Pathogenic TERT promoter variants in telomere diseases

Autor(es):Mostrar menos -

Gutierrez-Rodrigues, Fernanda ^{[1, 2]} ; Donaires, Flavia S. ^[2] ; Pinto, Andre ^[2] ; Vicente, Alana ^[1] ; Dillon, Laura W. ^[1] ; Cle, Diego V. ^[2] ; Santana, Barbara A. ^[2] ; Pirooznia, Mehdi ^[1] ; Ibanez, Maria del Pilar F. ^[1] ; Townsley, Danielle M. ^[1] ; Kajigaya, Sachiko ^[1] ; Hourigan, Christopher S. ^[1] ; Cooper, James N. ^[1] ; Calado, Rodrigo T. ^[2] ; Young, Neal S. ^[1]

Afiliação do(s) autor(es)

^[1] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 - USA

^[2] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Internal Med, Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Genetics in Medicine; v. 21, n. 7, p. 1594-1602, JUL 2019.
• Citações Web of Science: 5

Resumo

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. (AU)

• Processo FAPESP: 14/27294-7 - Identificação de moduladores genéticos da resposta à imunossupressão na anemia aplástica adquirida por sequenciamento de nova geração
• Beneficiário: Fernanda Gutierrez Rodrigues
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 15/19074-0 - Identificação de moduladores genéticos da resposta à imunossupressão na anemia aplástica adquirida por sequenciamento de nova geração
• Beneficiário: Fernanda Gutierrez Rodrigues
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado