Kelvin César de Andrade

Pathogenic germline variants in telomerase (TERT) cause telomere biology disorders (TBDs) and are associated with bone marrow failure, pulmonary fibrosis, and other complications. TERT c.3150 G > C (p.K1050N) is frequent in the Ashkenazi Jewish (ASH) population and has been identified in ASH families with TBDs. Whole-genome sequencing of 96 p.K1050N heterozygotes from the UK Biobank and All of Us databases revealed a shared haplotype block, supporting a founder effect. Analyses of 15 additional p.K1050N cases validated this haplotype and identified mitochondrial and Y-STR haplogroups consistent with ASH ancestry. Clinical assessments showed that p.K1050N contributes to TBD phenotypes and shortened telomeres, while population data suggest incomplete penetrance. p.K1050N reduces telomerase activity and processivity, and decreases PCNA expression and BrdU incorporation, impairing cell proliferation. Our findings establish TERT p.K1050N as an ASH founder variant associated with TBDs, underscoring the need for genetic screening and long-term clinical studies.

Supplementary Data S1 from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Supplementary Data S3 from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Variants in cancer predisposition genes (class 1–2) in the wildtype and variant TP53 cohorts, annotated with cancer type, sex, LFS criteria, inheritance status, segregation, variant location, variant function, and zygosity

Supplementary Data S6 from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Differential regulation of WNT signaling and LEF1 in LFS. A, Probes in the WNT signaling pathway (WNT4, SMAD3, SFRP4, SERPINF) significantly associated with cancer status. B, Probe in the body of LEF1 (cg03041109) associated with cancer status (FDR = 0.07). C, Methylation of probe in body of LEF1 (cg03041109) across members within each LFS family. Probands almost unanimously have higher LEF1 methylation than their unaffected family members. D, Plasma cfDNA methylation of the body of LEF1 (chr4:109056901-109057200), between patients with LFS and HBCs. E, Tumor methylation of the body of LEF1 (cg03041109) in CPTs, with and without a germline variant in TP53.

Supplementary Data S4 from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome

Differential regulation of WNT signaling and LEF1 in LFS. A, Probes in the WNT signaling pathway (WNT4, SMAD3, SFRP4, SERPINF) significantly associated with cancer status. B, Probe in the body of LEF1 (cg03041109) associated with cancer status (FDR = 0.07). C, Methylation of probe in body of LEF1 (cg03041109) across members within each LFS family. Probands almost unanimously have higher LEF1 methylation than their unaffected family members. D, Plasma cfDNA methylation of the body of LEF1 (chr4:109056901-109057200), between patients with LFS and HBCs. E, Tumor methylation of the body of LEF1 (cg03041109) in CPTs, with and without a germline variant in TP53.

Supplementary Data S2 from Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome