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Brief Report
MYELOID NEOPLASIA
Novel germ line DDX41 mutations define families with a lower age of
MDS/AML onset and lymphoid malignancies
Maya Lewinsohn,1,* Anna L. Brown,2-4,* Luke M. Weinel,2,5,* Connie Phung,1 George Rafidi,1 Ming K. Lee,6
Andreas W. Schreiber,7,8 Jinghua Feng,8 Milena Babic,2 Chan-Eng Chong,2,3 Young Lee,2,3 Agnes Yong,5,9
Graeme K. Suthers,10,11 Nicola Poplawski,10,11 Meryl Altree,10 Kerry Phillips,10 Louise Jaensch,10 Miriam Fine,10
Richard J. D’Andrea,3,4,9 Ian D. Lewis,5,9 Bruno C. Medeiros,12 Daniel A. Pollyea,13 Mary-Claire King,6 Tom Walsh,6
Siobán Keel,14 Akiko Shimamura,15 Lucy A. Godley,1,* Christopher N. Hahn,2,3,5,* Jane E. Churpek,1,* and
Hamish S. Scott2-5,7,8,*
1
Section of Hematology/Oncology, Department of Medicine and Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive
Cancer Center, The University of Chicago, Chicago, IL; 2Department of Genetics and Molecular Pathology, 3Centre for Cancer Biology, SA Pathology,
Adelaide, SA, Australia; 4School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia;
5
School of Medicine, University of Adelaide, Adelaide, SA, Australia; 6Division of Medical Genetics, Department of Medicine, and Department of Genome
Sciences, University of Washington, Seattle, WA; 7School of Molecular and Biological Sciences, University of Adelaide, Adelaide, SA, Australia;
8
Australian Cancer Research Foundation Cancer Genomics Facility, Centre for Cancer Biology, 9Department of Haematology, 10SA Clinical Genetics
Service, Directorate of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia; 11School of Paediatrics and Reproductive Health,
University of Adelaide, Adelaide, SA, Australia; 12Stanford University School of Medicine, Stanford, CA; 13University of Colorado School of Medicine and
University of Colorado Cancer Center, Aurora, CO; and 14Division of Hematology, Department of Medicine, and 15Department of Pediatrics, University of
Washington, Seattle, WA
Recently our group and others have identified DDX41 mutations both as germ line and
acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41
• Novel missense germ line
acts as a tumor suppressor. To determine whether novel DDX41 mutations could be
DDX41 mutations define an
identified in families with additional types of hematologic malignancies, our group
earlier age of onset of
screened two cohorts of families with a diverse range of hematologic malignancy
hematologic malignancies
subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As
than loss-of-function alleles.
previously observed, MDS and AML were the most common malignancies, often of the
• Carriers of DDX41 germ line
erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five
mutations usually have
novel mutations were identified, including missense mutations within important functional
normal blood counts until
domains and start-loss and splicing mutations predicted to result in truncated proteins. We
a myeloid or lymphoid
also show that most asymptomatic mutation carriers have normal blood counts until
malignancy develops.
malignancy develops. This study expands both the mutation and phenotypic spectra
observed in families with germ line DDX41 mutations. With an increasing number of both
inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies
is critical. (Blood. 2016;127(8):1017-1023)
Key Points
Introduction
Inherited hematologic malignancies (HMs) typically present at
earlier ages than de novo disease.1-4 Recently our group and others
identified a class of familial myeloid malignancies due to mutations
in DDX41, which encodes a DEAD-box RNA helicase.5 These
families exhibit a familial risk of myelodysplastic syndrome (MDS)
and acute myeloid leukemia (AML), but they develop these
malignancies at ages typical of de novo disease. More than 65% of
familial cases previously identified harbor a heterozygous germ line
frameshift mutation, DDX41 c.415_418dupGATG (p.D140Gfs*2),
and 50% of MDS or AML diseases that develop in germ line carriers
acquire a mutation on the other DDX41 allele, suggesting that DDX41
acts as a tumor suppressor.5 We searched for additional families with
novel DDX41 germ line mutations to advance our understanding of
this syndrome.
Submitted October 19, 2015; accepted December 22, 2015. Prepublished
online as Blood First Edition paper, December 28, 2015; DOI 10.1182/blood2015-10-676098.
There is an Inside Blood Commentary on this article in this issue.
*M.L., A.L.B., L.M.W., L.A.G., C.N.H., J.E.C., and H.S.S. contributed equally
to this study.
The online version of this article contains a data supplement.
BLOOD, 25 FEBRUARY 2016 x VOLUME 127, NUMBER 8
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked “advertisement” in accordance with 18 USC section 1734.
© 2016 by The American Society of Hematology
1017
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1018
LEWINSOHN et al
Methods
Patients
All patients in our study signed a written informed consent form to
participate in research approved by the institutional review board and
conducted in accordance with the Declaration of Helsinki under either the
Australian Familial Haematological Cancer Study or The University of
Chicago Familial Hematologic Malignancies registry. Study eligibility
criteria and cohort phenotype breakdown are provided in the Supplemental Data (available on the Blood Web site).
Sequencing
Sequencing of samples was predominantly performed by whole exome
sequencing for Australian samples as previously described6 or by MarrowSeq
assay7 for samples collected at The University of Chicago. Some samples were
screened by targeted polymerase chain reaction and Sanger sequencing of
DDX41. Sample types and coverage for all individuals are shown in
supplemental Table 5, and primers used for amplification and sequencing
are shown in supplemental Table 4 (Australia) and supplemental Table 3
(Chicago). Reference sequences used throughout for DDX41 are NM_016222.2
and NP_057306.2.
Results and discussion
Families with suspected inherited HMs (289 families; see supplemental
Data for phenotypic breakdown) were examined by whole exome
sequencing; MarrowSeq, a panel-based next-generation sequencing
assay; or by targeted Sanger sequencing of frequently mutated exons in
DDX41 (see supplemental Table 6 for full details). Heterozygous germ
line DDX41 mutations were identified in 9 new families (3%) who had
no other detectable predisposition allele. Among these, 3 families
carried the recurrent p.D140Gfs*2 mutation5; 1 family carried a germ
line p.R525H (c.1574G.A) mutation, previously described only as
a somatic mutation at the time of progression to MDS or AML; and
5 carried novel mutations (Figure 1, supplemental Table 1, and
supplemental Data). The mean age of onset of MDS or AML in
germ line DDX41 mutation carriers in this study was 57 years,
younger than the 67 years previously reported (P 5 .006, two tailed
Student t test).5 Combined, the mean age of onset of HMs in all
reported germ line DDX41 mutation carriers is 62 years.
All 3 new families carrying the germ line DDX41 p.D140Gfs*2
truncating mutation (Figure 1A-C) exhibited late-onset MDS or AML
(mean 67 years). Sequencing of leukemia DNA from 1 individual
(33755-III-1) revealed an acquired p.R525H mutation consistent with
previous findings (Figure 1A).5
A germ line substitution (c.435-2_435-1delAGinsCA) was identified in the splice acceptor site 59 to the start of exon 6 in Family 154
(Figure 1D). Polymerase chain reaction of complementary DNA from
skin fibroblasts from individual 154-II-2 revealed 2 aberrant splice
products generated between exons 4 and 7 (supplemental Figure 1)
that introduced frameshift mutations just downstream from the
p.D140Gfs*2 mutation and are predicted to produce similarly truncated
proteins (p.W146Hfs*29 and p.S145Rfs*17).
Clinical histories in several families suggested that germ line
DDX41 mutations may predispose to a wider range of HMs. In 2
families, a novel missense start-loss substitution (c.3G.A, p.M1I) was
identified (Figure 1E-F). Single nucleotide polymorphism analysis
showed that all individuals in both families who carried the c.3G.A
mutation also carried a tightly linked 59 untranslated region variant, but
BLOOD, 25 FEBRUARY 2016 x VOLUME 127, NUMBER 8
a second single nucleotide polymorphism in exon 3 was unique to
family 20432 (supplemental Table 2), suggesting that these families
share an ancestral allele but are only distantly related. Individuals with
p.M1I usually developed late onset MDS/AML, but one individual
(20432-III-1) developed chronic myeloid leukemia and another
(20432-II-3) developed both AML and non-Hodgkin lymphoma
(NHL). Family 25476 (Figure 1I) in whom we identified a novel
DDX41 missense variant, c.490C.T p.R164W segregating with
lymphoid malignancies, adds further support to this observation. In
total, 5 of 5 affected individuals with NHL (3 with follicular subtype,
early-onset; Table 1), Hodgkin lymphoma, or multiple myeloma carried
the p.R164W variant, whereas 3 of 3 unaffected individuals of similar
ages did not. Arginine 164 is highly conserved across species
(supplemental Figure 2) and is adjacent to the Q motif (Figure 1J), a
region involved in adenosine triphosphate binding and hydrolysis,8
likely key for regulating DDX41 helicase activity.
Finally, 2 families with germ line missense mutations in the helicase
domain were identified: 1 carried a p.R525H mutation (Figure 1G and
supplemental Figure 3), and 1 carried p.G530D (Figure 1H). Because
the p.R525H mutation has been shown to affect the interaction of
DDX41 with splicing factors,5 we predict that the nearby p.G530D
mutation would have a similarly disruptive capacity. Both families
feature high penetrance MDS/AML, with younger ages of HM onset
compared with other DDX41 variants (50 vs 63 years; P 5 .0004, twotailed Student t test).
Expression of the DDX41 wild type (WT) and mutant proteins
in human embryonic kidney cells showed that for WT, R525H, and
R164W, the full-length (70 kDa) protein was detected, and
localization was predominantly nuclear (supplemental Figure 6),
indicating that these mutations do not overtly affect protein translation or localization. In contrast, using a construct engineered to
mimic the consequences of the exon 6 splice acceptor mutant, a
truncated protein was observed as expected (supplemental Figure 6B).
For M1I, disruption of the initiating methionine resulted in a predominant smaller protein (;55 kDa), indicating the use of an alternate
internal translation initiation site (supplemental Figure 6A,C). Interestingly, in addition to full-length protein, the WT and point mutant
DDX41 constructs also produced the smaller DDX41 isoform,
suggesting that this isoform may occur naturally at some level.
Immunofluorescence showed that the smaller isoform was altered
in localization, with reduced nuclear and increased cytoplasmic
detection (M1I panel, supplemental Figure 6D), consistent with the
loss of a predicted nuclear localization signal at the amino terminus
(supplemental Figure 7).
Table 1 summarizes the clinical presentation of HMs in DDX41
mutation carriers and blood counts for any family members, when
available. The majority of carriers unaffected by or prior to HMs had
normal peripheral blood counts well into adulthood (9 of 15 [60%]; see
premalignancy characteristics in Table 1), suggesting that haploinsufficiency of DDX41 is sufficient for normal baseline hematopoiesis.
Cytopenias or macrocytosis (mean corpuscular volume .100 fL)
developed in the remaining 6 at a mean age of 66 years (range, 50-85
years) and led to an HM diagnosis shortly thereafter in 3. Bone marrow
morphology in 1 carrier with mild thrombocytopenia and anemia at age
85 years showed normal morphology, cellularity, and karyotype (supplemental Figure 4 A-C). Germ line mutation carriers who develop
MDS or AML most often present with leukopenia (10 of 12) with or
without macrocytosis or other cytopenias, hypocellular bone marrow
with prominent erythroid dysplasia, and a normal karyotype, often
leading to erythroleukemia (see Table 1 and supplemental Table 7 for
treatment and outcome data). Representative AML morphology is
shown in supplemental Figure 4D-G. Thus, complete blood count
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BLOOD, 25 FEBRUARY 2016 x VOLUME 127, NUMBER 8
DDX41 MUTATIONS IN HEMATOLOGIC MALIGNANCY
1019
Figure 1. Germ line DDX41 mutations in 9 families with inherited hematologic malignancies. (A-I) Pedigrees with germ line DDX41 mutations. (J) Germ line and
somatic DDX41 mutations in hematologic malignancies. BM, bone marrow; CML, chronic myeloid leukemia; CRC, colorectal cancer; HL, Hodgkin lymphoma; NOS, not
otherwise specified; SLE, systemic lupus erythematosis; ZnF, zinc finger
II.2
235
277
154
20432
20432
20432
236
236
31379
31379
31379
230
230
230
25476
25476
B
C
D
E
E
E
F
F
G
G
G
H
H
H
I
I
p.R164W
p.R164W
p.G530D
p.G530D‡
p.G530D‡
p.R525H
p.R525H
p.R525H
48
55
50
44
53
55
58
56
74
72
33
59
58
67
73
69
54
At dx
At dx
At dx
At dx
At dx
At dx
after dx
24 mo
At dx
At dx
At dx
after dx
1 mo
At dx2
At dx1
At dx
At dx
At dx
At dx
Status of
HM at time
of CBC
7.6
9.3
2.4
—
—
0.4
3.2
3.2
4.1
2.6
34.7
1.2
0.7
3.3
1.5
2.2
1.6
WBC (K/mL)
13.1
15.2
14.0
—
—
12.0
14.0
15.0
13.3
10.6
11.0
6.5
8.7
12.5
8.5
—
13.3
MCV (fL)
88.7
88.0
99.7
—
—
113.1
99.0
102.0
—
107.2
92.0
104.0
103.0
92.3
112.0
—
108.0
Malignancy
Hgb (g/dL)
—
—
0.6
—
—
0.2
1.6
1.7
1.4
0.7
25.3
0.08
0.1
1.9
0.3
—
0.5
ANC (K/mL)
347
320
151
—
—
47
179
171
66
41
333
27
34
102
62
89
128
Plt (K/mL)
FL (grade 1)
FL (grade 2)
AML
AML
AML
AML
MDS (RAEB-2)
MDS (RAEB-2)
AML
MDS (RAEB-2)
CML
aggregates
involvement
FL involvement
Hypercellular:
FL involvement
Hypercellular;
30%
—
—
20%
—
Hypercellular
15%-20%
5%-10%
Hypercellular
with NHL
consistent
lymphoid
Hypocellular;
Normal
No
dysplasia
Mild erythroid
No
—
—
No
dysplasia
Trilineage
dysplasia
Trilineage
No
dysplasia
Megakaryocytic
No
dysplasia
megakaryocytic
Erythroid and
dysplasia
megakaryocytic
Erythroid and
precursor
or myeloid
megakaryocyte
dysplastic
rare
dysplasia,
Erythroid
—
—
46,XY[15]
46,XY[20]
—
—
—
46,XX [20]
46,XX
46,XY[18]
47,XY,18[2]/
46,XX[20]
[16]/ 46,XX[2]
(q34;q11)
46,XX, t(9;22)
46,XY
46,XY[20]
46,XY[4]
(q21q31)[10]/
15%-25%
46,idem,inv(1)
(q31.1q34)[6]/
46,XY,del(5)
46,XX[20]
46,XY[20]
Karyotype
aggregates
dysplasia
Erythroid
No
dysplasia
Erythroid
BM dysplasia
lymphoid
CD51, CD191
20%-40%;
15%
20%
BM cellularity
with NHL
AML now
AML (M6)
MDS (RAEB-2)
AML
AML
AML (M6)
HM diagnosis
Dash indicates that information is not available.
AML, acute myeloid leukemia; ANC, absolute neutrophil count; BM, bone marrow; CBC, complete blood count; CML, chronic myeloid leukemia; dx, diagnosis; FL, follicular lymphoma; Hgb, hemoglobin; HM, hematologic malignancy; M6,
French-American-British subtype; MCV, mean corpuscular volume; MDS, myelodysplastic syndrome; NA, not applicable; NHL, non-Hodgkin lymphoma; Plt, platelet count; RAEB-2, refractory anemia with excess blasts 2; WBC, white blood
cell count, WT, wild type.
†Numbering for all complementary DNAs and proteins refers to NM_016222.2 and NP_057306.2.
‡Obligate carrier.
§Pedigree 127 is included in supplemental Figure 5.
III.4
III.1
III.6
II.6
II.5
III.6
III.1
III.1
p.M1I
p.M1I‡
p.M1I
p.M1I‡
p.M1I‡
delAGinsCA
c.435-2_435-1
p.D140Gfs*2
p.D140Gfs*2
p.D140Gfs*2
Age at time of
CBC (y)
LEWINSOHN et al
II.6
II.3
III.1
II.3
II.3
II.2
II.1
III.1
33755
A
Individual
Pedigree
DDX41
mutation†
1020
Panel in
Figure 1
Table 1. Complete blood count and bone marrow characteristics of individuals with germ line DDX41 mutations
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
BLOOD, 25 FEBRUARY 2016 x VOLUME 127, NUMBER 8
127
S5§
II.8
III.10
III.5
III.7
III.3
III.2
IV.3
IV.2
III.8
III.3
III.1
II.12
II.10
WT
WT
WT
WT
WT
p.D140Gfs*2
p.D140Gfs*2
p.D140Gfs*2
p.D140Gfs*2
p.D140Gfs*2
p.D140Gfs*2
p.D140Gfs*2
p.D140Gfs*2
p.D140Gfs*2
p.G530D
p.G530D
p.G530D
p.M1I
p.M1I
p.M1I
delAGinsCA
c.435-2_435-1
46
62
65
38
41
20
35
57
65
60
75
79
85
87
59
50
63
73
72
30
75
52
54
56
73
55
Age at time of
CBC (y)
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
AML dx
2 mo before
NA
AML dx
15 mo before
AML dx
23 mo before
CML dx
29 mo before
NA
AML dx
29 mo before
AML dx
4 mo before
At dx
At dx
At dx
Status of
HM at time
of CBC
6.8
4.9
6.2
11.3
8.3
4.5
8.4
6.0
9.4
5.1
7.5
10.0
5.8
8.4
3.1
2.8
5.7
3.5
—
7.9
8.7
5.2
2.3
1.1
3.6
7.1
WBC (K/mL)
95.8
97.9
88.0
MCV (fL)
13.5
13.3
14.2
15.1
14.0
13.3
14.4
16.7
15.0
14.6
13.9
13.0
12.9
14.2
12.8
14.6
14.2
13.3
—
12.7
12.3
15.7
15.0
Controls
90.0
88.3
94.4
98.0
89.3
94.2
91.3
89.2
90.0
89.6
103.0
96.0
93.7
94.0
100.5
97.8
91.3
—
—
87.0
90.0
92.0
102.0
Premalignancy
10.0
12.5
12.5
Hgb (g/dL)
4.4
2.8
—
—
5.7
2.6
—
3.8
—
—
3.7
—
3.7
4.4
1.4
1.0
3.6
1.5
—
6.2
5.6
3.5
1.0
0.2
—
3.3
ANC (K/mL)
313
213
262
202
213
165
348
187
231
189
354
213
126
296
180
185
336
72
123
274
184
225
145
27
135
223
Plt (K/mL)
HM diagnosis
None
AML
AML (M6)
FL (grade 1)
BM cellularity
20%-30%
20%
15%-20%
30%-50%
No
No
dysplasia
Erythroid
No
BM dysplasia
Karyotype
46,XY[19]
[4]/46,XY[14]
(q11.21-q13.33)
46,XY,del(20)
46,XY[20]
46,XX[20]
Dash indicates that information is not available.
AML, acute myeloid leukemia; ANC, absolute neutrophil count; BM, bone marrow; CBC, complete blood count; CML, chronic myeloid leukemia; dx, diagnosis; FL, follicular lymphoma; Hgb, hemoglobin; HM, hematologic malignancy; M6,
French-American-British subtype; MCV, mean corpuscular volume; MDS, myelodysplastic syndrome; NA, not applicable; NHL, non-Hodgkin lymphoma; Plt, platelet count; RAEB-2, refractory anemia with excess blasts 2; WBC, white blood
cell count, WT, wild type.
†Numbering for all complementary DNAs and proteins refers to NM_016222.2 and NP_057306.2.
‡Obligate carrier.
§Pedigree 127 is included in supplemental Figure 5.
127
127
S5§
S5§
127
S5§
230
127
S5§
H
127
S5§
277
127
277
127
S5§
S5§
C
127
S5§
II.6
III.5
II.6
II.6
III.1
II.1
p.D140Gfs*2
p.D140Gfs*2
p.D140Gfs*2
p.D140Gfs*2
p.R164W
DDX41
mutation†
BLOOD, 25 FEBRUARY 2016 x VOLUME 127, NUMBER 8
C
127
S5§
III.8
230
230
H
H
230
236
F
127
236
F
H
20432
E
S5§
III.6
154
D
III.1
33755
A
III.1
III.7
33755
127
S5§
II.11
III.7
Individual
A
127
25476
I
S5§
Pedigree
Panel in
Figure 1
Table 1. (continued)
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DDX41 MUTATIONS IN HEMATOLOGIC MALIGNANCY
1021
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1022
BLOOD, 25 FEBRUARY 2016 x VOLUME 127, NUMBER 8
LEWINSOHN et al
monitoring alone with bone marrow biopsy reserved for those with
progressive cytopenias may be a reasonable approach for clinical
follow-up of adult asymptomatic carriers in these families, in addition to
previously recommended approaches for assessing cases with a family
history.9
Granulomatous and immune disorders presenting prior to HM in
germ line mutation carriers were observed in 3 families (Figure 1E,I,
supplemental Figure 5, and supplemental Data). Of relevance, DDX41
has been shown to be a cytoplasmic DNA sensor in dendritic cells
and therefore has a documented role in the innate immune response.10-12
Dysregulation of such responses may be an initiator of disorders observed
in our pedigrees and may be linked to lymphoid malignancy.13,14 In
addition, inflammatory skin disorders have previously been associated
with RUNX1 mutation–mediated familial HMs.15 Therefore, the coexistence of immune and hematologic disorders in DDX41 germ line
mutation carriers highlights the importance of examining a potential
interaction between the role of DDX41 in immune function and
leukemogenesis.
Our findings show that germ line DDX41 mutations predispose to
a variety of HMs (MDS/AML, chronic myeloid leukemia, NHL,
and Hodgkin lymphoma). The frequent identification of truncating
loss-of-function (LOF) mutations and splicing mutations supports
the hypothesis that HM predisposition arises from haploinsufficiency of DDX41. The M1I variant described here, although
predicted to be an LOF allele, identified a new, potentially
relevant translation isoform of DDX41. There are 2 likely sites of
alternative translation initiation consistent with the small isoform
(M132 and M155) that include a previously described site of
mutation (p.M155I).5 This is suggestive of mutations differentially
affecting DDX41 isoforms and may explain the selection for a
D140 mutation hotspot as, in this scenario, it could result in isoform
switching from the long form to the short form of DDX41, something
which is commonly seen in germ line AML-predisposing CEBPA
mutations.16
The mean age of HM onset (62 years) of all cases to date emphasizes the importance of obtaining a family history and considering predisposition alleles in all adults with HMs. In addition, the
younger age of diagnosis in missense mutant DDX41 families vs
LOF mutants, is reminiscent of observations in GATA2 and RUNX1
families in which altered function of these mutant proteins more
strongly predisposes to malignant progression.2,17 Therefore,
the continued identification of DDX41 mutations will be crucial
for a comprehensive understanding of the phenotypic and clinical
consequence of mutations in this gene.
Acknowledgments
The authors thank the patients and their family members for their
willingness to participate in this research and Dr Andrew Roberts for
assistance with clinical information.
This work was supported by The Cancer Research Foundation
(L.A.G., J.E.C.), K12 CA139160 (J.E.C.), K08 HL129088 (J.E.C.),
Grants No. APP1024215 and APP1023059 from the National Health
and Medical Research Council of Australia (H.S.S., C.N.H.), and
No. APP565161 from the Cancer Council of South Australia (H.S.S.,
C.N.H.).
Authorship
Contribution: M.L. performed research, analyzed the data, and wrote the
manuscript; A.L.B. analyzed and interpreted the data and wrote the
manuscript; L.M.W. performed the research and analyzed the data; C.P.,
G.R., and M.K.L. contributed to research and edited the manuscript;
A.W.S. and J.F. analyzed the data; M.B., C.-E.C., and Y.L. performed
research; A.Y., G.K.S., and N.P. analyzed clinical data, assisted with
study design, and edited the manuscript; M.F., M.A., L.J., and K.P.
collected data and samples; R.J.D. and I.D.L. assisted with study design
and edited the manuscript; B.C.M., D.A.P., M.-C.K., T.W., S.K., and
A.S assisted with clinical data and samples and reviewed the manuscript;
and L.A.G., C.N.H., J.E.C., and H.S.S. designed the study, analyzed
data, and wrote the manuscript.
Conflict-of-interest disclosure: The authors declare no competing
financial interests.
Correspondence: Hamish S. Scott, Department of Genetics and
Molecular Pathology, Centre for Cancer Biology, SA Pathology, PO
Box 14, Rundle Mall, Adelaide, SA 5000, Australia; e-mail: hamish.
[email protected]; Jane E. Churpek, The University of Chicago,
Department of Medicine, Section of Hematology/Oncology, 5841 S
Maryland Ave, MC 2115, Chicago, IL 60637-1470; e-mail:
[email protected]; Christopher N. Hahn, Department of
Genetics and Molecular Pathology, Centre for Cancer Biology, SA
Pathology, PO Box 14, Rundle Mall, Adelaide, SA 5000, Australia;
e-mail: [email protected]; and Lucy A. Godley, The University
of Chicago, Department of Medicine, Section of Hematology/
Oncology, 5841 S Maryland Ave, MC 2115, Chicago, IL 60637-1470;
e-mail: [email protected].
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2016 127: 1017-1023
doi:10.1182/blood-2015-10-676098 originally published
online December 28, 2015
Novel germ line DDX41 mutations define families with a lower age of
MDS/AML onset and lymphoid malignancies
Maya Lewinsohn, Anna L. Brown, Luke M. Weinel, Connie Phung, George Rafidi, Ming K. Lee,
Andreas W. Schreiber, Jinghua Feng, Milena Babic, Chan-Eng Chong, Young Lee, Agnes Yong,
Graeme K. Suthers, Nicola Poplawski, Meryl Altree, Kerry Phillips, Louise Jaensch, Miriam Fine,
Richard J. D'Andrea, Ian D. Lewis, Bruno C. Medeiros, Daniel A. Pollyea, Mary-Claire King, Tom
Walsh, Siobán Keel, Akiko Shimamura, Lucy A. Godley, Christopher N. Hahn, Jane E. Churpek and
Hamish S. Scott
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