Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

Author(s):Show less -

Marsh, Judith C. W. ^{[1, 2]} ; Gutierrez-Rodrigues, Fernanda ^{[3, 4]} ; Cooper, James ^[3] ; Jiang, Jie ^[2] ; Gandhi, Shreyans ^{[1, 2]} ; Kajigaya, Sachiko ^[3] ; Feng, Xingmin ^[3] ; Ibanez, Maria del Pilar F. ^[3] ; Donaires, Flavia S. ^[4] ; Lopes da Silva, Joao P. ^[4] ; Li, Zejuan ^[5] ; Das, Soma ^[5] ; Ibanez, Maria ^[2] ; Smith, Alexander E. ^[2] ; Lea, Nicholas ^{[1, 2]} ; Best, Steven ^{[1, 2]} ; Ireland, Robin ^[1] ; Kulasekararaj, Austin G. ^[1] ; McLornan, Donal P. ^[1] ; Pagliuca, Anthony ^[1] ; Callebaut, Isabelle ^[6] ; Young, Neal S. ^[3] ; Calado, Rodrigo T. ^[4] ; Townsley, Danielle M. ^[3] ; Mufti, Ghulam J. ^{[1, 2]}

Affiliation

^[1] Kings Coll Hosp London, Dept Haematol Med, Denmark Hill, London SE5 9RS - England

^[2] Kings Coll London, Rayne Inst, Canc Studies Div, Dept Haematol Med, London - England

^[3] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 - USA

^[4] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Internal Med, Ribeirao Preto - Brazil

^[5] Univ Chicago, Genet Serv Lab, Chicago, IL 60637 - USA

^[6] Sorbonne Univ, Ctr Natl Rech Sci 7590, Unites Mixtes Rech, Inst Mineral & Phys Milieux Condenses, Paris - France

• Document type: Journal article
• Source: BLOOD ADVANCES; v. 2, n. 1, p. 36-48, JAN 9 2018.
• Web of Science Citations: 10

Abstract

Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3' telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants. Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants. (AU)

• FAPESP's process: 15/19074-0 - Study of genetic factors associated with immunosuppression therapy in acquired aplastic anemia by whole exome sequencing
• Grantee: Fernanda Gutierrez Rodrigues
• Support type: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC