The inherited bone marrow failure syndromes (IBMFS) are a heterogenous group of disorders caused by germline mutations in related genes and characterized by bone marrow failure (BMF), disease specific organ involvement, and, in most cases, predisposition to malignancy. Their distinction from immune marrow failure can often be challenging, particularly when presentations occur in adulthood or are atypical. A combination of functional (disease specific assays) and genetic testing is optimal in assessing all new BMF patients for an inherited etiology. However, genetic testing is costly and may not be available worldwide due to resource constraints; in such cases, clinical history, standard laboratory testing, and the use of algorithms can guide diagnosis. Interpretation of genetic results can be challenging and must reflect assessment of pathogenicity, inheritance pattern, clinical phenotype, and specimen type used. Due to the progressive use of genomics, new IBMFS continue to be identified, widening the spectrum of these disorders.

1.
Niewisch
MR
,
Savage
SA
.
An update on the biology and management of dyskeratosis congenita and related telomere biology disorders
.
Expert Rev Hematol
.
2019
;
12
(
12
):
1037
-
1052
.
doi:10.1080/17474086.2019.1662720
.
2.
Bluteau
O
,
Sebert
M
,
Leblanc
T
, et al.
A landscape of germ line mutations in a cohort of inherited bone marrow failure patients
.
Blood
.
2018
;
131
(
7
):
717
-
732
.
doi:10.1182/blood-2017-09-806489
.
3.
Young
NS
.
Aplastic anemia
.
N Engl J Med
.
2018
;
379
(
17
):
1643
-
1656
.
doi:10.1056/NEJMra1413485
.
4.
Groarke
EM
,
Young
NS
,
Calvo
KR
.
Distinguishing constitutional from acquired bone marrow failure in the hematology clinic
.
Best Pract Res Clin Haematol
.
2021
;
34
(
2
):
101275
.
doi:10.1016/j.beha.2021.101275
.
5.
Gutierrez-Rodrigues
F
,
Santana-Lemos
BA
,
Scheucher
PS
,
Alves-Paiva
RM
,
Calado
RT
.
Direct comparison of flow-FISH and qPCR as diagnostic tests for telomere length measurement in humans
.
PLoS One
.
2014
;
9
(
11
):
e113747
.
doi:10.1371/journal.pone.0113747
.
6.
Gutierrez-Rodrigues
F
,
Sahoo
SS
,
Wlodarski
MW
,
Young
NS
.
Somatic mosaicism in inherited bone marrow failure syndromes
.
Best Pract Res Clin Haematol
.
2021
;
34
(
2
):
101279
.
doi:10.1016/j.beha.2021.101279
.
7.
Betensky
M
,
Babushok
D
,
Roth
JJ
, et al.
Clonal evolution and clinical significance of copy number neutral loss of heterozygosity of chromosome arm 6p in acquired aplastic anemia
.
Cancer Genet
.
2016
;
209
(
1-2
):
1
-
10
.
doi:10.13039/100000050
.
8.
Shah
YB
,
Priore
SF
,
Li
Y
, et al.
The predictive value of PNH clones, 6p CN-LOH, and clonal TCR gene rearrangement for aplastic anemia diagnosis
.
Blood Adv
.
2021
;
5
(
16
):
3216
-
3226
.
doi:10.1182/bloodadvances.2021004201
.
9.
Groarke
EM
,
Patel
BA
,
Shalhoub
R
, et al.
Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia
.
Leukemia
.
2022
;
36
(
9
):
2328
-
2337
.
doi:10.1038/s41375-022-01636-8
.
10.
Yoshizato
T
,
Dumitriu
B
,
Hosokawa
K
, et al.
Somatic mutations and clonal hematopoiesis in aplastic anemia
.
N Engl J Med
.
2015
;
373
(
1
):
35
-
47
.
doi:10.1056/NEJMoa1414799
.
11.
Ogawa
S.
Genetics of MDS
.
Blood
.
2019
;
133
(
10
):
1049
-
1059
.
doi:10.1182/blood-2018-10-844621
.
12.
Muramatsu
H
,
Okuno
Y
,
Yoshida
K
, et al.
Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes
.
Genet Med
.
2017
;
19
(
7
):
796
-
802
.
doi:10.1038/gim.2016.197
.
13.
Ghemlas
I
,
Li
H
,
Zlateska
B
, et al.
Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes
.
J Med Genet
.
2015
;
52
(
9
):
575
-
584
.
doi:10.1136/jmedgenet-2015-103270
.
14.
McReynolds
LJ
,
Rafati
M
,
Wang
Y
, et al.
Genetic testing in severe aplastic anemia is required for optimal hematopoietic cell transplant outcomes
.
Blood
.
2022
;
140
(
8
):
909
-
921
.
doi:10.1182/blood.2022016508
.
15.
Feurstein
S
,
Trottier
AM
,
Estrada-Merly
N
, et al.
Germ line predisposition variants occur in myelodysplastic syndrome patients of all ages
.
Blood
.
2022
;
140
(
24
):
2533
-
2548
.
doi:10.1182/blood.2022015790
.
16.
Alter
BP
,
Giri
N
,
Savage
SA
,
Rosenberg
PS
.
Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up
.
Haematologica
.
2018
;
103
(
1
):
30
-
39
.
doi:10.3324/haematol.2017.178111
.
17.
Gutierrez-Rodrigues
F
,
Munger
E
,
Ma
X
, et al.
Differential diagnosis of bone marrow failure syndromes guided by machine learning
.
Blood
.
2022
.
doi:10.1182/blood.2022017518
.
18.
Kim
H-Y
,
Kim
H-J
,
Kim
S-H
.
Genetics and genomics of bone marrow failure syndrome
.
Blood Res
.
2022
;
57
(
S1
):
s86
-
S92
.
doi:10.5045/br.2022.2022056
.
19.
Niewisch
MR
,
Giri
N
,
McReynolds
LJ
, et al.
Disease progression and clinical outcomes in telomere biology disorders
.
Blood
.
2022
;
139
(
12
):
1807
-
1819
.
doi:10.1182/blood.2021013523
.
20.
Boria
I
,
Garelli
E
,
Gazda
HT
, et al.
The ribosomal basis of diamond-blackfan anemia: mutation and database update
.
Hum Mutat
.
2010
;
31
(
12
):
1269
-
1279
.
doi:10.1002/humu.21383
.
21.
Walne
AJ
,
Vulliamy
T
,
Beswick
R
,
Kirwan
M
,
Dokal
I.
TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes
.
Blood
.
2008
;
112
(
9
):
3594
-
3600
.
doi:10.1182/blood-2008-05-153445
.
22.
Calvo
KR
,
Hickstein
DD
.
The spectrum of GATA2 deficiency syndrome
.
Blood
.
2023
;
141
(
13
):
1524
-
1532
.
doi:10.1182/blood.2022017764
.
23.
Ganapathi
KA
,
Townsley
DM
,
Hsu
AP
, et al.
GATA2 deficiency-associated bone marrow disorder differs from idiopathic aplastic anemia
.
Blood
.
2015
;
125
(
1
):
56
-
70
.
doi:10.1182/blood-2014-06-580340
.
24.
Homan
CC
,
Scott
HS
,
Brown
AL
.
Hereditary platelet disorders associated with germ line variants in RUNX1, ETV6, and ANKRD26
.
Blood
.
2023
;
141
(
13
):
1533
-
1543
.
doi:10.1182/blood.2022017735
.
25.
Germeshausen
M
,
Ancliff
P
,
Estrada
J
, et al.
MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia
.
Blood Adv
.
2018
;
2
(
6
):
586
-
596
.
doi:10.1182/bloodadvances.2018016501
.
26.
Tangye
SG
,
Al-Herz
W
,
Bousfiha
A
, et al.
Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee
.
J Clin Immunol
.
2022
;
42
(
7
):
1473
-
1507
.
doi:10.1007/s10875-022-01289-3
.
27.
Sebert
M
,
Gachet
S
,
Leblanc
T
, et al.
Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia
.
Cell Stem Cell
.
2023
;
30
(
2
):
153
-
170.e9170e9
.
doi:10.1016/j.stem.2023.01.006
.
28.
Sahoo
SS
,
Pastor
VB
,
Goodings
C
, et al
;
European Working Group of MDS in Children (EWOG-MDS)
.
Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes
.
Nat Med
.
2021
;
27
(
10
):
1806
-
1817
.
doi:10.1038/s41591-021-01511-6
.
29.
Groarke
EM
,
Gutierrez-Rodrigues
F
,
Ma
X
, et al.
U2AF1 and other splicing factor gene mutations in telomere biology disorders are associated with hematologic neoplasia and worse overall survival
.
Blood
.
2021
;
138
:
862
.
doi:10.1182/blood-2021-146946
.
30.
Kennedy
AL
,
Myers
KC
,
Bowman
J
, et al.
Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman- Diamond syndrome
.
Nat Commun
.
2021
;
12
(
1
):
1334
.
doi:10.1038/s41467-021-21588-4
.
31.
Kraft
IL
,
Godley
LA
.
Identifying potential germline variants from sequencing hematopoietic malignancies
.
Blood
.
2020
;
136
(
22
):
2498
-
2506
.
doi:10.1182/blood.2020006910
.
32.
Feurstein
S
,
Hahn
CN
,
Mehta
N
,
Godley
LA
.
A practical guide to interpreting germline variants that drive hematopoietic malignancies, bone marrow failure, and chronic cytopenias
.
Genet Med
.
2022
;
24
(
4
):
931
-
954
.
doi:10.13039/501100018936
.
33.
Armes
H
,
Rio-Machin
A
,
Krizsán
S
, et al.
Acquired somatic variants in inherited myeloid malignancies
.
Leukemia
.
2022
;
36
(
5
):
1377
-
1381
.
doi:10.13039/100010661
.
34.
Li
P
,
Brown
S
,
Williams
M
, et al.
The genetic landscape of germline DDX41 variants predisposing to myeloid neoplasms
.
Blood
.
2022
;
140
(
7
):
716
-
755
.
doi:10.1182/blood.2021015135
.
35.
Bonfim
C.
Special pre- and posttransplant considerations in inherited bone marrow failure and hematopoietic malignancy predisposition syndromes
.
Hematology Am Soc Hematol Educ Program
.
2020
;
2020
(
1
):
107
-
114
.
doi:10.1182/hematology.2020000095
.
36.
Fioredda
F
,
Iacobelli
S
,
Korthof
ET
, et al.
Outcome of haematopoietic stem cell transplantation in dyskeratosis congenita
.
Br J Haematol
.
2018
;
183
(
1
):
110
-
118
.
doi:10.1111/bjh.15495
.
37.
Dufour
C
,
Pierri
F.
Modern management of Fanconi anemia
.
Hematology
.
2022
;
2022
(
1
):
649
-
657
.
doi:10.1182/hematology.2022000393
.
38.
Nelson
AS
,
Myers
KC
.
Diagnosis, treatment, and molecular pathology of Shwachman-Diamond syndrome
.
Hematol/Oncol Clin N Am
.
2018
;
32
(
4
):
687
-
700
.
doi:10.1016/j.hoc.2018.04.006
.
39.
Da Costa
L
,
Leblanc
T
,
Mohandas
N.
Diamond-Blackfan anemia
.
Blood
.
2020
;
136
(
11
):
1262
-
1273
.
doi:10.1182/blood.2019000947
.
40.
Shabanova
I
,
Cohen
E
,
Cada
M
,
Vincent
A
,
Cohn
RD
,
Dror
Y.
ERCC6L2- associated inherited bone marrow failure syndrome
.
Mol Genet Genomic Med
.
2018
;
6
(
3
):
463
-
468
.
doi:10.1002/mgg3.388
.
41.
Zhou
Q
,
Yang
D
,
Ombrello
AK
, et al.
Early-Onset stroke and vasculopathy associated with mutations in ADA2
.
N Engl J Med
.
2014
;
370
(
10
):
911
-
920
.
doi:10.1056/NEJMoa1307361
.
42.
Auerbach
AD
.
Diagnosis of Fanconi anemia by diepoxybutane analysis
.
Curr Protoc Hum Genet
.
2015
;
85
:8.7.1-8.717.
doi:10.1002/0471142905.hg0807s85
.
43.
Blanche
PA
,
Philip
SR
,
Neelam
G
,
Gabriela
MB
,
Peter
ML
,
Sharon
AS
.
Telomere length is associated with disease severity and declines with age in dyskeratosis congenita
.
Haematologica
.
2012
;
97
(
3
):
353
-
359
.
doi:10.3324/haematol.2011.055269
.
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