Heterozygous  variants in bone marrow failure and myeloid neoplasms

Judith C W Marsh; Fernanda Gutierrez-Rodrigues; James Cooper; Jie Jiang; Shreyans Gandhi; Sachiko Kajigaya; Xingmin Feng; Maria Del Pilar F Ibanez; Flávia S Donaires; João P Lopes da Silva; Zejuan Li; Soma Das; Maria Ibanez; Alexander E Smith; Nicholas Lea; Steven Best; Robin Ireland; Austin G Kulasekararaj; Donal P McLornan; Anthony Pagliuca; Isabelle Callebaut; Neal S Young; Rodrigo T Calado; Danielle M Townsley; Ghulam J Mufti

doi:10.1182/bloodadvances.2017008110

Heterozygous variants in bone marrow failure and myeloid neoplasms

Judith C W Marsh, Fernanda Gutierrez-Rodrigues, James Cooper, Jie Jiang, Shreyans Gandhi, Sachiko Kajigaya, Xingmin Feng, Maria Del Pilar F Ibanez, Flávia S Donaires, João P Lopes da Silva, Zejuan Li, Soma Das, Maria Ibanez, Alexander E Smith, Nicholas Lea, Steven Best, Robin Ireland, Austin G Kulasekararaj, Donal P McLornan, Anthony PagliucaIsabelle Callebaut, Neal S Young, Rodrigo T Calado, Danielle M Townsley, Ghulam J Mufti

Comprehensive Cancer Centre

Research output: Contribution to journal › Article › peer-review

47 Citations (Scopus)

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.

Original language	English
Pages (from-to)	36-48
Number of pages	13
Journal	Blood Advances
Volume	2
Issue number	1
Early online date	9 Jan 2018
DOIs	https://doi.org/10.1182/bloodadvances.2017008110
Publication status	Published - 9 Jan 2018

Keywords

Adult
Anemia, Aplastic/genetics
Bone Marrow Diseases/genetics
DNA Helicases/genetics
Female
Genetic Variation
Germ-Line Mutation
Hemoglobinuria, Paroxysmal/genetics
Heterozygote
Humans
Leukemia, Myeloid/genetics
Male
Middle Aged
Mutation
Telomere
Telomere Shortening

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Marsh, J. C. W., Gutierrez-Rodrigues, F., Cooper, J., Jiang, J., Gandhi, S., Kajigaya, S., Feng, X., Ibanez, M. D. P. F., Donaires, F. S., Lopes da Silva, J. P., Li, Z., Das, S., Ibanez, M., Smith, A. E., Lea, N., Best, S., Ireland, R., Kulasekararaj, A. G., McLornan, D. P., ... Mufti, G. J. (2018). Heterozygous variants in bone marrow failure and myeloid neoplasms. Blood Advances, 2(1), 36-48. https://doi.org/10.1182/bloodadvances.2017008110

@article{8c6335bba4384a28a9c7465419dad057,

title = "Heterozygous variants in bone marrow failure and myeloid neoplasms",

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.",

keywords = "Adult, Anemia, Aplastic/genetics, Bone Marrow Diseases/genetics, DNA Helicases/genetics, Female, Genetic Variation, Germ-Line Mutation, Hemoglobinuria, Paroxysmal/genetics, Heterozygote, Humans, Leukemia, Myeloid/genetics, Male, Middle Aged, Mutation, Telomere, Telomere Shortening",

author = "Marsh, {Judith C W} and Fernanda Gutierrez-Rodrigues and James Cooper and Jie Jiang and Shreyans Gandhi and Sachiko Kajigaya and Xingmin Feng and Ibanez, {Maria Del Pilar F} and Donaires, {Fl{\'a}via S} and {Lopes da Silva}, {Jo{\~a}o P} and Zejuan Li and Soma Das and Maria Ibanez and Smith, {Alexander E} and Nicholas Lea and Steven Best and Robin Ireland and Kulasekararaj, {Austin G} and McLornan, {Donal P} and Anthony Pagliuca and Isabelle Callebaut and Young, {Neal S} and Calado, {Rodrigo T} and Townsley, {Danielle M} and Mufti, {Ghulam J}",

year = "2018",

month = jan,

day = "9",

doi = "10.1182/bloodadvances.2017008110",

language = "English",

volume = "2",

pages = "36--48",

journal = "Blood Advances",

issn = "2473-9529",

publisher = "American Society of Hematology",

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Marsh, JCW, Gutierrez-Rodrigues, F, Cooper, J, Jiang, J, Gandhi, S, Kajigaya, S, Feng, X, Ibanez, MDPF, Donaires, FS, Lopes da Silva, JP, Li, Z, Das, S, Ibanez, M, Smith, AE, Lea, N, Best, S, Ireland, R, Kulasekararaj, AG, McLornan, DP, Pagliuca, A, Callebaut, I, Young, NS, Calado, RT, Townsley, DM & Mufti, GJ 2018, 'Heterozygous variants in bone marrow failure and myeloid neoplasms', Blood Advances, vol. 2, no. 1, pp. 36-48. https://doi.org/10.1182/bloodadvances.2017008110

TY - JOUR

T1 - Heterozygous variants in bone marrow failure and myeloid neoplasms

AU - Marsh, Judith C W

AU - Gutierrez-Rodrigues, Fernanda

AU - Cooper, James

AU - Jiang, Jie

AU - Gandhi, Shreyans

AU - Kajigaya, Sachiko

AU - Feng, Xingmin

AU - Ibanez, Maria Del Pilar F

AU - Donaires, Flávia S

AU - Lopes da Silva, João P

AU - Li, Zejuan

AU - Das, Soma

AU - Ibanez, Maria

AU - Smith, Alexander E

AU - Lea, Nicholas

AU - Best, Steven

AU - Ireland, Robin

AU - Kulasekararaj, Austin G

AU - McLornan, Donal P

AU - Pagliuca, Anthony

AU - Callebaut, Isabelle

AU - Young, Neal S

AU - Calado, Rodrigo T

AU - Townsley, Danielle M

AU - Mufti, Ghulam J

PY - 2018/1/9

Y1 - 2018/1/9

N2 - 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.

AB - 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.

KW - Adult

KW - Anemia, Aplastic/genetics

KW - Bone Marrow Diseases/genetics

KW - DNA Helicases/genetics

KW - Female

KW - Genetic Variation

KW - Germ-Line Mutation

KW - Hemoglobinuria, Paroxysmal/genetics

KW - Heterozygote

KW - Humans

KW - Leukemia, Myeloid/genetics

KW - Male

KW - Middle Aged

KW - Mutation

KW - Telomere

KW - Telomere Shortening

U2 - 10.1182/bloodadvances.2017008110

DO - 10.1182/bloodadvances.2017008110

M3 - Article

C2 - 29344583

SN - 2473-9529

VL - 2

SP - 36

EP - 48

JO - Blood Advances

JF - Blood Advances

IS - 1

ER -

Heterozygous variants in bone marrow failure and myeloid neoplasms

Abstract

Keywords

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