TERT c.3150 G > C (p.K1050N): a founder Ashkenazi Jewish variant associated with telomere biology disorders
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.
Authors
- Aaron H. Phillips (ORCID: https://orcid.org/0000-0003-0245-5124)
- Richard W. Kriwacki (ORCID: https://orcid.org/0000-0002-9798-6018)
- Tianna Zhao (ORCID: https://orcid.org/0000-0002-7821-7168)
- Michael Emerson (ORCID: https://orcid.org/0000-0002-5305-7575)
- Lisa J. McReynolds
- Gerard P. Zambetti (ORCID: https://orcid.org/0000-0002-0929-5007)
- Emília M. Pinto (ORCID: https://orcid.org/0000-0001-5567-000X)
- Sharon Savage (ORCID: https://orcid.org/0000-0002-6477-5222)
- Christine Kim Garcia (ORCID: https://orcid.org/0000-0002-0771-1249)
- Jeremy S. Haley (ORCID: https://orcid.org/0000-0002-3279-7873)
- G Urban (ORCID: https://orcid.org/0009-0002-0990-6872)
- Kelvin C. de Andrade (ORCID: https://orcid.org/0000-0003-4651-996X)
- Oscar Flórez-Vargas (ORCID: https://orcid.org/0000-0002-4393-2612)
- Tracy M. Bryan (ORCID: https://orcid.org/0000-0002-7990-5501)
- Diane T. Smelser (ORCID: https://orcid.org/0000-0002-3925-8864)
- Scott B. Cohen (ORCID: https://orcid.org/0000-0003-3741-1965)
- Douglas R. Stewart (ORCID: https://orcid.org/0000-0001-8193-1488)
- Cíntia Fridman (ORCID: https://orcid.org/0000-0003-2430-4888)
- Neelam Giri (ORCID: https://orcid.org/0000-0001-7353-1863)
- Sherifa A Akinniyi
- Jung Kim (ORCID: https://orcid.org/0000-0001-6274-2841)
- David J. Carey
- Logan P Zeigler
Institutions
- Geisinger Medical Center (US)
- The University of Sydney (AU)
- National Institutes of Health (US)
- St. Jude Children's Research Hospital (US)
- Children's Medical Research Institute (AU)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR)
- Geisinger Health System (US)
- Columbia University (US)
Publication Details
- Journal
- npj Genomic Medicine
- Published
- 2025-06-02
- DOI
- https://doi.org/10.1038/s41525-025-00501-8
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Children's Medical Research
- Regeneron Pharmaceuticals
- University of New South Wales
- National Institutes of Health
- National Cancer Institute