European journal of human genetics : EJHGSep 15, 2026

Genetic and computer analysis of changes in telomere control genes in people with bone marrow failure

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 16, 2026

Abstract

Pathogenic variants were identified in 18.18% of subjects with Bone Marrow Failure Syndromes linked to Telomere Regulatory Genes.

Defective telomere maintenance and progressive telomere shortening are associated with Telomere Biology Disorders.
Whole exome sequencing revealed pathogenic, likely pathogenic, and rare variants of uncertain significance in 22.9% of subjects across five telomere regulatory genes.
Significant telomere shortening was observed in subjects with TRG variants compared to age-matched controls, particularly in those with de novo TINF2 variants.
RTEL1 was frequently affected, with variants clustering in its C-terminal regulatory region.
A familial NOP10 variant was linked to specific clinical features, expanding the known mutation spectrum of this gene.
In-silico analyses indicated that variants could disrupt protein stability and telomere complex integrity, correlating with reduced TERT expression and clinical severity.

Simplified

Telomere Biology Disorders (TBDs) are a genetically heterogeneous and often under-recognized cause of Bone Marrow Failure Syndromes (BMFS), driven by defective telomere maintenance and progressive telomere attrition. We performed an integrated genomic, telomeric and computational analysis in 118 subjects presenting clinical features of BMFS to delineate the contribution of Telomere Regulatory Genes (TRGs) variants to disease pathogenesis. Whole exome sequencing (WES) identified pathogenic (18.18%), likely pathogenic (27.27%) and rare variants of uncertain significance (54.54%) in 27 subjects (22.9%) across five TRGs: RTEL1, TERT, TINF2, NOP10, and WRAP53. Telomere Length (TL) assessment revealed significant telomere shortening in TRG variant-positive subjects compared with age-matched controls, with the most profound attrition observed in individuals harboring de novo TINF2 gene variants. RTEL1 emerged as the most frequently affected gene, with recurrent clustering of variants within its C-terminal regulatory region. A familial NOP10 variant, Asp12His, segregated with cutaneous pigmentation and hematological abnormalities consistent with the established role of NOP10 in dyskeratosis congenita, further broadening the known mutational spectrum of the gene. Structure-guided in-silico analyses predicted that both novel and recurrent variants disrupt protein stability, telomerase assembly or trafficking and shelterin complex integrity. Reduced TERT expression and a significant inverse correlation between telomere length and clinical severity further underscored the functional impact of TRG defects. Collectively, this study provides the first comprehensive characterization of TRG variants in the Indian BMFS cohort and highlights the utility of integrating genomic sequencing, telomere length measurement and computational modeling to improve diagnostic precision, variant interpretation and clinical stratification in TBDs.

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Genetic and computer analysis of changes in telomere control genes in people with bone marrow failure

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