3.1 Overall result
In this study, a total of 813 pregnant women were enrolled in: 660 had a high risk in DS screening, 48 borderline risk, 9 abnormal Multiple of median (MOM), and 96 abnormal DS screening result with ultrasound abnormalities. CMA and karyotype findings were summarized in Table 1. In high risk group CMA identified 16 abnormal results, karyotype analysis identified 8. In borderline risk group, CMA identified 1 abnormal results, karyotype analysis identified none. In abnormal MOM group, none abnormal results were identified by both methods. In abnormal DS screening result/ ultrasound abnormalities group, CMA identified 4 abnormal results, karyotype analysis identified 2. In total, CMA identified 21/813 abnormal results, which was more efficient than karyotype analysis(10/813, P<0.001.)
Table 1 Abnormal results of CMA and karyotype analysis in 813 pregnant women with DS screening abnormalities
Group
|
n
|
CMA results/case
|
Karyotype analysis results case
|
P value
|
High risk
|
660
|
16
|
8
|
<0.001
|
Borderline risk
|
48
|
1
|
0
|
<0.001
|
Abnormal MOM
|
9
|
0
|
0
|
/
|
Abnormal DS screening results with ultrasound abnormalities
|
96
|
4
|
2
|
<0.001
|
Total
|
813
|
21
|
10
|
<0.001
|
3.2 CMA results
CMA identified 21 abnormal results in total, with the size ranged from 159Kb deletion (microdeletion of the X chromosome, including Duchenne muscular dystrophy (DMD) gene) to 155 Mb whole chromosome gain/loss(XXX/X). They could be grouped into aneuploidy(0.84%, 7/813), gross duplication(0.012%, 1/813), microdeletion(0.98%, 8/813), microduplication(0.74%, 5/813).(Table 2,3) Overall, 14 P/LP CNVs were detected in 14 fetuses(Table 3): 2 case had a microdeletion in the region of azoospermia factor (AZF) locus of the Y chromosome , 2 case had microdeletion in the X chromosome involving DMD and ichthyosis respectively. 10 cases had an autosomal CNVs including 1 case of 1q21.1 recurrent microduplication syndrome, 1 case of 2p16.1p15 microduplication, 1 case of 3q29 microdeletion, 1 case of 11q22.1q23.1 duplication, 1 case of 16p13.11 recurrent microdeletion syndrome, 1 case of 16p13.11 recurrent microduplication syndrome, 1 case of recurrent 16p12.1 microdeletion syndrome, 1 case of 16p11.2 microduplication syndrome, 1 case of renal cysts and diabetes(RCAD) syndrome, and 1 case of 22q11 duplication syndrome. Among the CNVs mentioned above, only one(11q22.1q23.1 duplication,9606kb) was identified by karyotype analysis.
CMA identified 7 VUS results, including 6 microduplication and 1 microdeletion, with the size ranged from 840kb-1484kb. None of them was identified by karyotype analysis. CMA identified 1 ROH(arr[GRCh38] 4q21.22q22.3(83481723_95588274) hmz).
Table 2 The findings of CMA in 813 pregnant women with abnormal DS screening results
Categorization
|
n
|
%
|
Aneuploidy
|
7
|
0.84%
|
Gross duplication
|
1
|
0.012%
|
Microdeletion
|
8
|
0.98%
|
Microduplication
|
5
|
0.74%
|
VUS
|
7
|
0.84%
|
Total
|
28
|
3.44%
|
Table 3 P/LP CNVs in 14 fetuses by CMA
No
|
CMA results
|
categorization
|
known syndromes
|
dosage sensitive gene/region
|
OMIM gene count
|
size of CNVs/kb
|
Inheritance
|
1
|
arr[GRCh38]Yq11.223 22658726_ 26274233x0
|
P
|
AZFc
|
/
|
11
|
3616
|
NA
|
2
|
arr[GRCh38] Yq11.223 (24889425_28231736)x0
|
P
|
AZFc
|
/
|
11
|
3342
|
father
|
3
|
arr[GRCh38]Xp21.1 (31809962_31968905)x0
|
P
|
/
|
DMD
|
1
|
159
|
mother
|
4
|
arr[GRCh38]Xp22.31 6537109_8167604)x1
|
P
|
STS
|
STS/Xp22.31 recurrent region
|
4
|
1630
|
NA
|
5
|
arr[GRCh38]1q21.1q21.2(147053151_148360058)x3
|
P
|
1q21.1 recurrent microduplication
|
1q21.1 recurrent region
|
9
|
1812
|
NA
|
6
|
arr[GRCh38]2p16.1p15(60148343_61784764)x3
|
LP
|
/
|
/
|
7
|
1636
|
de novo
|
7
|
arr[GRCh38]3q29 (193373606_195885016)x1
|
LP
|
/
|
/
|
16
|
2511
|
NA
|
8
|
arr[GRCh38]11q22.1q23.1 102192300_111795977)x3
|
LP
|
/
|
/
|
50
|
9606
|
de novo
|
9
|
arr[GRCh38]16p13.11 (14799119_16364567)x1
|
P
|
16p13.11 recurrent microdeletion
|
16p13.11 recurrent region
|
14
|
1565
|
mother(learning disorder)
|
10
|
arr[GRCh38]16p13.11p12.3 (15225421_18148856)x3
|
P
|
16p13.11 recurrent microduplication
|
16p13.11 recurrent region
|
10
|
2923
|
mother
|
11
|
arr[GRCh38]16p12.1 (21728879_22430686)x1
|
p
|
Recurrent 16p12.1 microdeletion
|
/
|
5
|
702
|
father
|
12
|
arr[GRCh38]16p11.2 29401182_30178708)x3
|
P
|
16p11.2 microduplication syndrome
|
16p11.2 recurrent region
|
26
|
778
|
father
|
13
|
arr[GRCh38]17q12(36466620_37940921)x1
|
P
|
RCAD syndrome
|
HNF1B/17q12 recurrent (RCAD syndrome) region
|
14
|
1474
|
NA
|
14
|
arr[GRCh38]22q11.21(18153983_21110475)x3
|
P
|
22q11 duplication syndrome
|
/
|
45
|
2956
|
mother
|
DMD: Duchenne muscular dystrophy, STS: Steroid sulphatase deficiency, RCAD: renal cysts and diabetes, HNF1B: hepatocyte nuclear factor 1beta.
3.2 Karyotype results
Traditional karyotype identified 10/813 abnormal results: including 4 trisomy 21(No 1-4), 2 superfemale syndrome(No 5-6), 1 Tunner syndrome(No 7), 2 mosaic sex chromosome aneuploidy( No 8-9),1 gross duplication(No10). Besides, 2 balanced translocation(No 11-12) and 1 mosaic balanced translocation(No 13) were identified. CMA identified all of these aneuploidies. However, CMA identified neither of the two mosaic sex chromosome aneuploidy for their low proportion(<=10%). Both of the balanced translocation were inherited from healthy father, and normal results of CMA also suggested they were truly balanced. For the mosaic balanced translocation, although CMA result was normal, we couldn’t discriminate it between truly balanced and unbalance.
Table 4 The findings of karyotype analysis in 813 pregnant women with abnormal DS screening results
No
|
karyotype results
|
Known syndromes
|
Inheritance
|
1-3
|
47,--,+21
|
Down’s syndrome
|
de novo
|
4
|
46,--,rob(14;21)(q10q10),+21
|
Down’s syndrome
|
NA
|
5-6
|
47,XXX
|
Superfemale syndrome
|
de novo
|
7
|
45,X
|
Tunner syndrome
|
de novo
|
8
|
mos 45,X[7]/46,XX[127]
|
Tunner syndrome(mosaic)
|
de novo
|
9
|
mos 45,X[15]/46,XY[135]
|
Tunner syndrome/Hermaphroditism
|
de novo
|
10
|
46,--,dup(11)(q22.2q23.1)
|
/
|
de novo
|
11
|
45,--,rob(14;22)(q10;q10)
|
/
|
Inherited from normal father
|
12
|
46,--,t(2;20)(p23;q13.1)
|
/
|
Inherited from normal father
|
13
|
mos 46,--,t(3;6)(q11.2;q25)[9]/46,--[43]
|
/
|
de novo
|