PT - JOURNAL ARTICLE AU - Christopher R. Reilly AU - Mikko Myllymäki AU - Robert Redd AU - Shilpa Padmanaban AU - Druha Karunakaran AU - Valerie Tesmer AU - Frederick D. Tsai AU - Christopher J. Gibson AU - Huma Q. Rana AU - Liang Zhong AU - Wael Saber AU - Stephen R. Spellman AU - Zhen-Huan Hu AU - Esther H. Orr AU - Maxine M. Chen AU - Immaculata De Vivo AU - Corey Cutler AU - Joseph H. Antin AU - Donna Neuberg AU - Judy E. Garber AU - Jayakrishnan Nandakumar AU - Suneet Agarwal AU - R. Coleman Lindsley TI - The clinical and functional effects of <em>TERT</em> variants in myelodysplastic syndrome AID - 10.1101/2021.02.11.430624 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.02.11.430624 4099 - http://biorxiv.org/content/early/2021/03/02/2021.02.11.430624.short 4100 - http://biorxiv.org/content/early/2021/03/02/2021.02.11.430624.full AB - Germline pathogenic TERT variants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of telomere biology disorder who underwent allogeneic transplantation. Patients with TERT rare variants had shorter telomere length (p&lt;0.001) and younger age at MDS diagnosis (52 vs. 59 years, p=0.03) than patients without a TERT rare variant. In multivariable analyses, TERT rare variants were associated with inferior overall survival (p=0.034) driven by an increased incidence of non-relapse mortality (NRM) (p=0.015). Death from a non-infectious pulmonary cause was more frequent among patients with a TERT rare variant. According to ACMG/AMP guidelines and Sherloc criteria, 39 TERT rare variants were classified as VUS and one as likely pathogenic. Therefore, we cloned all rare missense variants and quantified their impact on telomere elongation in a cell-based assay. We found that 36 of 40 variants had severe or intermediate impairment in their capacity to elongate telomeres. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants disrupt domain-specific functions, including catalysis, protein-RNA interactions, and recruitment to telomeres. Our results indicate that the contribution of TERT rare variants to MDS pathogenesis and NRM risk is underrecognized and routine screening for TERT rare variants in MDS patients regardless of age or clinical suspicion could identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches.Competing Interest StatementD.N. has received research support from Pharmacyclics and owns stock in Madrigral Pharmaceuticals. M.M. has received honoraria from Celgene and Sanofi. R.C.L. has received research support from Jazz Pharmaceuticals and consulting fees from Takeda Pharmaceuticals and bluebird bio.