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RTEL1
regulator of telomere elongation helicase 1
RTEL1 is located on the long (q) arm of chromosome 20, at band 20q13.33. Arm ratio per GRCh38 - banding schematic.
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Overview
RTEL1 encodes a DNA helicase enzyme belonging to the iron-sulphur cluster helicase family. The protein plays dual roles in cellular maintenance: it prevents excessive lengthening of telomeres during DNA replication and helps resolve stalled replication forks throughout the genome. These functions are essential for genomic stability, as telomere dysfunction and unresolved DNA damage structures both contribute to chromosomal abnormalities.
Pathogenic variants in RTEL1 can cause dyskeratosis congenita, a disorder characterised by bone marrow failure, abnormal skin pigmentation, and nail dystrophy. The gene exhibits both autosomal dominant and autosomal recessive inheritance patterns depending on variant type and severity. Individuals with biallelic pathogenic variants typically develop more severe manifestations earlier in life, whilst those with monoallelic variants may show milder or adult-onset features.
What the gene does
The RTEL1 protein functions as an ATP-dependent helicase that unwinds double-stranded DNA and dismantles protein-DNA complexes. At chromosome ends, RTEL1 removes protein-RNA assemblies that would otherwise obstruct normal chromosome replication and segregation. This activity prevents inappropriate recombination events that could destabilise telomeric regions.
Beyond telomere regulation, RTEL1 participates in general DNA repair pathways by dismantling D-loop structures and reversing stalled replication forks. When DNA polymerases encounter obstacles such as damaged bases or bound proteins, the replication machinery can stall and form branched DNA intermediates. RTEL1 resolves these structures to allow repair enzymes access and prevent fork collapse, which could otherwise lead to double-strand breaks. The protein also interacts with proliferating cell nuclear antigen (PCNA), coordinating its helicase activity with other replication and repair factors.
The enzyme's role in maintaining telomere length appears particularly important in highly proliferative tissues such as bone marrow stem cells, where continuous cell division places sustained demand on telomere maintenance mechanisms.
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Chromosome location
RTEL1 is located on the long arm of chromosome 20 at position 13.33 (20q13.33). This chromosomal region contains several genes involved in cellular proliferation and genome maintenance. The gene spans approximately 36 kilobases of genomic DNA and comprises 34 exons that encode the full-length protein isoform.
Protein structure
The RTEL1 protein contains 1,219 amino acids organised into functionally distinct regions. The N-terminal region houses a helicase ATP-binding domain spanning amino acids 7-296, which provides the energy required for unwinding DNA through ATP hydrolysis. Within this region sits the DEAH box motif at positions 250-253, a sequence signature characteristic of this helicase subfamily.
Two nuclear localisation signals are present at amino acids 151-167 and 871-877, directing the protein to the nucleus where it accesses chromatin. The C-terminal region contains a PIP-box motif at positions 1,178-1,185 that mediates binding to PCNA, anchoring RTEL1 to active replication forks.
Multiple disordered regions are distributed throughout the protein at positions 287-306, 757-786, 839-877, 979-1,005, 1,017-1,054, 1,132-1,151, and 1,159-1,219. These intrinsically disordered segments likely provide structural flexibility, allowing the protein to adopt different conformations when engaging various DNA substrates and protein partners during telomere maintenance and DNA repair.
Key variants
Pathogenic variants in RTEL1 include both loss-of-function and missense changes affecting helicase activity or protein stability. Biallelic pathogenic variants typically cause severe, early-onset dyskeratosis congenita with profound bone marrow failure, whilst heterozygous variants may produce milder or later-onset phenotypes. Variants disrupting the helicase domain or ATP-binding capacity generally abolish enzymatic function, whilst those affecting regulatory regions may alter protein localisation or interaction with partners.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
The primary condition associated with RTEL1 pathogenic variants is dyskeratosis congenita (autosomal recessive), a telomere biology disorder characterised by the diagnostic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia. Affected individuals frequently develop bone marrow failure during childhood or adolescence, with progressive cytopenias requiring supportive transfusions or haematopoietic stem cell transplantation. Additional features may include pulmonary fibrosis, liver cirrhosis, gastrointestinal complications, and predisposition to malignancies, particularly myelodysplastic syndrome and acute myeloid leukaemia. The severity and age of onset vary considerably depending on the specific variants inherited and their impact on residual RTEL1 function.
Inheritance pattern
Conditions caused by pathogenic RTEL1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
RTEL1 holds green (high confidence) classification on multiple NHS Genomic Medicine Service gene panels. These include the Adult solid tumours cancer susceptibility panel, Childhood solid tumours panel, and Haematological malignancies cancer susceptibility panel, reflecting the gene's association with cancer predisposition. RTEL1 also appears on panels addressing cytopenia and bone marrow failure conditions, including Cytopenia - NOT Fanconi anaemia, Cytopenias and congenital anaemias, and Haematological malignancies for rare disease. The gene features on the Familial pulmonary fibrosis and Pulmonary fibrosis familial panels due to its link with progressive lung disease in some affected individuals. Additional green-rated memberships include Primary immunodeficiency or monogenic inflammatory bowel disease, Gastrointestinal epithelial barrier disorders, and Infantile enterocolitis & monogenic inflammatory bowel disease panels, recognising the broader spectrum of tissue dysfunction that can occur with severe telomere maintenance defects.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What inheritance pattern does RTEL1 follow?
RTEL1 exhibits both autosomal dominant and autosomal recessive inheritance patterns. Individuals with two pathogenic variants (biallelic) typically develop severe, early-onset dyskeratosis congenita, whilst those with one variant (monoallelic) may have milder or later-onset features, though inheritance pattern depends on specific variant characteristics.
How does RTEL1 dysfunction lead to bone marrow failure?
RTEL1 maintains telomere integrity in rapidly dividing cells such as bone marrow stem cells. When RTEL1 function is impaired, telomeres progressively shorten with each cell division, eventually triggering cellular senescence or death. This depletion of haematopoietic stem cells results in reduced production of blood cells, manifesting as progressive cytopenias.
Why are RTEL1 variants associated with cancer predisposition?
Dysfunctional RTEL1 leads to genomic instability through both telomere dysfunction and impaired resolution of DNA replication problems. Critically short or unstable telomeres can cause chromosomal rearrangements, whilst unresolved replication stress promotes DNA damage accumulation. These processes increase mutation burden and chromosomal abnormalities that drive malignant transformation, particularly in haematopoietic tissues.