TY - JOUR
T1 - Pathogenic TERT promoter variants in telomere diseases
AU - Gutierrez-Rodrigues, Fernanda
AU - Donaires, Flávia S.
AU - Pinto, André
AU - Vicente, Alana
AU - Dillon, Laura W.
AU - Clé, Diego V.
AU - Santana, Barbara A.
AU - Pirooznia, Mehdi
AU - Ibanez, Maria del Pilar F.
AU - Townsley, Danielle M.
AU - Kajigaya, Sachiko
AU - Hourigan, Christopher S.
AU - Cooper, James N.
AU - Calado, Rodrigo T.
AU - Young, Neal S.
N1 - Funding Information:
The authors would like to thank Olga Rios for assistance in obtaining patients’ samples, Valentina Giudice and Zhijie Wu for their advice and helpful discussion, the Bioinformatics and Computational Core Facility at the NHLBI for data analysis, and the DNA sequencing and Genomics Core Facility at NHLBI. This work was funded by the Intramural Research Program of the National Heart, Lung, and Blood Institute/NIH, and by the Coordination of Improvement of Higher Education Personnel (CAPES) and the São Paulo Research Foundation (FAPESP); grants 2014/ 27294-7, 2015/19074-0, and 2013/08135-2.
Publisher Copyright:
© 2018, The Author(s).
PY - 2019/7/1
Y1 - 2019/7/1
N2 - Purpose: The acquisition of pathogenic variants in the TERT promoter (TERTp) region is a mechanism of tumorigenesis. In nonmalignant diseases, TERTp variants have been reported only in patients with idiopathic pulmonary fibrosis (IPF) due to germline variants in telomere biology genes. Methods: We screened patients with a broad spectrum of telomeropathies (n = 136), their relatives (n = 52), and controls (n = 195) for TERTp variants using a customized massively parallel amplicon-based sequencing assay. Results: Pathogenic −124 and −146 TERTp variants were identified in nine (7%) unrelated patients diagnosed with IPF (28%) or moderate aplastic anemia (4.6%); five of them also presented cirrhosis. Five (10%) relatives were also found with these variants, all harboring a pathogenic germline variant in telomere biology genes. TERTp clone selection did not associate with peripheral blood counts, telomere length, and response to danazol treatment. However, it was specific for patients with telomeropathies, more frequently co-occurring with TERT germline variants and associated with aging. Conclusion: We extend the spectrum of nonmalignant diseases associated with pathogenic TERTp variants to marrow failure and liver disease due to inherited telomerase deficiency. Specificity of pathogenic TERTp variants for telomerase dysfunction may help to assess the pathogenicity of unclear constitutional variants in the telomere diseases.
AB - Purpose: The acquisition of pathogenic variants in the TERT promoter (TERTp) region is a mechanism of tumorigenesis. In nonmalignant diseases, TERTp variants have been reported only in patients with idiopathic pulmonary fibrosis (IPF) due to germline variants in telomere biology genes. Methods: We screened patients with a broad spectrum of telomeropathies (n = 136), their relatives (n = 52), and controls (n = 195) for TERTp variants using a customized massively parallel amplicon-based sequencing assay. Results: Pathogenic −124 and −146 TERTp variants were identified in nine (7%) unrelated patients diagnosed with IPF (28%) or moderate aplastic anemia (4.6%); five of them also presented cirrhosis. Five (10%) relatives were also found with these variants, all harboring a pathogenic germline variant in telomere biology genes. TERTp clone selection did not associate with peripheral blood counts, telomere length, and response to danazol treatment. However, it was specific for patients with telomeropathies, more frequently co-occurring with TERT germline variants and associated with aging. Conclusion: We extend the spectrum of nonmalignant diseases associated with pathogenic TERTp variants to marrow failure and liver disease due to inherited telomerase deficiency. Specificity of pathogenic TERTp variants for telomerase dysfunction may help to assess the pathogenicity of unclear constitutional variants in the telomere diseases.
KW - bone marrow failure
KW - somatic TERT promoter variants
KW - telomere diseases
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U2 - 10.1038/s41436-018-0385-x
DO - 10.1038/s41436-018-0385-x
M3 - Article
C2 - 30523342
AN - SCOPUS:85058051392
SN - 1098-3600
VL - 21
SP - 1594
EP - 1602
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 7
ER -