de Andrade Kelvin César, Pinto Emilia M, Zhao Tianna, Zeigler Logan P, Kim Jung, Giri Neelam, Haley Jeremy S, McReynolds Lisa J, Florez-Vargas Oscar, Phillips Aaron H, Kriwacki Richard W, Akinniyi Sherifa A, Cohen Scott B, Emerson Matthew R, Smelser Diane T, Urban Gretchen M, Fridman Cintia, Zambetti Gerard P, Bryan Tracy M, Carey David J, Garcia Christine Kim, Stewart Douglas R, Savage Sharon A
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
NPJ Genom Med. 2025 Jun 2;10(1):46. doi: 10.1038/s41525-025-00501-8.
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.
端粒酶（TERT）中的致病性种系变异会导致端粒生物学障碍（TBD），并与骨髓衰竭、肺纤维化及其他并发症相关。TERT c.3150 G > C（p.K1050N）在阿什肯纳兹犹太（ASH）人群中很常见，并且在患有TBD的ASH家族中已被鉴定出来。对来自英国生物银行和“我们所有人”数据库的96名p.K1050N杂合子进行全基因组测序，发现了一个共享的单倍型块，支持奠基者效应。对另外15例p.K1050N病例的分析验证了这种单倍型，并确定了与ASH血统一致的线粒体和Y-STR单倍群。临床评估表明，p.K1050N导致TBD表型并缩短端粒，而群体数据表明其外显率不完全。p.K1050N降低端粒酶活性和持续合成能力，并降低PCNA表达和BrdU掺入，损害细胞增殖。我们的研究结果确定TERT p.K1050N是一种与TBD相关的ASH奠基者变异，强调了基因筛查和长期临床研究的必要性。
