMF and B-/NK-cell lymphopenia; three with homozygous mutations also exhibited immunodeficiency, cerebellar hypoplasia, and enteropathy (Hoyeraal-Hreidarsson syndrome).
- RTEL1-deficient cells showed replicative exhaustion, spontaneous apoptosis, and senescence, with impaired CD34+ cell expansion and compromised B-cell development.
- Chromosomal breakage was observed in fibroblasts but not hematopoietic cells; telomeric circles did not accumulate, suggesting alternative pathomechanisms for telomere loss.
Conclusions:
- RTEL1 deficiency presents a heterogeneous clinical spectrum in DC, ranging from mild BMF with lymphopenia to severe, rapidly progressing cellular deficiency.
- Novel RTEL1 mutations contribute significantly to DC pathogenesis, impacting hematopoiesis, immunity, and organ development.
- Hematopoietic stem cell transplantation (HSCT) can lead to sustained engraftment, but chemotherapy's impact and early-onset lung disease post-HSCT warrant further investigation.
