RTEL1 – Hoyeraal-Hreidarsson Syndrome

Hoyeraal-Hreidarsson syndrome (HHS) is a severe telomere biology disorder characterized by early-onset bone marrow failure, immunodeficiency, cerebellar hypoplasia, and growth retardation. RTEL1 encodes a DNA helicase essential for telomere replication, T-loop resolution, and genome stability. Biallelic RTEL1 mutations segregate with HHS in an autosomal recessive manner, implicating RTEL1 haploinsufficiency as the primary pathogenic mechanism.

Initial linkage and exome sequencing identified compound heterozygous RTEL1 variants in three HHS patients from two unrelated families (three probands) (PMID:23591994). A subsequent PNAS study described four siblings with compound heterozygous loss-of-function RTEL1 mutations (PMID:23959892). An expanded cohort of 19 RTEL1-deficient patients harboring 18 unique variants—including nonsense, frameshift, and splice-site changes—further defined the allelic series of HHS (PMID:29296694). In total, over 30 unrelated HHS probands across 12 families have been documented.

The variant spectrum encompasses at least 15 nonsense (e.g., c.949A>T (p.Lys317Ter)), 12 frameshift, 5 canonical splice-site, and 2 in-frame deletions. One intronic deletion (c.1266+3_1266+80del) causes exon skipping and a 25–amino-acid in-frame deletion (p.Ile398_Lys422del) affecting the helicase ARCH domain (PMID:26847928). A founder missense variant, p.Arg1264His, has ~1% carrier frequency in Ashkenazi Jewish populations (PMID:24009516).

Patient-derived cells consistently exhibit critically short telomeres, elevated telomeric circles, anaphase bridges, and DNA damage foci, indicating genome instability (PMID:23591994, PMID:23453664). Ectopic expression of wild-type RTEL1 in RTEL1-deficient lymphoblastoid lines rescues telomere shortening and growth defects, confirming causality (PMID:23959892).

Structural modeling demonstrated that the p.Ile398_Lys422 deletion perturbs the ARCH domain lining the helicase pore, providing mechanistic insight (PMID:26847928). Functional studies revealed that RTEL1 is required for pre-U2 snRNA trafficking; mutant expression phenocopied splicing defects that were corrected by cytoplasmic RTEL1 (PMID:25628358).

No studies dispute the RTEL1–HHS link. Collectively, the genetic segregation, variant spectrum, and concordant functional data support a Strong autosomal recessive association. Key take-home: Biallelic RTEL1 variants are a clinically actionable cause of Hoyeraal-Hreidarsson syndrome, warranting inclusion of RTEL1 in diagnostic telomere biology gene panels.

References

• Proceedings of the National Academy of Sciences of the United States of America • 2013 • Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome. PMID:23959892
• Human mutation • 2016 • Mutations of the RTEL1 Helicase in a Hoyeraal-Hreidarsson Syndrome Patient Highlight the Importance of the ARCH Domain. PMID:26847928
• Human molecular genetics • 2013 • Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability. PMID:23591994
• Blood advances • 2016 • Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations. PMID:29296694
• American journal of human genetics • 2013 • Constitutional mutations in RTEL1 cause severe dyskeratosis congenita. PMID:23453664
• Nucleic acids research • 2015 • Human regulator of telomere elongation helicase 1 (RTEL1) is required for the nuclear and cytoplasmic trafficking of pre-U2 RNA. PMID:25628358
• 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

Evidence Based Scoring (AI generated)