RTEL1 – Dyskeratosis Congenita

RTEL1 encodes the regulator of telomere elongation helicase 1, a DNA helicase essential for telomere replication, repair, and genome stability. Germline mutations in RTEL1 disrupt T-loop resolution, leading to excessive telomere shortening and the clinical spectrum of dyskeratosis congenita (DC) and its severe variant Hoyeraal-Hreidarsson syndrome (HHS).

Genetic Evidence

Autosomal recessive inheritance is the predominant mode for RTEL1-related DC, with rare autosomal dominant presentations (PMID:23329068). Over 50 unrelated probands have been reported with biallelic or heterozygous RTEL1 variants, including splice, nonsense, frameshift, and missense changes. One recurrent missense variant, c.1368G>T (p.Trp456Cys), segregates with disease in multiple consanguineous families (6 patients) and was identified in HHS cases with cerebellar hypoplasia, immunodeficiency, and enteropathy (PMID:28507545). Founder mutation p.Arg1264His in Ashkenazi Jewish families further supports autosomal recessive inheritance (PMID:24009516). Case series and systematic WES studies confirm RTEL1 as a major DC gene across diverse populations.

Functional & Experimental Evidence

Cellular assays demonstrate that RTEL1-deficient fibroblasts and hematopoietic cells exhibit short telomeres, elevated telomeric circles, DNA damage foci, and replicative exhaustion. Rescue of pre-U2 snRNA trafficking defects by wild-type RTEL1 highlights a novel RNP biogenesis role (PMID:25628358). In vivo and in vitro models show impaired T-loop resolution leading to genome instability and bone marrow failure phenotypes. Extended clinical–genetic spectrum studies document that biallelic RTEL1 mutations cause HHS with intrauterine growth retardation and microcephaly, while heterozygous variants predispose to DC without extra-hematopoietic features (PMID:29296694).

Clinical Correlation & Utility

Patients present with the classic triad of oral leukoplakia (HP:0002745), reticular hyperpigmentation (HP:0001000), and nail dystrophy (HP:0002164), often accompanied by pancytopenia (HP:0001876) and pulmonary fibrosis (HP:0002206). RTEL1 testing should be included in DC gene panels to guide genetic counseling, prognostication, surveillance for bone marrow failure and malignancy, and consideration of hematopoietic stem cell transplantation.

Key Take-home: RTEL1 variants have a definitive causal role in dyskeratosis congenita, with both genetic and functional data supporting their inclusion in diagnostic workflows for telomere biology disorders.

References

• Human genetics • 2013 • Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita PMID:23329068
• American journal of human genetics • 2013 • Constitutional mutations in RTEL1 cause severe dyskeratosis congenita PMID:23453664
• PLoS genetics • 2013 • A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome PMID:24009516
• Frontiers in immunology • 2017 • Clinical and Molecular Heterogeneity of RTEL1 Deficiency PMID:28507545
• Blood advances • 2016 • Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations PMID:29296694
• American journal of medical genetics. Part A • 2018 • Complex phenotype of dyskeratosis congenita and mood dysregulation with novel homozygous RTEL1 and TPH1 variants PMID:29696773

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