Table 1 Clinical features of the 24 FA patients
Case No.
|
Gender
|
Age of referral (years)
|
Age of clinical BMF onset (years)
|
Congenital malformations
|
Growth retardation
|
Family history
|
1
|
F
|
16
|
15
|
None
|
No
|
Negative
|
2
|
M
|
12
|
2
|
S, C, M
|
Yes
|
Negative
|
3
|
M
|
7
|
2
|
S, C, G
|
Yes
|
Negative
|
4
|
M
|
10
|
5
|
S, G
|
Yes
|
One sibling manifested as polydactyly and died from anemia
|
|
|
|
|
|
|
5
|
M
|
11
|
5
|
C, G, M,
|
Yes
|
IVF and paternal grandmother died from pancreatic cancer
|
|
|
|
|
|
|
6
|
F
|
11
|
10
|
C, H
|
Yes
|
Negative
|
7
|
M
|
7
|
5
|
S, M
|
No
|
Negative
|
8
|
M
|
17
|
10
|
S, M
|
No
|
Negative
|
9
|
M
|
7
|
7
|
S, C, M, H
|
No
|
Negative
|
10
|
M
|
5
|
4
|
S, M
|
No
|
Negative
|
11
|
M
|
13
|
13
|
E
|
Yes
|
Negative
|
12
|
M
|
9
|
6
|
S
|
Yes
|
Negative
|
13
|
F
|
7
|
7
|
M
|
Yes
|
Negative
|
14
|
M
|
7
|
1
|
S, M
|
Yes
|
Negative
|
15
|
M
|
5
|
2
|
S
|
No
|
Negative
|
16
|
M
|
4
|
1
|
S, M
|
No
|
Negative
|
17
|
M
|
14
|
5
|
C, G
|
Yes
|
Two family members died from anemia
|
18*
|
M
|
6
|
4
|
S, C, M
|
Yes
|
2nd degree consanguinity
|
19
|
M
|
4
|
3
|
None
|
No
|
Negative
|
20
|
F
|
9
|
4
|
S, M
|
No
|
Negative
|
21
|
F
|
7
|
4
|
S, G, N
|
Yes
|
Negative
|
22
|
M
|
9
|
7
|
None
|
No
|
Negative
|
23
|
F
|
6
|
3
|
S, C, G
|
Yes
|
Negative
|
24
|
F
|
6
|
4
|
S, M, H, E, G
|
Yes
|
2nd degree consanguinity
|
* Case 18 is a Uyghur Chinese.
F, female; M, male; S, skin and annex; C, craniofacial anomalies; M, musculoskeletal system; G, genitourinary system; H, cardiovascular system; E, endocrine system; N, nervous system. IVF, in vitro fertilized.
Skin and annex abnormalities include skin pigmentation, café au lait spots, excess hair; craniofacial anomalies include microcephalus, ptosis, hypertelorism, hypotelorism, flat nose bridge; malformations in musculoskeletal system include polydactyly, deformity of thumbs, absence of thumbs, hypoplasia of thenar eminence, and scoliosis; genitourinary system malformations include kidney malformation, hydronephrosis, indirect inguinal hernia, cryptorchidism, ovary absence, and uterine malformation/absence; cardiovascular system defects include patent ductus arteriosus and ventricular septal defect; nervous system abnormalities include encephalatrophy and moyamoya disease; endocrine system defects include hypothyroidism, primary adrenocortical insufficiency, and obesity.
Table 2 Bone marrow morphology, karyotype, chromosome breakage tests, and ALDH2 genotypes of the 24 FA patients.
Case No.
|
BM morphology
|
BM karyotype
|
Chromosome breakage test
|
ALDH2 genotype
|
1
|
Dysplasia
|
47,XX,+8[1]/46,XX[20]
|
Negative
|
G/G
|
2
|
Dysplasia
|
NA
|
Positive
|
G/A
|
3
|
Dysplasia
|
47,XY,+15[1]/46,XY[20]
|
Positive
|
G/A
|
4
|
Hypoplasia
|
normal
|
Positive
|
G/A
|
5
|
NA
|
NA
|
Positive
|
G/G
|
6*
|
AML
|
46,XX,der(7)t(1;7)(q21;q36)[20]
|
Positive
|
G/G
|
7
|
Hypoplasia
|
Normal
|
Positive
|
G/A
|
8
|
Dysplasia
|
46,XY,-7,+21[5]/46,XY[16]
|
Positive
|
G/G
|
9
|
Hypoplasia
|
Normal
|
Positive
|
G/G
|
10
|
Hypoplasia
|
Normal
|
Positive
|
G/A
|
11**
|
MDS
|
Complex
|
Positive
|
G/G
|
12
|
Hypoplasia
|
Normal
|
Positive
|
G/A
|
13
|
Dysplasia
|
Normal
|
Positive
|
G/G
|
14
|
Dysplasia
|
Normal
|
Positive
|
G/G
|
15
|
Dysplasia
|
Normal
|
Positive
|
G/A
|
16
|
Hypoplasia
|
Normal
|
Negative
|
G/A
|
17
|
Dysplasia
|
46,XY,del(7)(p13)[13]/46,XY[7]
|
Positive
|
G/A
|
18
|
Hypoplasia
|
Normal
|
Positive
|
G/A
|
19
|
Dysplasia
|
Normal
|
Positive
|
G/A
|
20
|
Dysplasia
|
46,XX,t(1;5)(p36.1;q13)[1]/46,XX[19]
|
Positive
|
G/G
|
21
|
Dysplasia
|
46,XX,del(14)(q24)[1]/46,XX[20]
|
Positive
|
G/G
|
22
|
Dysplasia
|
45,XY,-7[19]/46,XY[3]
|
Negative
|
G/A
|
23
|
Dysplasia
|
46,XX,del(7)(q22)[8]/46,XX,del(5)(p11)/46,XX[19]
|
Positive
|
G/A
|
24
|
Hypoplasia
|
Normal
|
Positive
|
G/A
|
* Case 6 is diagnosed as acute myeloid leukemia. The myeloblasts count 41% of the nucleated cells according to morphologic test of bone marrow smears.
** Case 11 is diagnosed as myelodysplastic syndrome. His bone marrow morphology shows dysplasia was observed in his granulocytic lineage and megakaryocytic lineage with the myeloblasts count 6% of the nucleated cells. The result of his karyotype is:46,XY,dup(1)(q21q23),add(2)(p11.2),add(3)(q27),der(5)t(1;5)(q21;q35),add(20)(p12)[17]/
45,XY,der(1)(?::1q42->1q21::1p36.3->1q32::1q21->1q44::?),add(2)(p11.2),add(3)(q27),add(4)(p16),der(5)t(1;5)(q21;q35),-18,add(20)(p12),ace[2]/46,XY[1]
Chromosome breakage tests were induced by mitomycin C.
NA, not available; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.
Table 3 Variant details
|
|
Mutation 1 (maternal)
|
Mutation 2 (paternal)
|
Case No.
|
Gene
|
Genomic location
|
cDNA/Protein
|
Ref./Com.
|
Genomic location
|
cDNA/Protein
|
Ref./Com.
|
1
|
FANCA
|
chr16:89831465
|
c.2611C>G/p.L871V;c.
|
NA
|
chr16: 89808940-89809954
|
c.3627-607_3765+268del
|
12
|
2
|
FANCA
|
chr16:89833593
|
c.2557C>T/p.R853X
|
16
|
chr16:89877396
|
c.367C>T/p.Q123X
|
NA
|
3
|
FANCA
|
chr16:89815145-89815146
|
c.3270_3271delCT/p.C1090RfsX25
|
Novel
|
chr16:89868906-89875410
|
c.792+761_c.523-635del
|
Novel
|
4
|
FANCA
|
chr16:89877396
|
c.367C>T/p.Q123X
|
NA
|
chr16:89818822
|
c.2982-192A>G
|
18
|
5*
|
FANCA
|
chr16:89842183
|
c.1867C>T/p.Q623X
|
Novel
|
chr16:89842183
|
c.1867C>T/p.Q623X
|
Novel
|
6
|
FANCA
|
chr16:89804935-89806139
|
c.3935-178_4368+74del
|
Novel
|
chr16:89819567-89839134
|
c.c.2014+545_2982-937del
|
Novel
|
7
|
FANCA
|
chr16:89811185-89815741
|
c.3239+397_3626+202del
|
Novel
|
chr16:89858887
|
c.1074_1075delGT/p.Y359PfsX49
|
NA
|
8
|
FANCA
|
chr16:89826812-89919023
|
FANCA c.2852+1545_SPIRE2 c.646-1671del
|
Novel
|
chr16:89825071
|
c.2894_2895delCT/p.P965RfsX9
|
Novel
|
9
|
FANCA
|
chr16:89780001-89822000
|
VPS9D1 c.432-877_FANCA c.2981+2985del
|
12
|
chr16: 89808940-89809954
|
c.3627-607_3765+268del
|
12
|
10
|
FANCA
|
chr16:89823177-89825446
|
c.2853-333_2981+1808del
|
Novel
|
chr16:89809270
|
c.3703C>T/p.Q1235X
|
Novel
|
11
|
FANCA
|
chr16:89818619
|
c.2990_2993delGTTA/p.S997MfsX28
|
NA
|
chr16:89862229
|
c.987_990delTCAC/p.H330AfsX4
|
19,22
|
12
|
FANCA
|
chr16:89816286
|
c.3091C>T/p.Q1031X
|
NA
|
chr16:89792569-89821767
|
ZNF276 c.1007-1118_FANCA c.2982-3137del
|
Novel
|
13
|
FANCA
|
chr16:89806417
|
c.3918dupT/p.Q1307SfsX6
|
20
|
chr16:89831438
|
c.2638C>G/p.R880G
|
NA
|
14
|
FANCA
|
chr16:89858941
|
c.1021C>T/p.Q341X
|
Novel
|
chr16:89811412
|
c.3581C>T/p.P1194L
|
20
|
15
|
FANCB
|
chrX:14868651
|
c.1472T>A/p.V491E
|
Novel
|
—
|
—
|
—
|
16
|
FANCB
|
chrX:14875979
|
c.1197+5insA
|
Novel
|
—
|
—
|
—
|
17
|
FANCB
|
chrX:14877390
|
c.1018C>A/p.Q340K
|
Novel
|
—
|
—
|
—
|
18*
|
FANCC
|
chr9:97912346
|
c.545C>A/p.S182Y
|
Novel
|
chr9:97912346
|
c.545C>A/p.S182Y
|
Novel
|
19
|
FANCD2
|
chr3:10084828
|
c.983G>A/p.R328Q
|
NA
|
chr3:10114634
|
c.2574T>G/p.I858M
|
Novel
|
20
|
FANCD2
|
chr3:10132005
|
c.3713T>A/p.M1238K
|
NA
|
chr3:10089599
|
c.1279-2A>T
|
Novel
|
21
|
FANCE
|
—
|
—
|
NA
|
chr6:35426215
|
c.1111C>T/p.R371W
|
17,18,19
|
22
|
FANCE
|
chr6:35423547
|
c.272C>T/p.P91L
|
Novel
|
chr6:35427467-35427470
|
c.1246_1249delCAAA/p.T417SfsX7
|
NA
|
23
|
SLX4
|
chr16:3645671
|
c.1948C>T/p.L650F
|
NA
|
chr16:3633419
|
c.4832A>G/p.E1611G
|
NA
|
24*
|
ERCC4
|
chr16:14015937
|
c.257G>A/p.R86H
|
NA
|
chr16:14015937
|
c.257G>A/p.R86H
|
NA
|
* Case 5, Case 18, and Case 24 carries homozygous variants.
NA, not available.
Table 4 Treatment and outcomes of the 24 FA patients.
Case No.
|
Therapeutics
|
Donor type
|
Pre-HSCT conditioning regimen
|
Outcomes
|
1
|
HSCT
|
UUD
|
Bu+CTX+Flu+Alemtuzumab
|
Alive
|
2
|
HSCT
|
UUD
|
Bu+CTX+Flu+Alemtuzumab
|
Dead (aGVHD, infections)
|
3
|
HSCT
|
UUD
|
Bu+CTX+Flu+ATG+Me-CCNU
|
Alive
|
4
|
HSCT
|
MUD
|
Bu+Flu+CTX+ATG
|
Alive
|
5
|
HSCT
|
HRD
|
Bu+CTX+Flu+ATG+Me-CCNU
|
Alive
|
6
|
HSCT
|
HRD
|
Decitabine+Ara-C+Bu+Flu+ATG+Me-CCNU
|
Dead (aGVHD, drug-induced encephalopathy)
|
|
|
|
7
|
Androgen and transfusion
|
—
|
—
|
Alive
|
|
|
|
|
8
|
HSCT
|
HRD
|
Decitabine+Ara-C+Bu+Flu+ATG+Me-CCNU
|
Dead (aGVHD, MODS)
|
|
|
|
|
9
|
Lost
|
—
|
—
|
—
|
10
|
HSCT
|
MRD
|
Bu+Flu+CTX+ATG
|
Dead (aGVHD, septic shock)
|
11
|
HSCT
|
HRD
|
Decitabine+Ara-C+Bu+Flu+ATG+Me-CCNU
|
Dead (aGVHD, septic shock)
|
|
|
|
|
12
|
HSCT
|
UUC
|
Bu+Flu+CTX+ATG
|
Dead (aGVHD, pulmonary infection, CMV infection)
|
|
|
|
|
13
|
Androgen, cytokine, transfusion
|
—
|
—
|
Alive
|
|
|
|
|
14
|
Androgen and cytokine
|
—
|
—
|
Alive
|
|
|
|
|
15
|
HSCT
|
HRD
|
Bu+Flu+CTX+ATG
|
Dead (aGVHD, TMA, pulmonary infection)
|
|
|
|
|
16
|
HSCT
|
MUD
|
Bu+Flu+CTX+ATG
|
Alive
|
17
|
HSCT
|
HRD
|
Bu+Flu+CTX+ATG
|
Alive
|
18
|
Androgen and transfusion
|
—
|
—
|
Dead (pulmonary infection, septic shock)
|
|
|
|
|
19
|
HSCT
|
MUD
|
Bu+Flu+CTX+ATG
|
Alive
|
20
|
HSCT
|
UUD
|
Bu+Flu+CTX+ATG
|
Alive
|
21
|
HSCT
|
UUD
|
TBI+CTX+Flu+ATG
|
Alive
|
22
|
HSCT
|
HRD
|
Bu+Flu+CTX+ATG
|
Alive
|
23
|
HSCT
|
MUD
|
Bu+Flu+CTX+ATG
|
Alive
|
24
|
Lost
|
—
|
—
|
—
|
HSCT, hematologic stem cell transplantation; UUD, HLA-unmatched unrelated donor; MUD, HLA-matched unrelated donor; HRD, HLA-haploidentical related donor; MRD, HLA-matched related donors; UUC, HLA-unmatched unrelated cord blood; Bu, Busulfan; CTX, cyclophosphamide; Flu, Fludarabine; ATG, antithymocyte globulin; Me-CCNU Semustine; TBI; total body irradiation; aGVHD, acute graft-versus-host disease; CMV, cytomegalovirus.