TERT c.3150 G > C (p.K1050N): a founder Ashkenazi Jewish variant associated with telomere biology disorders

TERT c.3150 G > C (p.K1050N): a founder Ashkenazi Jewish variant associated with telomere biology disorders

Abstract 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...

Full description

Saved in:
Bibliographic Details
Main Authors: Kelvin César de Andrade, Emilia M. Pinto, Tianna Zhao, Logan P. Zeigler, Jung Kim, Neelam Giri, Jeremy S. Haley, Lisa J. McReynolds, Oscar Florez-Vargas, Aaron H. Phillips, Richard W. Kriwacki, Sherifa A. Akinniyi, Scott B. Cohen, Matthew R. Emerson, Diane T. Smelser, Gretchen M. Urban, Cintia Fridman, Gerard P. Zambetti, Tracy M. Bryan, David J. Carey, Christine Kim Garcia, Douglas R. Stewart, Sharon A. Savage
Format: Article
Language:English
Published: Nature Portfolio 2025-06-01
Series:npj Genomic Medicine
Online Access:https://doi.org/10.1038/s41525-025-00501-8
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract 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.
ISSN:2056-7944

Similar Items