Detailed assessment of rare and common TERT variation in a family with a telomere biology disorder

作者：Logan P Zeigler, Oscar Flórez-Vargas, Burak Altintas, Marena R. Niewisch, Weiyin Zhou, Neelam Giri, Maryam Rafati, Michael Poeschla, Vijay G. Sankaran, Tsung‐Po Lai, Abraham Aviv, Kristine Jones, Wen Luo, Jia Liu, Lisa J. McReynolds, Tianna Zhao, Ludmila Prokunina‐Olsson, Sharon A. Savage · 发表于：Human Genetics and Genomics Advances · 年份：2025 · DOI：10.1016/j.xhgg.2025.100536 · 被引用次数：1 · 研究领域：Telomeres, Telomerase, and Senescence

Telomere biology disorders (TBDs) are caused by rare pathogenic variants in telomere maintenance genes and often present with variable penetrance of multi-organ system manifestations. We evaluated a family with 14 individuals heterozygous for TERT c.2591T>C (p.L864P) and 13 non-carriers. TRAP assays showed that p.L864P causes a complete loss of telomerase activity. Carriers had shorter lymphocyte telomeres than non-carriers. Carriers presented different TBD manifestations, but had similar telomere length (TL) distributions, suggesting variable penetrance and possible genetic anticipation. Somatic TERT promoter mutations were detected in four carriers aged >50 years (variant allele fractions <4% in three and 18%-19% in one). Exome sequencing did not identify other variants of interest. Although not statistically significant, polygenic scores derived from common TL-associated genetic variation were lower in c.2591T>C carriers with more TBD clinical manifestations. Alleles associated with alternative TERT splicing, VNTR6-1-Long and rs10069690-T, co-segregated with c.2591T>C. This haplotype was associated with a reduction in TL Z score (β = -1.81, p < 0.0001). Another haplotype, c.2591T, VNTR6-1-Long, and rs10069690-T, demonstrated an independent reduction of TL Z score (β = -0.84, p = 0.0111). The TBD manifestations in this family may relate to common TL-associated genetic variation and alternative TERT splicing, emphasizing the importance of investigations into TBD manifestatio...