17.Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid...
18
MYELOID NEOPLASIA Brief report Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia *Kate A. Alford, 1 *Katarina Reinhardt, 2 *Catherine Garnett, 1 *Alice Norton, 1 Katarina Bo ¨hmer, 2 Christine von Neuhoff, 2 Alexandra Kolenova, 3 Emanuele Marchi, 1 Jan-Henning Klusmann, 2 Irene Roberts, 4 Henrik Hasle, 5 Dirk Reinhardt, 2 and Paresh Vyas, 1 on behalf of the International Myeloid Leukemia–Down Syndrome Study Group 1 Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; 2 Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany; 3 Department of Pediatric Oncology, Comenius University Medical School and University Children’s Hospital, Bratislava, Slovakia; 4 Department of Haematology, Imperial College London, London, United Kingdom; and 5 Nordic Society of Pediatric Hematology and Oncology, Department of Pediatrics, Aarhus University Hospital, Skejby, Denmark Children with Down syndrome (DS) up to the age of 4 years are at a 150-fold excess risk of developing myeloid leukemia (ML-DS). Approximately 4%-5% of new- borns with DS develop transient my- eloproliferative disorder (TMD). Blast cell structure and immunophenotype are simi- lar in TMD and ML-DS. A mutation in the hematopoietic transcription factor GATA1 is present in almost all cases. Here, we show that simple techniques detect GATA1 mutations in the largest series of TMD (n 134; 88%) and ML-DS (n 103; 85%) cases tested. Furthermore, no sig- nificant difference in the mutational spec- trum between the 2 disorders was seen. Thus, the type of GATA1 sequence muta- tion is not a reliable tool and is not prognostic of which patients with TMD are probable to develop ML-DS. (Blood. 2011;118(8):2222-2238) Introduction Children with trisomy 21 (T21; Down syndrome [DS]) have 150-fold increased incidence of myeloid leukemia (ML-DS). 1,2 Incidence of transient myeloproliferative disorder (TMD) is esti- mated at 4%-5% of neonates with DS. 1,3 Approximately 20%- 30% of these neonates develop ML-DS by 4 years of age. 4,5 Both diseases are characterized by a clonal population of blasts, with similar immunophenotype and structure in blood and BM. How- ever, TMD spontaneously regresses, whereas ML-DS is stably transformed. In addition to T21, blast cells in TMD and ML-DS carry acquired mutations in the hematopoietic transcription factor GATA1. 6-14 These mutations lead to expression of N-terminally truncated GATA1s protein. Mutations are detectable in disease but not in remission. 3,6-14 Most reported mutations are found in GATA1 exon 2, including insertions, deletions, and point mutations. When TMD progresses to ML-DS, the same GATA1 mutation is usually present in blasts of both, showing their clonal relationship. 5,14 Debate exists about whether the type of GATA1 mutation determines progression to ML-DS. 9,15-17 To examine this, we analyzed GATA1 mutations in 134 TMD and 103 ML-DS cases, the largest patient cohort reported to date. Of these 8 paired TMD and follow-up ML-DS samples were available. GATA1 mutations were detected in 226 patients (95%). The lower limit blast percentage for successful detection of GATA1 mutations was 0.5%. No difference was observed in types of mutation between patients with TMD and with ML-DS. Contrary to previous data, 15 we did not detect specific GATA1 mutation types more commonly in ML-DS. Therefore, the type of GATA1 mutation in our series is not prognostic of which patients with TMD will progress to ML-DS. Methods Mutation detection DNA was prepared from peripheral blood or BM with the use of the DNeasy Blood and Tissue kit (QIAGEN). PCR was performed with primers and conditions outlined in supplemental Methods (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). PCR amplicons were analyzed by denaturing high-performance liquid chromatography (WAVE; Transgenomic) and direct sequencing. In sample subsets with blast percentage 1%, blasts were sorted before DNA extraction (supplemental Methods), or PCR product was cloned with the pGEM-T-Easy vector system 1 kit (Promega) and sequenced. Statistical analysis was performed with the Fisher exact test. Results and discussion GATA1 mutation screening was performed in the central reference of Acute Myeloid Leukemia Berlin-Frankfurt-Mu ¨ nster Study group in Hannover, Germany, and the Weatherall Institute of Molecular Medicine, Oxford, United Kingdom (134 TMD and 103 ML-DS samples). The mean age of patients with TMD was 0.78 months Submitted March 17, 2011; accepted June 13, 2011. Prepublished online as Blood First Edition paper, June 29, 2011; DOI 10.1182/blood-2011-03-342774. *K.A.A., K.R., C.G., and A.N. contributed equally to the work and are joint first authors. The online version of this article contains a data supplement. 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. © 2011 by The American Society of Hematology 2222 BLOOD, 25 AUGUST 2011 VOLUME 118, NUMBER 8 For personal use only. on July 29, 2015. by guest www.bloodjournal.org From
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Transcript of 17.Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid...
MYELOID NEOPLASIA
Brief report
Analysis of GATA1 mutations in Down syndrome transient myeloproliferativedisorder and myeloid leukemia
*Kate A. Alford,1 *Katarina Reinhardt,2 *Catherine Garnett,1 *Alice Norton,1 Katarina Bohmer,2 Christine von Neuhoff,2
Alexandra Kolenova,3 Emanuele Marchi,1 Jan-Henning Klusmann,2 Irene Roberts,4 Henrik Hasle,5 Dirk Reinhardt,2 andParesh Vyas,1 on behalf of the International Myeloid Leukemia–Down Syndrome Study Group
1Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; 2PediatricHematology and Oncology, Hannover Medical School, Hannover, Germany; 3Department of Pediatric Oncology, Comenius University Medical School andUniversity Children’s Hospital, Bratislava, Slovakia; 4Department of Haematology, Imperial College London, London, United Kingdom; and 5Nordic Society ofPediatric Hematology and Oncology, Department of Pediatrics, Aarhus University Hospital, Skejby, Denmark
Children with Down syndrome (DS) up tothe age of 4 years are at a 150-fold excessrisk of developing myeloid leukemia(ML-DS). Approximately 4%-5% of new-borns with DS develop transient my-eloproliferative disorder (TMD). Blast cellstructure and immunophenotype are simi-
lar in TMD and ML-DS. A mutation in thehematopoietic transcription factor GATA1is present in almost all cases. Here, weshow that simple techniques detectGATA1 mutations in the largest series ofTMD (n � 134; 88%) and ML-DS (n � 103;85%) cases tested. Furthermore, no sig-
nificant difference in the mutational spec-trum between the 2 disorders was seen.Thus, the type of GATA1 sequence muta-tion is not a reliable tool and is notprognostic of which patients with TMDare probable to develop ML-DS. (Blood.2011;118(8):2222-2238)
Introduction
Children with trisomy 21 (T21; Down syndrome [DS]) have� 150-fold increased incidence of myeloid leukemia (ML-DS).1,2
Incidence of transient myeloproliferative disorder (TMD) is esti-mated at � 4%-5% of neonates with DS.1,3 Approximately 20%-30% of these neonates develop ML-DS by 4 years of age.4,5 Bothdiseases are characterized by a clonal population of blasts, withsimilar immunophenotype and structure in blood and BM. How-ever, TMD spontaneously regresses, whereas ML-DS is stablytransformed.
In addition to T21, blast cells in TMD and ML-DS carryacquired mutations in the hematopoietic transcription factorGATA1.6-14 These mutations lead to expression of N-terminallytruncated GATA1s protein. Mutations are detectable in disease butnot in remission.3,6-14 Most reported mutations are found in GATA1exon 2, including insertions, deletions, and point mutations. WhenTMD progresses to ML-DS, the same GATA1 mutation is usuallypresent in blasts of both, showing their clonal relationship.5,14
Debate exists about whether the type of GATA1 mutationdetermines progression to ML-DS.9,15-17 To examine this, weanalyzed GATA1 mutations in 134 TMD and 103 ML-DS cases, thelargest patient cohort reported to date. Of these 8 paired TMD andfollow-up ML-DS samples were available. GATA1 mutations weredetected in 226 patients (95%). The lower limit blast percentage forsuccessful detection of GATA1 mutations was 0.5%. No differencewas observed in types of mutation between patients with TMD andwith ML-DS. Contrary to previous data,15 we did not detect specificGATA1 mutation types more commonly in ML-DS. Therefore, the
type of GATA1 mutation in our series is not prognostic of whichpatients with TMD will progress to ML-DS.
Methods
Mutation detection DNA was prepared from peripheral blood or BM withthe use of the DNeasy Blood and Tissue kit (QIAGEN). PCR wasperformed with primers and conditions outlined in supplemental Methods(available on the Blood Web site; see the Supplemental Materials link at thetop of the online article). PCR amplicons were analyzed by denaturinghigh-performance liquid chromatography (WAVE; Transgenomic) anddirect sequencing. In sample subsets with blast percentage � 1%, blastswere sorted before DNA extraction (supplemental Methods), or PCRproduct was cloned with the pGEM-T-Easy vector system 1 kit (Promega)and sequenced.
Statistical analysis was performed with the Fisher exact test.
Results and discussion
GATA1 mutation screening was performed in the central referenceof Acute Myeloid Leukemia Berlin-Frankfurt-Munster Study groupin Hannover, Germany, and the Weatherall Institute of MolecularMedicine, Oxford, United Kingdom (134 TMD and 103 ML-DSsamples). The mean age of patients with TMD was 0.78 months
Submitted March 17, 2011; accepted June 13, 2011. Prepublished online asBlood First Edition paper, June 29, 2011; DOI 10.1182/blood-2011-03-342774.
*K.A.A., K.R., C.G., and A.N. contributed equally to the work and are joint firstauthors.
The online version of this article contains a data supplement.
The publication costs of this article were defrayed in part by page chargepayment. Therefore, and solely to indicate this fact, this article is herebymarked ‘‘advertisement’’ in accordance with 18 USC section 1734.
© 2011 by The American Society of Hematology
2222 BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
(range, 0-11 months). Mean blast count was 42% (range, 0.5%-95%), white blood cell count was 60.79 � 109/L (range,1-1193.3 � 109/L), hemoglobin level was 13.77 g/dL (range,2-21.3 g/dL), and platelet count was 201.78 � 109/L (range,12-1800 � 109/L; Table 1). The mean age of the patients withDS-ML was 20.19 months (range, 1-60 months). Mean blast countwas 27.8% (range, 1%-96%), white blood cell count was13.95 � 109/L (range, 1-200.3 � 109/L), hemoglobin level was9.06 g/dL (range, 3.1-15.1 g/dL) and platelet count was 52.2 � 109/L(range, 1.5-257 � 109/L; Table 2).
GATA1 mutations were analyzed by WAVE and direct sequenc-ing of PCR products. GATA1 sequence mutations were determinedin 118 of 134 patients with TMD (88.1%) and in 88 of 103 patientswith ML-DS (85.4%). Mutations were detected by WAVE in afurther 9 and 11 patients, respectively (Tables 1-2). The mainreason for failure to detect mutations was low blast count.Alternative techniques such as high-resolution melt analysis ornested PCR may be able to detect mutations in some cases. Thelower limit of blasts that allowed successful mutation detection was0.5% (supplemental Methods). However, in one patient (blastcount, 42%) failure to detect mutation suggests an uncommonmutation involving sequence outside the genomic area, spanningthe PCR, or a deletion inside this area, affecting the primerannealing site.
Relative positions of sequence mutations are shown in Figure 1A.Insertion/deletion/duplications comprised 78% of mutations inboth TMD and ML-DS (Figure 1B), consistent with previousreports.12 Point mutations were detected in 21% and 22% of TMDand ML-DS samples, respectively. Substitutions were rare, uniquelydetected in 1% of patients with TMD. Therefore, there is littledifference in mutational spectrum between TMD and ML-DS.Thirteen patients with TMD are known to have progressed toML-DS. In these samples the spectrum of mutations was similar tothe TMD group that did not progress to ML-DS (insertion/deletion/duplications, 77%; point mutations, 23%). Eight patients hadpaired TMD and follow-up ML-DS samples. The same mutationwas present in both TMD and ML-DS for 7 of 8 samples, similar toprevious observations.12,14
Predicted consequence of mutations was similar for both TMDand ML-DS (Figure 1C). Most mutations inserted a prematuretermination codon (PTC) either by introducing a stop codon orframeshift. Mutations affecting the splice site at GATA1 exon2 exon/intron boundary were next most frequent. In some cases(3 TMD and 3 DS-ML) where a point mutation occurred in intronicsequence, predicted consequence was unclear. They may occur insplice site regulatory elements and may affect gene splicing.18 In13 patients with TMD who progressed to ML-DS predictedconsequences in the protein were similar.
Characterizing the sequence of GATA1 mutations provides anopportunity to develop patient mutation-specific quantitative PCRanalysis to monitor resolution of TMD, persistence/re-emergenceof GATA1 mutant clone leading to ML-DS, and therapy response inpatients with ML-DS.13 Direct sequencing of DNA from blasts thatunderwent FACS was successful in identifying sequence mutationin 19 patients, whereas direct sequencing of DNA from unfraction-ated samples failed. In 20 cases it was necessary to subclone theGATA1 PCR product to pinpoint mutation sequence.
A previous study divided GATA1 mutations in TMD andML-DS into 2 classes on the basis of levels of GATA1s proteinexpression.15 Mutations affecting gene splicing, the start codon (1stMet) or that introduced a PTC in the 3� end of exon 2 (PTC 1-3�)resulted in high GATA1s protein levels; whereas a PTC in the 5�
end of exon 2 (PTC 1-5�) or in exon 3.1 (PTC-2) resulted in lowGATA1s expression.15 Patients with TMD with mutations predictedto result in low GATA1s protein expression were more probable todevelop ML-DS because this type of mutation had significantlyhigher incidence in ML-DS.15 We asked whether this was true forour sample cohort. No significant differences were found betweennumbers of samples in each of the mutation types when TMD andML-DS were compared (supplementary Table 1; 1st Met, P � .7011;splice errors, P � .6741; PTC 1-3�, P � .3388; PTC 1-5�,P � .3021; PTC-2, P � .2667). Similarly, we found no significantincrease in predicted GATA1s low-expressing mutations in ML-DSsamples versus TMD (P � .5534; Tables 1-2). In 12 TMD samplesthat progressed to ML-DS whereby we obtained a sequencemutation predicted to affect protein expression, equal numberswere predicted to result in high and low GATA1s protein expres-sion (ie, 6 of each). GATA1s cDNA qPCR for 36 TMD and20 ML-DS patient samples showed no significant differences inGATA1s mRNA expression in patients with PTC 1-3�, Splice, PTC1-5�, or unknown effect mutations (supplemental Figure 1).
Cytogenetic data were available for 31 patients with TMD and68 patients with ML-DS (Tables 1-2). In neonates with TMD, nosignificant correlation was observed between not progressing toML-DS and presenting with T21 as the only cytogenetic abnormal-ity (P � .2533; supplemental Table 2). Therefore, karyotype doesnot predict patients who will progress to ML-DS.
In conclusion, simple techniques detect GATA1 mutations inmost patients TMD and patients with ML-DS. It is not possible topredict progression of TMD to ML-DS on the basis of type ofGATA1 mutation, at least in mainly white patients.
Acknowledgments
The authors thank Esther Edlundh-Rose for technical help process-ing patient samples.
This work was supported in Oxford by the Leukemia &Lymphoma Research Specialist Program (award 08030; K.A.A.,P.V., and I.R.), NIHR Biomedical Research Centres fundingscheme (P.V.), the Medical Research Council Disease Team Award(P.V.), the MRC Molecular Hematology Unit (P.V.), and theImperial College London Comprehensive Biomedical ResearchCenter (I.R.). This work was supported in Hannover by GermanResearch Foundation (grant DFG RE2580/1-1) and by a grant fromthe Madeleine-Schickedanz Leukemia Foundation.
Authorship
Contribution: K.A.A. performed and analyzed experiments andwrote the manuscript; A.N. and K.R. designed, performed, andanalyzed experiments and data; C.G. performed experiments,analyzed data, and compiled figures; K.B., C.v.N., and A.K.performed and analyzed experiments; E.M. analyzed data; and P.V.,D.R., J-H.K., H.H., and I.R. designed experiments, analyzed data,and wrote or reviewed the manuscript.
Conflict-of-interest disclosure: The authors declare no compet-ing financial interests.
A complete list of the participants of the International ML-DSStudy Group can be found in the supplemental Appendix.
GATA1 MUTATIONS IN TMD AND ML-DS 2223BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
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2224 ALFORD et al BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
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C1-
5�47
,XY
,�21
cC
CR
2625
Ex2
Del
146
62F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
239
.619
.822
PT
C1-
5�47
,XY
,�21
cC
CR
27‡
18E
x2D
up8
4717
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
010
113
.321
PT
C1-
5�47
,XY
,t(5
;11)
(p15
;q13
),
�21
c
ML-
DS
2870
Ex2
Del
446
84F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
420
07.
687
PT
C1-
5�N
/AC
CR
2962
Ex2
Ins
446
43F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
1N
/AN
/AN
/AP
TC
1-5�
N/A
Unk
now
n
3011
.4E
x2D
up8
4732
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
033
.59.
169
5P
TC
1-3�
47,X
Y,�
21c
Unk
now
n
3129
Ex2
Poi
nt1
4670
Non
syno
nym
ous
chan
gein
amin
oac
idse
quen
ce
intr
oduc
ing
ast
opco
don
221
.713
24P
TC
1-5�
N/A
Unk
now
n
3260
Ex2
Del
146
97F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
28w
eeks
gest
atio
n
405.
154
PT
C1-
5�N
/AU
nkno
wn
3379
N/D
Del
246
38F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
019
8.2
10.6
312
PT
C1-
5�N
/AU
nkno
wn
3466
N/D
Dup
4047
40F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
0.25
9.8
12.7
60P
TC
1-3�
N/A
Unk
now
n
3560
N/D
Dup
1047
10F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
0.25
46.6
20.4
89P
TC
1-5�
N/A
Unk
now
n
36‡
35.5
N/D
Ins
1447
07F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
055
.617
.357
0P
TC
1-5�
N/A
ML-
DS
3754
N/D
Poi
nt1
4768
Loss
ofsp
lice
acce
ptor
site
055
.617
.357
0S
plic
eN
/AU
nkno
wn
3823
N/D
Poi
nt1
4767
Syn
onym
ous
mut
atio
n1.
2519
.26.
712
5U
nkno
wn
N/A
Unk
now
n
39‡
84N
/DD
el2
4604
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
011
93.3
14.7
255
PT
C1-
5�N
/AM
L-D
S
4010
N/D
Del
�In
s2
�1
4770
�47
74Lo
ssof
splic
edo
nor
site
29.
19.
677
Spl
ice
N/A
Unk
now
n
41‡
88N
/DD
el3
4680
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
023
215
.625
4P
TC
1-5�
N/A
ML-
DS
4275
N/D
Del
�In
s1
�2
4679
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
017
2.8
16.2
101
PT
C1-
5�N
/AU
nkno
wn
4314
N/D
Poi
nt1
4734
Unk
now
n0.
2516
.914
.935
3U
nkno
wn
N/A
Unk
now
n
4413
.5N
/DD
up36
4737
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
0.5
3.2
11.1
16P
TC
1-3�
N/A
Unk
now
n
WB
Cin
dica
tes
whi
tebl
ood
cell;
Hb,
hem
oglo
bin;
Plt,
plat
elet
;Poi
nt,p
oint
subs
titut
ion;
CC
R,c
ompl
ete
clin
ical
rem
issi
on;D
up,d
uplic
atio
nof
nucl
eotid
es;I
ns,i
nser
tion
ofnu
cleo
tides
;Del
,del
etio
nof
nucl
eotid
es;N
/A,n
otav
aila
ble;
and
N/D
,not
done
.*E
xon
num
berc
onta
inin
gth
em
utat
ion
asde
fined
byW
AV
Ean
alys
is.
†Nuc
leot
ide
0is
the
first
nucl
eotid
eof
GA
TA1
exon
1in
clud
ing
exon
san
din
tron
s.N
CB
Iref
eren
ceN
T_0
7957
3.4
(Hom
osa
pien
sch
rom
osom
eX
geno
mic
cont
ig,s
tart
ing
posi
tion
1149
6706
)was
used
.‡P
atie
nts
with
TM
Dpr
ogre
ssed
toM
L-D
S.
GATA1 MUTATIONS IN TMD AND ML-DS 2225BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
Tab
le1.
Su
mm
ary
ofG
ATA
1m
uta
tio
ns
and
pat
ien
tch
arac
teri
stic
sfo
rT
MD
sam
ple
s(c
on
tin
ued
)
Pat
ien
tn
o.
Bla
stco
un
t,%
oft
ota
ln
ucl
eate
dco
un
tW
AV
E*
Mu
tati
on
typ
e
No
.of
nu
cleo
tid
esch
ang
ed,b
pP
osi
tio
no
fm
uta
tio
n†
Pre
dic
ted
effe
cto
fm
uta
tio
no
nR
NA
Ag
eat
dia
gn
osi
s,m
oW
BC
cou
nt,
�10
9 /L
Hb
leve
l,g
/dL
Plt
cou
nt,
�10
9 /L
Kan
ezak
ieta
l15
clas
sK
aryo
typ
eO
utc
om
e
4531
N/D
Dup
1947
22F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
028
.616
.257
PT
C1-
3�N
/AU
nkno
wn
4643
N/D
Ins
�D
up2
�13
4723
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
061
17.6
149
PT
C1-
3�N
/AU
nkno
wn
4769
N/D
Poi
nt1
4550
Loss
ofst
artc
odon
034
1526
1stM
etN
/AU
nkno
wn
4810
N/D
Dup
2147
23F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
0.25
7.7
13.2
78P
TC
1-3�
N/A
Unk
now
n
4978
N/D
Del
�In
s19
�17
4698
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
068
.610
.921
2P
TC
1-5�
N/A
Unk
now
n
5034
N/D
Ins
747
13F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
0.25
6.2
16.9
25P
TC
1-5�
N/A
Unk
now
n
5160
N/D
Del
246
38F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
051
.214
.815
9P
TC
1-5�
N/A
Unk
now
n
5275
N/D
Poi
nt1
4747
Non
syno
nym
ous
chan
gein
amin
oac
idse
quen
ce
intr
oduc
ing
ast
opco
don
0N
/AN
/AN
/AP
TC
1-3�
N/A
Unk
now
n
5318
.5N
/DD
el16
245
40Lo
ssof
star
tcod
on0
17.3
1417
31s
tMet
N/A
Unk
now
n
541
N/D
Del
�In
s2
�3
4698
Fra
mes
hift
and
intr
oduc
tion
ofso
pco
don
0.25
57.5
10.6
36P
TC
1-5�
N/A
Unk
now
n
558
N/D
Ins
�D
up3
�36
4724
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
0.25
1618
.548
PT
C1-
3�N
/AU
nkno
wn
5666
.5N
/DD
el2
4638
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
0.75
62.9
12.3
93P
TC
1-5�
N/A
Unk
now
n
57‡
75N
/DD
up13
4744
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
014
9.1
16.9
131
PT
C1-
3�47
,XY
,�21
.ish
21qt
er(D
21S
1446
�3)
ML-
DS
5885
N/D
Poi
nt1
4762
Non
syno
nym
ous
chan
gein
amin
oac
idse
quen
ce
intr
oduc
ing
ast
opco
don
046
.420
.619
7P
TC
1-3�
N/A
Unk
now
n
5945
N/D
Del
�In
s7
�10
4760
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
0.5
78.3
1518
00P
TC
1-3�
N/A
Unk
now
n
6038
N/D
Ins
�D
up3
�9
4740
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
0.25
32.9
11.9
220
PT
C1-
3�N
/AU
nkno
wn
61‡
64.5
N/D
Dup
1847
33F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
069
.415
.411
78P
TC
1-3�
N/A
ML-
DS
6258
N/D
Del
146
98F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
0.25
24.9
15.6
154
PT
C1-
5�N
/AU
nkno
wn
6334
N/D
Del
146
90F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
027
.217
134
PT
C1-
5�N
/AU
nkno
wn
6485
N/D
Del
246
04F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
022
16.3
108
PT
C1-
5�N
/AU
nkno
wn
6511
N/D
Poi
nt1
4549
Loss
ofs
17.
412
.324
11s
tMet
N/A
Unk
now
n
WB
Cin
dica
tes
whi
tebl
ood
cell;
Hb,
hem
oglo
bin;
Plt,
plat
elet
;Poi
nt,p
oint
subs
titut
ion;
CC
R,c
ompl
ete
clin
ical
rem
issi
on;D
up,d
uplic
atio
nof
nucl
eotid
es;I
ns,i
nser
tion
ofnu
cleo
tides
;Del
,del
etio
nof
nucl
eotid
es;N
/A,n
otav
aila
ble;
and
N/D
,not
done
.*E
xon
num
berc
onta
inin
gth
em
utat
ion
asde
fined
byW
AV
Ean
alys
is.
†Nuc
leot
ide
0is
the
first
nucl
eotid
eof
GA
TA1
exon
1in
clud
ing
exon
san
din
tron
s.N
CB
Iref
eren
ceN
T_0
7957
3.4
(Hom
osa
pien
sch
rom
osom
eX
geno
mic
cont
ig,s
tart
ing
posi
tion
1149
6706
)was
used
.‡P
atie
nts
with
TM
Dpr
ogre
ssed
toM
L-D
S.
2226 ALFORD et al BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
Tab
le1.
Su
mm
ary
ofG
ATA
1m
uta
tio
ns
and
pat
ien
tch
arac
teri
stic
sfo
rT
MD
sam
ple
s(c
on
tin
ued
)
Pat
ien
tn
o.
Bla
stco
un
t,%
oft
ota
ln
ucl
eate
dco
un
tW
AV
E*
Mu
tati
on
typ
e
No
.of
nu
cleo
tid
esch
ang
ed,b
pP
osi
tio
no
fm
uta
tio
n†
Pre
dic
ted
effe
cto
fm
uta
tio
no
nR
NA
Ag
eat
dia
gn
osi
s,m
oW
BC
cou
nt,
�10
9 /L
Hb
leve
l,g
/dL
Plt
cou
nt,
�10
9 /L
Kan
ezak
ieta
l15
clas
sK
aryo
typ
eO
utc
om
e
6632
N/D
Ins
146
54F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
031
.616
.415
8P
TC
1-5�
N/A
Unk
now
n
673.
5N
/DP
oint
145
97N
onsy
nony
mou
sch
ange
in
amin
oac
idse
quen
ce
28.
49.
310
5U
nkno
wn
N/A
Unk
now
n
6822
N/D
Del
3446
93F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
0.25
17.3
13.1
270
PT
C1-
5�N
/AU
nkno
wn
69‡
87N
/DP
oint
145
52N
onsy
nony
mou
sch
ange
in
amin
oac
idse
quen
ce
0.25
133.
913
.832
.9U
nkno
wn
N/A
ML-
DS
705.
5N
/DP
oint
147
68Lo
ssof
splic
eac
cept
orsi
te0
23.8
39.
915
4S
plic
eN
/AU
nkno
wn
7132
N/D
Ins
�D
up1
�12
4742
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
027
.614
.646
PT
C1-
3�N
/AU
nkno
wn
7291
N/D
Ins
146
47F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
010
.610
.729
4P
TC
1-5�
N/A
Unk
now
n
7316
.5N
/DD
el1
4653
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
0.75
8.9
12.5
120
PT
C1-
5�N
/AU
nkno
wn
7414
N/D
Dup
1947
22F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
113.
3910
.591
PT
C1-
3�N
/AU
nkno
wn
7578
N/D
Del
147
66Lo
ssof
splic
eac
cept
orsi
te0
91.2
13.6
33S
plic
e47
,XY
,t(2
1;21
)
(Q10
;Q10
)�
21c
Unk
now
n
7660
.5N
/DP
oint
147
34N
onsy
nony
mou
sch
ange
in
amin
oac
idse
quen
ce
025
.413
.998
Unk
now
nN
/AU
nkno
wn
7716
N/D
Dup
247
34F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
0.5
8.5
10.8
52P
TC
1-3�
N/A
Unk
now
n
7812
N/D
Del
5147
06F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
023
.214
.237
9P
TC
1-5�
N/A
Unk
now
n
7995
N/D
Ins
�D
up6
�7
4708
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
041
011
.126
1P
TC
1-5�
N/A
Unk
now
n
8086
N/D
Poi
nt1
4633
Non
syno
nym
ous
chan
gein
amin
oac
idse
quen
ce
010
7.5
13.1
70U
nkno
wn
47,X
X,d
er(6
)del
(6)
(p21
)del
(6)(
q24,
�de
r(6)
del(6
)(p1
2p22
)t
(6;1
0)(q
16;q
22),
der(
10)
t(10
;12)
(q21
;p12
),
der(
11)t
(11;
12)
(p15
;q11
),�
12,�
21c�
17,
47,X
X,�
21c�
2
Unk
now
n
81‡
68N
/DP
oint
147
69Lo
ssof
splic
eac
cept
orsi
te0
100
11.5
326
Spl
ice
N/A
ML-
DS
8272
N/D
Del
1247
33F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
0.5
49.8
14.2
43P
TC
1-3�
N/A
Unk
now
n
8330
N/D
Del
447
41F
ram
eshi
ftan
din
trod
uctio
n
ofto
pco
don
052
13.9
71P
TC
1-3�
N/A
Unk
now
n
WB
Cin
dica
tes
whi
tebl
ood
cell;
Hb,
hem
oglo
bin;
Plt,
plat
elet
;Poi
nt,p
oint
subs
titut
ion;
CC
R,c
ompl
ete
clin
ical
rem
issi
on;D
up,d
uplic
atio
nof
nucl
eotid
es;I
ns,i
nser
tion
ofnu
cleo
tides
;Del
,del
etio
nof
nucl
eotid
es;N
/A,n
otav
aila
ble;
and
N/D
,not
done
.*E
xon
num
berc
onta
inin
gth
em
utat
ion
asde
fined
byW
AV
Ean
alys
is.
†Nuc
leot
ide
0is
the
first
nucl
eotid
eof
GA
TA1
exon
1in
clud
ing
exon
san
din
tron
s.N
CB
Iref
eren
ceN
T_0
7957
3.4
(Hom
osa
pien
sch
rom
osom
eX
geno
mic
cont
ig,s
tart
ing
posi
tion
1149
6706
)was
used
.‡P
atie
nts
with
TM
Dpr
ogre
ssed
toM
L-D
S.
GATA1 MUTATIONS IN TMD AND ML-DS 2227BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
Tab
le1.
Su
mm
ary
ofG
ATA
1m
uta
tio
ns
and
pat
ien
tch
arac
teri
stic
sfo
rT
MD
sam
ple
s(c
on
tin
ued
)
Pat
ien
tn
o.
Bla
stco
un
t,%
oft
ota
ln
ucl
eate
dco
un
tW
AV
E*
Mu
tati
on
typ
e
No
.of
nu
cleo
tid
esch
ang
ed,b
pP
osi
tio
no
fm
uta
tio
n†
Pre
dic
ted
effe
cto
fm
uta
tio
no
nR
NA
Ag
eat
dia
gn
osi
s,m
oW
BC
cou
nt,
�10
9 /L
Hb
leve
l,g
/dL
Plt
cou
nt,
�10
9 /L
Kan
ezak
ieta
l15
clas
sK
aryo
typ
eO
utc
om
e
8435
N/D
Ins
146
54F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
028
12.8
274
PT
C1-
5�N
/AU
nkno
wn
8578
N/D
Sub
stitu
tion
4045
45U
nkno
wn
072
.719
.460
6U
nkno
wn
N/A
Unk
now
n
8679
N/D
Ins
147
36F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
010
010
.970
PT
C1-
3�N
/AU
nkno
wn
8746
.5N
/DD
el2
4637
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
0.25
23.3
17.5
80P
TC
1-5�
N/A
Unk
now
n
88‡
43N
/DD
el2
4638
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
0.25
N/A
N/A
N/A
PT
C1-
5�47
,XY
,�21
c�15
M
L-D
S
8915
N/D
Ins
247
25F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
0.5
1124
.215
8P
TC
1-3�
N/A
Unk
now
n
9016
.5N
/DD
el2
4604
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
0.25
24.2
13.2
78P
TC
1-5�
N/A
Unk
now
n
91‡
66N
/DD
up5
4723
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
026
.116
.548
PT
C1-
3�47
,XX
,�21
cM
L-D
S
9238
.5N
/DD
up43
4742
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
0.5
20.2
12.3
12P
TC
1-3�
N/A
Unk
now
n
9358
N/D
Poi
nt1
4768
Loss
ofsp
lice
acce
ptor
site
020
.714
.190
1S
plic
eN
/AU
nkno
wn
941
N/D
Poi
nt�
Poi
nt
1�
192
�12
6U
nkno
wn
0.25
5.6
14.3
67U
nkno
wn
N/A
Unk
now
n
9583
N/D
Del
�D
el15
�1
4888
�49
07F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
0.25
114.
716
.614
1P
TC
2N
/AU
nkno
wn
9620
N/D
Dup
647
14F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
014
.12
18.6
15P
TC
1-5�
N/A
Unk
now
n
9743
N/D
Poi
nt1
4769
Loss
ofsp
lice
acce
ptor
site
049
.817
209
Spl
ice
N/A
Unk
now
n
9849
.9N
/DD
el2
4638
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
0.5
7.06
1264
PT
C1-
5�N
/AU
nkno
wn
9961
N/D
Dup
1247
20F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
0.75
91.6
16.6
150
PT
C1-
3�N
/AU
nkno
wn
100
53.5
N/D
Ins
145
98F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
051
18.3
56P
TC
1-5�
N/A
Unk
now
n
101
34N
/DD
el13
4706
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
015
.417
.162
PT
C1-
5�N
/AU
nkno
wn
102
25N
/DIn
s1
4753
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
019
.918
.311
5P
TC
1-3�
N/A
Unk
now
n
103
60N
/DD
up8
4707
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
023
.812
.926
5P
TC
1-5�
N/A
Unk
now
n
104
51N
/DP
oint
147
48S
ynon
ymou
sm
utat
ion
016
.612
.556
7U
nkno
wn
47,X
X,�
21�5
/
47,X
X,d
er(7
),�
21�2
105
15.5
N/D
Del
�In
s3
�2
4742
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
0.25
64.4
13.8
547
PT
C1-
3�N
/AU
nkno
wn
WB
Cin
dica
tes
whi
tebl
ood
cell;
Hb,
hem
oglo
bin;
Plt,
plat
elet
;Poi
nt,p
oint
subs
titut
ion;
CC
R,c
ompl
ete
clin
ical
rem
issi
on;D
up,d
uplic
atio
nof
nucl
eotid
es;I
ns,i
nser
tion
ofnu
cleo
tides
;Del
,del
etio
nof
nucl
eotid
es;N
/A,n
otav
aila
ble;
and
N/D
,not
done
.*E
xon
num
berc
onta
inin
gth
em
utat
ion
asde
fined
byW
AV
Ean
alys
is.
†Nuc
leot
ide
0is
the
first
nucl
eotid
eof
GA
TA1
exon
1in
clud
ing
exon
san
din
tron
s.N
CB
Iref
eren
ceN
T_0
7957
3.4
(Hom
osa
pien
sch
rom
osom
eX
geno
mic
cont
ig,s
tart
ing
posi
tion
1149
6706
)was
used
.‡P
atie
nts
with
TM
Dpr
ogre
ssed
toM
L-D
S.
2228 ALFORD et al BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
Tab
le1.
Su
mm
ary
ofG
ATA
1m
uta
tio
ns
and
pat
ien
tch
arac
teri
stic
sfo
rT
MD
sam
ple
s(c
on
tin
ued
)
Pat
ien
tn
o.
Bla
stco
un
t,%
oft
ota
ln
ucl
eate
dco
un
tW
AV
E*
Mu
tati
on
typ
e
No
.of
nu
cleo
tid
esch
ang
ed,b
pP
osi
tio
no
fm
uta
tio
n†
Pre
dic
ted
effe
cto
fm
uta
tio
no
nR
NA
Ag
eat
dia
gn
osi
s,m
oW
BC
cou
nt,
�10
9 /L
Hb
leve
l,g
/dL
Plt
cou
nt,
�10
9 /L
Kan
ezak
ieta
l15
clas
sK
aryo
typ
eO
utc
om
e
106
50N
/DD
up19
4722
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
043
.515
.412
8P
TC
1-3�
N/A
Kno
wn
107
21N
/DD
up11
4735
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
01
10.7
45P
TC
1-3�
N/A
Unk
now
n
108
N/A
N/D
Ins
147
31F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
N/A
N/A
N/A
N/A
PT
C-3
�N
/AU
nkno
wn
109
22N
/DP
oint
147
69Lo
ssof
splic
eac
cept
orsi
te1.
574
.76
554
Spl
ice
N/A
Unk
now
n
110
57.5
N/D
Dup
105
4698
Non
syno
nym
ous
chan
gein
amin
oac
idse
quen
ce
intr
oduc
ing
ast
opco
don
064
.311
.842
7P
TC
1-5�
N/A
Unk
now
n
111
62N
/DD
el12
4764
Loss
ofsp
lice
acce
ptor
site
1.5
21.9
6.7
102
Spl
ice
47,X
Y,�
21c
Unk
now
n
112
45N
/DD
el4
4672
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
1N
/AN
/AN
/AP
TC
1-5�
N/A
Unk
now
n
113
73N
/DD
up6
4706
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
019
512
150
PT
C1-
5�N
/AU
nkno
wn
114
N/A
N/D
Del
245
86F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
N/A
N/A
N/A
N/A
PT
C1-
5�N
/AU
nkno
wn
115
77N
/DD
up10
4719
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
017
010
.665
5P
TC
1-3�
N/A
Unk
now
n
116‡
0.5
N/D
Ins
147
33F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
1.5
47
89P
TC
1-3�
48,X
Y,�
Y(q
12),
�11
,
�21
c�8
/47,
XY
,�21
c�7
ML-
DS
117
30E
x2N
otfo
und
Unk
now
nU
nkno
wn
N/A
14.
212
.925
Unk
now
n47
,XX
,del
(16)
,�21
cU
nkno
wn
118
10E
x2N
otfo
und
Unk
now
nU
nkno
wn
N/A
120
.413
119
Unk
now
nN
/AU
nkno
wn
119
2E
x2N
otfo
und
Unk
now
nU
nkno
wn
N/A
0.38
21.4
1521
8U
nkno
wn
47,X
Y,�
21c
Unk
now
n
120
4E
x2N
otfo
und
Unk
now
nU
nkno
wn
N/A
320
.716
.163
Unk
now
n47
,XY
,�21
cU
nkno
wn
121
3E
x2N
otfo
und
Unk
now
nU
nkno
wn
N/A
46.
866.
483
Unk
now
n47
,XY
,�21
cU
nkno
wn
122
30E
x2N
otfo
und
Unk
now
nU
nkno
wn
N/A
2.5
813
1000
Unk
now
nN
/AU
nkno
wn
123
80E
x2N
otfo
und
Unk
now
nU
nkno
wn
N/A
026
5.3
1835
3U
nkno
wn
N/A
Unk
now
n
124
20E
x2N
otfo
und
Unk
now
nU
nkno
wn
N/A
0.5
13.4
11.9
371
Unk
now
n47
,XY
,�21
cU
nkno
wn
125
39E
x2N
otfo
und
Unk
now
nU
nkno
wn
N/A
012
.516
.119
3U
nkno
wn
N/A
Unk
now
n
126
35E
x3.
1D
el16
4871
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
033
.59.
169
5P
TC
2N
/AU
nkno
wn
127
30E
x3.
1D
up2
4778
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
221
.713
24P
TC
2N
/AU
nkno
wn
128
13.5
N/D
Not
foun
dU
nkno
wn
Unk
now
nN
/A0.
258.
9118
.446
Unk
now
n47
,XX
,�21
c�17
C
CR
129
3N
/DN
otfo
und
Unk
now
nU
nkno
wn
N/A
010
.618
.965
Unk
now
nN
/AC
CR
130
5N
/DN
otfo
und
Unk
now
nU
nkno
wn
N/A
0.75
8.3
8.1
100
Unk
now
nN
/AU
nkno
wn
131
8N
/DN
otfo
und
Unk
now
nU
nkno
wn
N/A
022
.321
60U
nkno
wn
N/A
Unk
now
n
132
5N
/DN
otfo
und
Unk
now
nU
nkno
wn
N/A
0.5
15.2
20.8
276
Unk
now
nN
/AU
nkno
wn
133
12N
/DN
otfo
und
Unk
now
nU
nkno
wn
N/A
1N
/AN
/AN
/AU
nkno
wn
N/A
Unk
now
n
134
2N
/DN
otfo
und
Unk
now
nU
nkno
wn
N/A
64.
1513
100
Unk
now
nN
/AU
nkno
wn
WB
Cin
dica
tes
whi
tebl
ood
cell;
Hb,
hem
oglo
bin;
Plt,
plat
elet
;Poi
nt,p
oint
subs
titut
ion;
CC
R,c
ompl
ete
clin
ical
rem
issi
on;D
up,d
uplic
atio
nof
nucl
eotid
es;I
ns,i
nser
tion
ofnu
cleo
tides
;Del
,del
etio
nof
nucl
eotid
es;N
/A,n
otav
aila
ble;
and
N/D
,not
done
.*E
xon
num
berc
onta
inin
gth
em
utat
ion
asde
fined
byW
AV
Ean
alys
is.
†Nuc
leot
ide
0is
the
first
nucl
eotid
eof
GA
TA1
exon
1in
clud
ing
exon
san
din
tron
s.N
CB
Iref
eren
ceN
T_0
7957
3.4
(Hom
osa
pien
sch
rom
osom
eX
geno
mic
cont
ig,s
tart
ing
posi
tion
1149
6706
)was
used
.‡P
atie
nts
with
TM
Dpr
ogre
ssed
toM
L-D
S.
GATA1 MUTATIONS IN TMD AND ML-DS 2229BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
Tab
le2.
Su
mm
ary
ofG
ATA
1m
uta
tio
ns
and
pat
ien
tch
arac
teri
stic
sfo
rM
L-D
Ssa
mp
les
Pat
ien
tn
o.
Bla
stco
un
t,%
oft
ota
ln
ucl
eate
dco
un
tW
AV
E*
Mu
tati
on
Siz
e,b
pP
osi
tio
no
fm
uta
tio
n†
Pre
dic
ted
effe
cto
fm
uta
tio
no
nR
NA
Ag
eat
dia
gn
osi
s,m
o
WB
Cco
un
t,�
109 /
LH
ble
vel,
g/d
L
Plt
cou
nt,
�10
9 /L
Kan
ezak
ieta
l15
clas
sK
aryo
typ
eO
utc
om
e
170
Ex2
Del
5647
50F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
2412
.65.
722
PT
C1-
3�47
,XY
,Del
(7)(
q32)
,�8,
�21
c
CC
R
215
Ex2
Dup
1347
09F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
N/A
5.3
7.6
22P
TC
1-5�
47,X
X,�
21c
CC
R
384
Ex2
Ins
1147
24F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
2327
.78.
519
PT
C1-
3�47
,XX
,�21
cC
CR
4‡90
Ex2
Dup
2047
22F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
368.
511
.320
PT
C1-
3�56
,XX
,�2,
�6,
�8,
�13
,
�13
,�14
,�14
,�16
,
del(1
7)(q
?22�
24),
�19
,
�de
l(19)
(p13
),�
21,�
21c�
7,
CC
R
520
Ex2
Poi
nt1
4549
Loss
ofst
artc
odon
203.
1611
361s
tMet
48,X
Y,�
8,�
21C
CR
6N
/AE
x2D
el13
4753
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
540
8.9
27P
TC
1-3�
48,X
Y,d
er(1
)add
(1)
(p32
)dup
(1)(
q21q
42),
del(3
)(q2
1q26
),I(
7)
(q10
),de
l(16)
(q22
q24)
,
�21
Die
d
714
Ex2
Del
1047
67F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
2127
.85.
485
PT
C1-
3�47
,XY
,�21
cD
ied
8N
/AE
x2P
oint
145
48Lo
ssof
splic
eac
cept
orsi
te24
4.1
2.1
6S
plic
e47
XX
,i(7)
(q10
),�
16,
�21
c,�
mar
�7
CC
R
9N
/AE
x2D
up20
4728
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
1.2
11.9
7.5
18P
TC
1-3�
47,X
X,
add(
1)(q
24),
del(5
)(p1
3),
�21
c
CC
R
1050
Ex2
Poi
nt1
4768
Loss
ofsp
lice
acce
ptor
site
312.
89.
721
Spl
ice
48,X
X,A
dd(8
)(p2
3),�
11,
�21
c�16
/47
,XX
,�21
c
�19
CC
R
11N
/AE
x2D
el29
4669
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
214
1311
2P
TC
1-5�
47,X
Y,�
21,�
8C
CR
12N
/AE
x2P
oint
147
68Lo
ssof
splic
eac
cept
orsi
te24
33.4
2.9
3.6
Spl
ice
46,X
X,
der(
7)ad
d(7)
(p?)
,
�13
,�21
c�9
/47,
XX
,�21
c
Die
d
1360
Ex2
Poi
nt1
4768
Loss
ofsp
lice
acce
ptor
site
6017
.411
32S
plic
e55
�57
,XX
,
del(1
)(q2
1;q2
5),�
2,
�3?
adk1
(5)(
q33)
,
i(7)(
q10)
,�8,
der(
12)(
t1;1
2)(q
21;p
13),
�13
,�14
,�18
,�19
,
�21
,�22
Die
d
WB
Cin
dica
tes
whi
tebl
ood
cell;
Hb,
hem
oglo
bin;
Plt,
plat
elet
;Del
,del
etio
nof
nucl
eotid
es;C
CR
,com
plet
ecl
inic
alre
mis
sion
;Dup
,dup
licat
ion
ofnu
cleo
tides
;N/A
,not
avai
labl
e;In
s,in
sert
ion
ofnu
cleo
tides
;Poi
nt,p
oint
subs
titut
ion;
and
N/D
,no
tdon
e.*E
xon
num
berc
onta
inin
gth
em
utat
ion
asde
fined
byW
AV
Ean
alys
is.
†Nuc
leot
ide
0is
the
first
nucl
eotid
eof
GA
TA1
exon
1in
clud
ing
exon
san
din
tron
s.N
CB
Iref
eren
ceN
T_0
7957
3.4
(Hom
osa
pien
sch
rom
osom
eX
geno
mic
cont
ig,s
tart
ing
posi
tion
1149
6706
)was
used
.‡P
atie
nts
with
TM
Dpr
ogre
ssed
toM
L-D
S.
2230 ALFORD et al BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
Tab
le2.
Su
mm
ary
ofG
ATA
1m
uta
tio
ns
and
pat
ien
tch
arac
teri
stic
sfo
rM
L-D
Ssa
mp
les
(co
nti
nu
ed)
Pat
ien
tn
o.
Bla
stco
un
t,%
oft
ota
ln
ucl
eate
dco
un
tW
AV
E*
Mu
tati
on
Siz
e,b
pP
osi
tio
no
fm
uta
tio
n†
Pre
dic
ted
effe
cto
fm
uta
tio
no
nR
NA
Ag
eat
dia
gn
osi
s,m
o
WB
Cco
un
t,�
109 /
LH
ble
vel,
g/d
L
Plt
cou
nt,
�10
9 /L
Kan
ezak
ieta
l15
clas
sK
aryo
typ
eO
utc
om
e
1420
Ex2
Poi
nt1
4768
Loss
ofsp
lice
acce
ptor
site
2611
.29.
728
Spl
ice
47.X
X.�
21c�
36
Unk
now
n
1578
Ex2
Ins
147
36F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
2542
.88.
233
PT
C1-
3�47
,XY
,dup
(X)
(p11
.2,p
21),
�21
c�2
,47
,
idem
,der
(4),
t(2;
4)(q
31;q
31),
?del
(6)(
q2?5
;q2?
7),�
21c
�5,
47,X
Y,�
21c�
3
CC
R
1637
Ex2
Ins
146
93F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
N/A
N/A
N/A
N/A
PT
C1-
5�N
/AR
elap
sed
1716
Ex2
Poi
nt1
4597
Non
syno
nym
ous
chan
gein
amin
oac
idse
quen
ce
intr
oduc
ing
ast
opco
don
311.
78.
714
PT
C1-
5�48
,XX
,�8,
�21
cU
nkno
wn
18N
/AE
x2In
s1
4632
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
1729
11.5
5P
TC
1-5�
47X
X,�
21c
Die
d
1936
Ex2
Del
3546
84F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
369.
89
24P
TC
1-5�
48,X
X,�
8,�
21C
CR
2093
Ex2
Ins
147
69Lo
ssof
splic
eac
cept
orsi
teN
/A20
0.3
4.7
23S
plic
e47
,XX
,t(3
;17)
(q25
;q25
),de
l(6)(
q13;
q22)
,
�21
c�19
CC
R
2120
Ex2
Del
747
05F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
245.
43.
79
PT
C1-
5�47
,XY
,�21
,�8
Die
d
22‡
23E
x2D
up8
4717
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
632
8.7
22P
TC
1-5�
47,X
Y,t
(5;1
1)
(p15
;q13
),ad
d(9)
(q34
),
�21
c�6
/47,
XY
,�21
c�14
CC
R
2321
Ex2
Del
246
38F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
116.
415
.15.
1P
TC
1-5�
47,X
X,d
el(6
),de
l(21
),
�21
Die
d
2444
Ex2
Del
2347
05F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
138.
3N
/AN
/AP
TC
1-5�
48,X
X,d
el(6
)(q
?13q
?21)
�21
c,�
21�5
CC
R
2550
Ex2
Del
246
38F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
127.
3N
/AN
/AP
TC
1-5�
50,X
Y,�
10,�
21c,
�21
,
�22
�6
CC
R
26‡
16N
/DD
up10
4710
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
113.
511
.930
PT
C1-
5�47
�49
,XY
,
�?1
9,�
21c,
�21
�cp7
/47
,
XY
,�21
c�5
CC
R
2720
N/D
Dup
1547
15F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
156.
47.
660
PT
C1-
5�47
,XY
,�21
c2/
47,
idem
,t(4;
15),
(q?2
1;q?
21),
del(7
)(q?
31q?
33)
Unk
now
n
288.
5N
/DD
el1
4698
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
84
13.4
70P
TC
1-5�
N/A
Unk
now
n
WB
Cin
dica
tes
whi
tebl
ood
cell;
Hb,
hem
oglo
bin;
Plt,
plat
elet
;Del
,del
etio
nof
nucl
eotid
es;C
CR
,com
plet
ecl
inic
alre
mis
sion
;Dup
,dup
licat
ion
ofnu
cleo
tides
;N/A
,not
avai
labl
e;In
s,in
sert
ion
ofnu
cleo
tides
;Poi
nt,p
oint
subs
titut
ion;
and
N/D
,no
tdon
e.*E
xon
num
berc
onta
inin
gth
em
utat
ion
asde
fined
byW
AV
Ean
alys
is.
†Nuc
leot
ide
0is
the
first
nucl
eotid
eof
GA
TA1
exon
1in
clud
ing
exon
san
din
tron
s.N
CB
Iref
eren
ceN
T_0
7957
3.4
(Hom
osa
pien
sch
rom
osom
eX
geno
mic
cont
ig,s
tart
ing
posi
tion
1149
6706
)was
used
.‡P
atie
nts
with
TM
Dpr
ogre
ssed
toM
L-D
S.
GATA1 MUTATIONS IN TMD AND ML-DS 2231BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
Tab
le2.
Su
mm
ary
ofG
ATA
1m
uta
tio
ns
and
pat
ien
tch
arac
teri
stic
sfo
rM
L-D
Ssa
mp
les
(co
nti
nu
ed)
Pat
ien
tn
o.
Bla
stco
un
t,%
oft
ota
ln
ucl
eate
dco
un
tW
AV
E*
Mu
tati
on
Siz
e,b
pP
osi
tio
no
fm
uta
tio
n†
Pre
dic
ted
effe
cto
fm
uta
tio
no
nR
NA
Ag
eat
dia
gn
osi
s,m
o
WB
Cco
un
t,�
109 /
LH
ble
vel,
g/d
L
Plt
cou
nt,
�10
9 /L
Kan
ezak
ieta
l15
clas
sK
aryo
typ
eO
utc
om
e
2931
N/D
Del
547
04F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
133.
911
.247
PT
C1-
5�47
,XX
,der
(5)t
(1;5
)
(q12
;p14
)?de
l(1)
(q23
q25)
,�21
c�4
/48,
XX
,�8,
der
(12)
t(1;
12)(
q12;
p12)
,
�21
c�2
/47,
XX
,�21
c�9
Unk
now
n
3093
N/D
Del
246
38F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
2426
.49.
114
7P
TC
1-5�
47,X
Y,�
21c�
25
Unk
now
n
3139
N/D
Del
246
38F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
278.
58.
526
PT
C1-
5�N
/AU
nkno
wn
32‡
4.5
N/D
Del
246
04F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
131
7.7
107
PT
C1-
5�N
/AU
nkno
wn
3319
.5N
/DIn
s�
Dup
2�
1447
22F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
2126
.47.
215
1P
TC
1-3�
N/A
Unk
now
n
3450
.5N
/DIn
s1
4768
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
281.
28
109
Spl
ice
47�
48,X
X,?
add
(5)(
p1?5
),�
8,
�21
,�21
c,�
mar
1,
�m
ar2�
cp8
/47,
XX
,�21
c
Unk
now
n
3510
.5N
/DP
oint
147
68Lo
ssof
splic
eac
cept
orsi
te35
3.4
10.4
17S
plic
eN
/AU
nkno
wn
3636
N/D
Dup
547
34F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
1412
.47.
214
4P
TC
1-3�
47,X
X,�
21c
Unk
now
n
3734
N/D
Del
2247
04F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
2215
.19.
625
7P
TC
1-5�
48,X
Y,�
8,�
21c
Unk
now
n
3855
N/D
Del
�In
s31
�6
4783
Loss
ofsp
lice
dono
rsi
te31
1.9
6.9
22S
plic
eN
/AU
nkno
wn
3935
N/D
Dup
347
37F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
314.
29.
220
PT
C1-
3�N
/AU
nkno
wn
4038
N/D
Del
�in
s24
�4
4683
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
316.
19.
816
PT
C1-
5�N
/AU
nkno
wn
4143
N/D
Dup
2147
36F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
134.
96.
738
PT
C1-
3�N
/AU
nkno
wn
4215
N/D
Dup
446
68F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
208.
112
.721
9P
TC
1-5�
47,X
X,�
21c
Unk
now
n
4316
N/D
Dup
747
17F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
3616
05
1.5
PT
C1-
5�47
,XY
,�21
c,�3
/47
,
idem
,t(1;
8)(q
32;q
22)
�2/
48,id
em,t(
1;8)
(q32
;q22
),�
der(
8)t
(1;8
)(q3
2;q2
2)
�10}
Unk
now
n
WB
Cin
dica
tes
whi
tebl
ood
cell;
Hb,
hem
oglo
bin;
Plt,
plat
elet
;Del
,del
etio
nof
nucl
eotid
es;C
CR
,com
plet
ecl
inic
alre
mis
sion
;Dup
,dup
licat
ion
ofnu
cleo
tides
;N/A
,not
avai
labl
e;In
s,in
sert
ion
ofnu
cleo
tides
;Poi
nt,p
oint
subs
titut
ion;
and
N/D
,no
tdon
e.*E
xon
num
berc
onta
inin
gth
em
utat
ion
asde
fined
byW
AV
Ean
alys
is.
†Nuc
leot
ide
0is
the
first
nucl
eotid
eof
GA
TA1
exon
1in
clud
ing
exon
san
din
tron
s.N
CB
Iref
eren
ceN
T_0
7957
3.4
(Hom
osa
pien
sch
rom
osom
eX
geno
mic
cont
ig,s
tart
ing
posi
tion
1149
6706
)was
used
.‡P
atie
nts
with
TM
Dpr
ogre
ssed
toM
L-D
S.
2232 ALFORD et al BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
Tab
le2.
Su
mm
ary
ofG
ATA
1m
uta
tio
ns
and
pat
ien
tch
arac
teri
stic
sfo
rM
L-D
Ssa
mp
les
(co
nti
nu
ed)
Pat
ien
tn
o.
Bla
stco
un
t,%
oft
ota
ln
ucl
eate
dco
un
tW
AV
E*
Mu
tati
on
Siz
e,b
pP
osi
tio
no
fm
uta
tio
n†
Pre
dic
ted
effe
cto
fm
uta
tio
no
nR
NA
Ag
eat
dia
gn
osi
s,m
o
WB
Cco
un
t,�
109 /
LH
ble
vel,
g/d
L
Plt
cou
nt,
�10
9 /L
Kan
ezak
ieta
l15
clas
sK
aryo
typ
eO
utc
om
e
4424
N/D
Ins
547
08F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
106.
889.
735
PT
C1-
5�N
/AU
nkno
wn
4511
N/D
Poi
nt1
4956
Syn
onym
ous
mut
atio
n16
2.5
8.1
101
Unk
now
nN
/AU
nkno
wn
4628
N/D
Ins
147
36F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
3112
.93.
176
PT
C1-
3�N
/AU
nkno
wn
4714
N/D
Poi
nt1
4535
Unk
now
n31
228.
537
Unk
now
n48
,XY
,�14
,�21
Unk
now
n
4813
N/D
Del
945
46Lo
ssof
Sta
rtco
don
196.
210
.613
11s
tMet
48,X
Y,i(
7)(q
10),
t(11
;11)
(p15
;q13
),
�21
,�21
�13
/
47,X
Y,�
21�2
Unk
now
n
4915
N/D
Poi
nt1
4768
Loss
ofsp
lice
acce
ptor
site
125
12.1
45S
plic
eN
/AU
nkno
wn
5015
N/D
Del
747
02F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
202.
7410
.711
0P
TC
1-5�
50,X
X,�
8,
�14
,�21
,�21
c,
inc�
5/4
7,
XX
,�21
c�7
Unk
now
n
51‡
16N
/DP
oint
145
52N
onsy
nony
mou
sch
ange
in
amin
oac
idse
quen
ce
123.
411
.127
Unk
now
n47
,XY
,?de
r(11
)
(q24
�25
),
�21
c�2
/47,
XY
,�21
c�8
Unk
now
n
529
N/D
Del
�in
s2
�1
4619
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
153.
59.
247
PT
C1-
5�46
,XY
,i(7)
(q10
),de
r(21
;21)
(q10
;q10
)c,
�21
�6/
46,X
Y,d
er(2
1;21
)
(q10
;q10
)c,
�21
�5
Unk
now
n
5312
N/D
Del
�in
s3
�1
4654
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
72.
93.
317
PT
C1-
5�48
,XX
,der
(1)
(p?q
?),�
21c,
�m
ar�1
4
/47,
XX
,�
21c�
4
Unk
now
n
5410
.5N
/DD
up20
4727
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
164.
812
59P
TC
1-3�
N/A
Unk
now
n
5517
N/D
Not
Fou
ndU
nkno
wn
Unk
now
nU
nkno
wn
215.
911
.442
Unk
now
n47
,XX
,�21
cU
nkno
wn
56N
/AN
/DD
up16
4734
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
N/A
N/A
N/A
N/A
PT
C1-
3�N
/AU
nkno
wn
5723
N/D
Poi
nt1
4767
Loss
ofsp
lice
acce
ptor
site
265.
113
.311
Spl
ice
48�
50,X
Y,
�8,
�?1
4,
�21
,�21
c�cp
6/
47,X
Y,�
21c�
4
Unk
now
n
WB
Cin
dica
tes
whi
tebl
ood
cell;
Hb,
hem
oglo
bin;
Plt,
plat
elet
;Del
,del
etio
nof
nucl
eotid
es;C
CR
,com
plet
ecl
inic
alre
mis
sion
;Dup
,dup
licat
ion
ofnu
cleo
tides
;N/A
,not
avai
labl
e;In
s,in
sert
ion
ofnu
cleo
tides
;Poi
nt,p
oint
subs
titut
ion;
and
N/D
,no
tdon
e.*E
xon
num
berc
onta
inin
gth
em
utat
ion
asde
fined
byW
AV
Ean
alys
is.
†Nuc
leot
ide
0is
the
first
nucl
eotid
eof
GA
TA1
exon
1in
clud
ing
exon
san
din
tron
s.N
CB
Iref
eren
ceN
T_0
7957
3.4
(Hom
osa
pien
sch
rom
osom
eX
geno
mic
cont
ig,s
tart
ing
posi
tion
1149
6706
)was
used
.‡P
atie
nts
with
TM
Dpr
ogre
ssed
toM
L-D
S.
GATA1 MUTATIONS IN TMD AND ML-DS 2233BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
Tab
le2.
Su
mm
ary
ofG
ATA
1m
uta
tio
ns
and
pat
ien
tch
arac
teri
stic
sfo
rM
L-D
Ssa
mp
les
(co
nti
nu
ed)
Pat
ien
tn
o.
Bla
stco
un
t,%
oft
ota
ln
ucl
eate
dco
un
tW
AV
E*
Mu
tati
on
Siz
e,b
pP
osi
tio
no
fm
uta
tio
n†
Pre
dic
ted
effe
cto
fm
uta
tio
no
nR
NA
Ag
eat
dia
gn
osi
s,m
o
WB
Cco
un
t,�
109 /
LH
ble
vel,
g/d
L
Plt
cou
nt,
�10
9 /L
Kan
ezak
ieta
l15
clas
sK
aryo
typ
eO
utc
om
e
5821
N/D
Poi
nt�
Del
1�
146
37�
4639
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
376.
311
.413
.7U
nkno
wn
47,X
X,?
del(2
)(q3
5),
del(7
)(p1
2),�
21c�
7/
47,X
X,�
21c�
5
Unk
now
n
5913
N/D
Del
146
98F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
116.
310
.384
PT
C1-
5�47
,XY
,�21
c�9
;
48,X
Y,d
el(5
)
(p11
p14)
,r(7
)
(p22
q11)
,
�8,
�21
c�7
Unk
now
n
6035
N/D
Del
145
48U
nkno
wn
1116
838
Unk
now
nN
/AU
nkno
wn
617
N/D
Del
146
42F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
151.
89.
343
PT
C1-
5�47
,XY
,�21
�1
Unk
now
n
621
N/D
Not
Fou
ndU
nkno
wn
Unk
now
nU
nkno
wn
192.
65.
810
9U
nkno
wn
N/A
Unk
now
n
6320
.5N
/DD
el�
ins
4�
246
56F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
113.
710
.713
0P
TC
1-5�
48,X
X,�
8,�
21c�
3/
47,X
X,�
21c�
8
Unk
now
n
642.
5N
/DD
el2
4656
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
324.
87.
417
PT
C1-
5�47
,XX
,�21
c�6
Unk
now
n
6546
N/D
Dup
1647
19F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
205.
612
19P
TC
1-3�
N/A
Unk
now
n
6619
.5N
/DP
oint
147
67Lo
ssof
splic
eac
cept
orsi
te32
5.46
13.6
52S
plic
eN
/AU
nkno
wn
672
N/D
Del
147
37F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
263.
37.
169
PT
C1-
3�N
/AU
nkno
wn
6816
N/D
Del
246
38F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
352.
89.
520
PT
C1-
5�48
,XX
,�8,
�21
cU
nkno
wn
6923
N/D
Del
246
38F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
133.
29
25P
TC
1-5�
47,X
Y,�
21c�
10
Unk
now
n
7076
N/D
Del
246
38F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
1723
6.5
28P
TC
1-5�
46,X
Y,t(
4;13
)
(q33
�34
;q14
),
der(
5)t(
5;7)
(p14
�15
;q12
),
�7,
�21
c�cp
11
Unk
now
n
713.
5N
/DD
el2
4656
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
133.
311
.446
PT
C1-
5�47
,XX
,�21
c�17
U
nkno
wn
72N
/AN
/DP
oint
146
37U
nkno
wn
N/A
N/A
N/A
N/A
Unk
now
nN
/AU
nkno
wn
7320
N/D
Poi
nt1
4713
Syn
onym
ous
mut
atio
n19
4.1
9.5
13U
nkno
wn
48�
49,X
Y,�
21,
�21
c,in
c�cp
2
/47,
XY
,�21
c�12
Unk
now
n
7442
N/D
Not
Fou
ndU
nkno
wn
Unk
now
nU
nkno
wn
245.
410
.321
Unk
now
n47
,XY
,�21
c,
?der
(22)
(p12
)
�5/
47,X
Y,
�21
c�15
Unk
now
n
WB
Cin
dica
tes
whi
tebl
ood
cell;
Hb,
hem
oglo
bin;
Plt,
plat
elet
;Del
,del
etio
nof
nucl
eotid
es;C
CR
,com
plet
ecl
inic
alre
mis
sion
;Dup
,dup
licat
ion
ofnu
cleo
tides
;N/A
,not
avai
labl
e;In
s,in
sert
ion
ofnu
cleo
tides
;Poi
nt,p
oint
subs
titut
ion;
and
N/D
,no
tdon
e.*E
xon
num
berc
onta
inin
gth
em
utat
ion
asde
fined
byW
AV
Ean
alys
is.
†Nuc
leot
ide
0is
the
first
nucl
eotid
eof
GA
TA1
exon
1in
clud
ing
exon
san
din
tron
s.N
CB
Iref
eren
ceN
T_0
7957
3.4
(Hom
osa
pien
sch
rom
osom
eX
geno
mic
cont
ig,s
tart
ing
posi
tion
1149
6706
)was
used
.‡P
atie
nts
with
TM
Dpr
ogre
ssed
toM
L-D
S.
2234 ALFORD et al BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
Tab
le2.
Su
mm
ary
ofG
ATA
1m
uta
tio
ns
and
pat
ien
tch
arac
teri
stic
sfo
rM
L-D
Ssa
mp
les
(co
nti
nu
ed)
Pat
ien
tn
o.
Bla
stco
un
t,%
oft
ota
ln
ucl
eate
dco
un
tW
AV
E*
Mu
tati
on
Siz
e,b
pP
osi
tio
no
fm
uta
tio
n†
Pre
dic
ted
effe
cto
fm
uta
tio
no
nR
NA
Ag
eat
dia
gn
osi
s,m
o
WB
Cco
un
t,�
109 /
LH
ble
vel,
g/d
L
Plt
cou
nt,
�10
9 /L
Kan
ezak
ieta
l15
clas
sK
aryo
typ
eO
utc
om
e
75‡
25N
/DD
up13
4744
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
262.
711
.820
PT
C1-
3�47
,XY
,�21
.ish
21qt
er(D
21
S14
46�
3)
Unk
now
n
7696
N/D
Poi
nt1
4737
Non
syno
nym
ous
chan
gein
amin
oac
idse
quen
ce
2212
45.
921
Unk
now
n47
,X,�
X,
del(6
)(q1
3q16
),
�21
c,�
21
Unk
now
n
7710
.5N
/DN
otF
ound
Unk
now
nU
nkno
wn
Unk
now
n17
5.2
10.6
82U
nkno
wn
47,X
X,a
dd(1
6)
(p13
),�
21c�
5/
47,X
X,�
21c�
5
Unk
now
n
7826
N/D
Poi
nt1
4956
Syn
onym
ous
mut
atio
n20
26.
413
0U
nkno
wn
48,X
Y,d
er(8
)t
(1;8
)(q2
1;p2
2�23
),
�11
,�21
c�7
/
47,X
Y,�
21c�
8
Unk
now
n
7911
N/D
Poi
nt1
4768
Loss
ofsp
lice
acce
ptor
site
436.
3512
70S
plic
eN
/AU
nkno
wn
8013
N/D
Poi
nt1
4633
Non
syno
nym
ous
chan
gein
amin
oac
idse
quen
ce
163.
310
.584
Unk
now
nN
/AU
nkno
wn
81‡
26N
/DD
el2
4638
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
113.
410
.228
PT
C1-
5�47
,XY
,�21
c�15
U
nkno
wn
826
N/D
Ins
247
25F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
144
10.2
70P
TC
1-3�
N/A
Unk
now
n
834
N/D
Dup
647
14F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
88.
7511
.469
PT
C1-
5�N
/AU
nkno
wn
84N
/AN
/DD
up48
4771
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
N/A
N/A
N/A
N/A
PT
C1-
3�N
/AU
nkno
wn
8517
.5N
/DD
el2
4638
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
114.
79.
383
PT
C1-
5�N
/AU
nkno
wn
8645
N/D
Dup
1047
23F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
1411
.58.
644
PT
C1-
3�N
/AU
nkno
wn
8770
.5N
/DD
el2
4638
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
1632
.57.
910
3P
TC
1-5�
46,X
Y�2
2.n
ucis
h
8q22
(ET
Ox2
),
21q2
2(A
ML1
�2)
,
13q1
4(R
B1
�2)
,
13q3
4�
2),
11q2
3(M
LLx2
)�10
0
Unk
now
n
8831
N/D
Del
246
38F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
2911
.413
.257
.4P
TC
1-5�
46,X
X,d
el
(9)(
q?13
q33)
,
der(
19)t
(1;1
9)
(q31
;p13
),
der(
21;2
1)
(q10
;q10
)?c
Unk
now
n
WB
Cin
dica
tes
whi
tebl
ood
cell;
Hb,
hem
oglo
bin;
Plt,
plat
elet
;Del
,del
etio
nof
nucl
eotid
es;C
CR
,com
plet
ecl
inic
alre
mis
sion
;Dup
,dup
licat
ion
ofnu
cleo
tides
;N/A
,not
avai
labl
e;In
s,in
sert
ion
ofnu
cleo
tides
;Poi
nt,p
oint
subs
titut
ion;
and
N/D
,no
tdon
e.*E
xon
num
berc
onta
inin
gth
em
utat
ion
asde
fined
byW
AV
Ean
alys
is.
†Nuc
leot
ide
0is
the
first
nucl
eotid
eof
GA
TA1
exon
1in
clud
ing
exon
san
din
tron
s.N
CB
Iref
eren
ceN
T_0
7957
3.4
(Hom
osa
pien
sch
rom
osom
eX
geno
mic
cont
ig,s
tart
ing
posi
tion
1149
6706
)was
used
.‡P
atie
nts
with
TM
Dpr
ogre
ssed
toM
L-D
S.
GATA1 MUTATIONS IN TMD AND ML-DS 2235BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
Tab
le2.
Su
mm
ary
ofG
ATA
1m
uta
tio
ns
and
pat
ien
tch
arac
teri
stic
sfo
rM
L-D
Ssa
mp
les
(co
nti
nu
ed)
Pat
ien
tn
o.
Bla
stco
un
t,%
oft
ota
ln
ucl
eate
dco
un
tW
AV
E*
Mu
tati
on
Siz
e,b
pP
osi
tio
no
fm
uta
tio
n†
Pre
dic
ted
effe
cto
fm
uta
tio
no
nR
NA
Ag
eat
dia
gn
osi
s,m
o
WB
Cco
un
t,�
109 /
LH
ble
vel,
g/d
L
Plt
cou
nt,
�10
9 /L
Kan
ezak
ieta
l15
clas
sK
aryo
typ
eO
utc
om
e
897.
5N
/DD
el22
4706
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
177.
811
.127
PT
C1-
5�48
,XY
,add
(7)
(p2?
2),�
8,
del(1
3)(q
1?4)
,
�21
c�7
/46,
XY
,�21
,�21
cor
46,X
Y�3
/47
,XY
,�21
c�2
Unk
now
n
9033
N/D
Del
�in
s2
�6
4707
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
84.
67.
53
PT
C1-
5�N
/AU
nkno
wn
91‡
24N
/DIn
s1
4733
Fra
mes
hift
and
intr
oduc
tion
ofst
opco
don
113
7.1
57P
TC
1-3�
48,X
,add
(Y)
(q12
),�
11,
�21
c�8
/
47,X
Y,
�21
c�7
Unk
now
n
9228
N/D
Dup
1047
19F
ram
eshi
ftan
din
trod
uctio
n
ofst
opco
don
225.
213
.714
3P
TC
1-3�
N/A
Unk
now
n
9316
Ex2
Not
Fou
ndN
/AN
/AN
/A1
1.5
10.4
13U
nkno
wn
47,X
Y,�
21c
Die
d
9430
Ex2
Not
Fou
ndN
/AN
/AN
/A15
14.4
74.
138
Unk
now
n47
,XX
,t(3
;3)(
q21;
q26)
,
t(3;
3)(p
2?3;
q13.
3),
�21
c�13
/47
,ide
m,
der(
3)t(
3;3)
add(
3)(q
29)�
7
CC
R
9520
Ex2
Not
Fou
ndN
/AN
/AN
/A17
119.
952
Unk
now
n47
,XY
,der
(11)
t
(q23
p15)
t
(1:1
1)(q
23;q
85),
�21
c
CC
R
9610
Ex2
Not
Fou
ndN
/AN
/AN
/A11
N/A
8.6
86U
nkno
wn
47,X
Y,d
el(7
),�
21U
nkno
wn
9721
Ex2
Not
Fou
ndN
/AN
/AN
/A33
4.9
615
Unk
now
n48
,XY
,�21
,�21
cC
CR
9820
Ex2
Not
Fou
ndN
/AN
/AN
/A15
15.2
9.9
18U
nkno
wn
47X
X,?
dup(
3)
(p23
p25)
,del
(8)
(p11
.2p2
1),
der(
15)t
(1:1
5)
(q21
;p11
),
del(1
6)(q
22q2
4,de
l(20)
CC
R
996
Ex2
Not
Fou
ndN
/AN
/AN
/A23
5.1
7.2
49U
nkno
wn
N/A
Unk
now
n
100
20E
x2N
otF
ound
N/A
N/A
N/A
38N
/AN
/AN
/AU
nkno
wn
46,X
X,�
21,�
7U
nkno
wn
101
38E
x2N
otF
ound
N/A
N/A
N/A
2111
.97.
334
Unk
now
n47
,XX
,�21
cC
CR
102
10E
x2N
otF
ound
N/A
N/A
N/A
103.
910
.965
Unk
now
nN
/AU
nkno
wn
103
20E
x2N
otF
ound
N/A
N/A
N/A
123.
88.
616
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2236 ALFORD et al BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
Correspondence: Paresh Vyas, Molecular Haematology Unit,Weatherall Institute of Molecular Medicine, John Radcliffe Hospi-tal, Oxford OX3 9DS, United Kingdom; e-mail: paresh.
[email protected]; or Dirk Reinhardt, Department of PediatricHematology/Oncology, Medical School Hannover, Carl Neuberg Str1, 30625 Hannover, Germany; e-mail: reinhardt.dirk@ mh.hannover.de.
ML-DS
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Figure 1. Position and types of GATA1 sequence mutations found in TMD and ML-DS samples. (A) A schematic diagram of GATA1 showing the positions and types of thesequence mutations found in TMD and ML-DS samples. Each arrow represents a different patient. (B) Diagram showing the mutational spectrum of patients with TMD and withML-DS and (C) the effect that these mutations have on the sequence of GATA1.
GATA1 MUTATIONS IN TMD AND ML-DS 2237BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
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2238 ALFORD et al BLOOD, 25 AUGUST 2011 � VOLUME 118, NUMBER 8
For personal use only.on July 29, 2015. by guest www.bloodjournal.orgFrom
online June 29, 2011 originally publisheddoi:10.1182/blood-2011-03-342774
2011 118: 2222-2238
Hasle, Dirk Reinhardt and Paresh VyasNeuhoff, Alexandra Kolenova, Emanuele Marchi, Jan-Henning Klusmann, Irene Roberts, Henrik Kate A. Alford, Katarina Reinhardt, Catherine Garnett, Alice Norton, Katarina Böhmer, Christine von myeloproliferative disorder and myeloid leukemiaAnalysis of GATA1 mutations in Down syndrome transient
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