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

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 manifestations within and between TBD families.