2.1 Fetal chromosome examination
Among the 9867 amniotic fluid chromosomes, 8 cases had complex structural abnormalities. Chromosome structural abnormalities in cases 1, 6, 7 and 8 came from new mutations (see Table 1, FIG. 1a, FIG. 6a, FIG. 7a and FIG. 8a), chromosome structural abnormalities in case 2 came from their mothers (see Table 1 and FIG. 2a), chromosome structural abnormalities in cases 3, 4 and 5 were due to the fact that their parents were balanced translocation carriers. It was followed by an unbalanced translocation (see Table 1, FIG 3a, 4a, 5a).
2.2 Check on the fetal chip
The CMA result of case
1 was that arr 3p14.2p12.3(62,450,296 − 79,586,304)x1, 3p14.2p12.3 had 16.34Mb deletion, which contained CADPS, SYNPR, SYNPR-AS1, FHIT, FOXP1 and other genes, there may be developmental delays, mental retardation, multiple deformities and other clinical symptoms (see Fig.
1b). The CMA result of case 2 was arr[hg19] 7q11.23q21.3(77,283,926 − 93,528,760)x3, 7q11.23q21.3 with 15.5Mb amplification, including SEMA3A, FZD1, CACNA2D1, SLC25A40, SEMA3A, FZD1, CACNA2D1, and SLC25A40, there are 41 OMIM genes, including CYP51A1, SAMD9, which are related to brain neuron development, blood vessel and immune protein expression (see Fig.
2b). The CMA results of case
3 were arr[hg19] 16p13.3(85,880-1,256,722)x1,18q12.3q23(43,312,367 − 78,013,728)x3, 16p13.3 with 1.17Mb fragment deletion, it contains 36 OMIM genes such as POLR3K, RHBDF1 and MPG, which can present clinical symptoms such as language and mental retardation, atrioventricular septal defect, facial morphological abnormalities, kidney enlargement, and wide thumb, there is 34.7Mb fragment amplification in 18q12.3q23, it contains 105 OMIM genes such as SLC14A1, EPG5, PSTPIP2, and so on, which may have mental retardation and low muscular tone symptoms (see Fig. 3b). CMA results of case
4 were as follows: arr[hg19] 20p13p12.1(61,661 − 13,722,351)x3, 20p13p12.1 had 13.66Mb fragment amplification, which contained 82 OMIM genes including SOX12, NRSN2, TRIB3 and RBCK1, patients may have developmental delays, mental retardation, language disorders, and broad nose (see Fig. 4b). The CMA results of case
5 were arr[hg19] 2p25.3p22.2(12,770 − 37,352,776)x3,21q11.2q21.3(15,016,486 − 31,024,019)x3, 2p25.3p22.2 had 37.34Mb of fragment repeats, it contains 82 OMIM genes such as SOX12, NRSN2, TRIB3, RBCK1, and so on, patients may show developmental delay, mental retardability, language disorder, broad nose bridge and other phenotypes, 21q11.2q21.3 has 16Mb fragment duplication, covering the Early-onset_Alzheimer_disease_with_cerebral_amyloid_angiopathy region and containing 31 OMIM genes such as LIPI, APP, ABCC13 and HSPA13, symptoms of abnormal finger morphology, mental retardation, and developmental delay may occur (see Fig. 5b). The CMA result of case
6 was arr[hg19] 18q12.3q23(37,974,391 − 78,013,728)x3, and there were 40.039Mb replicates in the 18q12.3q23 region, which contained 115 OMIM genes such as PIK3C3, RIT2, SYT4 and SETBP1, symptoms such as stunting, mental retardation, short stature and enlarged heart may occur (Fig. 6b). The CMA results of case
7 were arr[GRCh37]4q26q35.2(116376542_188138856)x3, arr[GRCh37] 4q35.2(188155531_190957460)x1, 4q26q35.2 with 71.762Mb replicates, it contains 179 OMIM genes, including TRAM1L1, NDST3, PRSS12, and so on, which may cause intellectual disability, comprehensive developmental delay, autism, and so on, there is 2.802Mb deletion in the 4q35.2 region, including 3 OMIM genes ZFP42, FRG1, FRG2, this segment had no pathogenic significance (Fig. 7b). The CMA results of case
8 were arr[GRCh37] Xp22.31p11.1(9041083_58455353)x3, arr[GRCh37] Xp22.33p22.31(168552_9040480)x1, there were 49.414Mb repeats in Xp22.31p11.1 region, including 268 OMIM genes such as TBL1X, GPR143, SHROOM2, CLCN4,and so on, and 8.872Mb deletion in Xp22.33p22.31 region, it contains 43 OMIM genes, including PLCXD1, GTPBP6, PPP2R3B, and SHOX, which can cause symptoms such as global stunting, ichthyosis, and short stature (see Fig. 8b).
2.3 Verification of Fish probe
Figure 2c shows that the red fluorescence represents 7p22.3(1,645,493-1,814,816), orange fluorescence represents 7q21.12(86,802,721 − 86,97,97,95,95,903), the green fluorescence represents 4p16.3(2,156,895-2,351,734), ins(4; 7)→ The chromosome indicated indicates that the repeated 7q11.23q21.3 fragment is inserted into the 4q31.1 position, resulting in a derived chromosome 4.
2.4 Fetal ultrasound detection during pregnancy
In case 1, ultrasound examination showed multiple deformities of the fetus, which were consistent with tetralogy of Fallot, hydrocephalus, and double renal dysplasia (see Fig. 1c, 1d). In case 2, the fetal ventricular septal defect was detected by ultrasound (see Fig. 2d). In other cases, no abnormality was detected by ultrasound before abortion.
Table 1
Amniotic fluid karyotype and chip detection
case
|
Clinical indication
|
Fetal karyotype
|
Parental karyotype
|
CMA
|
ending
|
1
|
Husband karyotype 46,XY,inv(1)(p13q21)
|
46,Xn,inv(1)(p13q21),del(3)(p13p14)
|
Paternal karyotype: 46,XY,inv(1)(p13q21); The mother's karyotype was normal
|
del(3)(p12.3p14.2) is missing 16.34Mb
|
Induction of Labour
|
2
|
NIPT shows a 15.54Mb duplication in 7q21.11-q21.3
|
46,Xn,der(4)ins(4;?)(q31.3;?)
|
Father karyotype normal, mother: 46,XX,der(4)ins(4; ?). (q31.3; ?).
|
dup(7)(q11.23q21.3) repeat 15.5Mb
|
eutocia
|
3
|
NIPT shows high risk on chromosome 18
|
46,Xn,der(16)t(16;18)(p13.3;q12.3)
|
Father karyotype normal, mother: 46,XX,t(16; 18) (p13.3; Q12.3)
|
del(16)(p13.3)missing1.17Mb;dup(18)(q12.3q23) repeat 34.7Mb
|
Induction of Labour
|
4
|
Pregnant women have 46,XX,t(9; 22. 20)(q12; p11; p12)
|
46,Xn,der(9)t(9;22;20)(q12;p11;p12),der(22)t((9;22;20)mat
|
Father karyotype normal, mother: 46,XX,t(9; 22. 20)(q12; p11; p12)
|
dup(20)(p12.1p13) repeat 13.66Mb
|
Induction of Labour
|
5
|
NIPT shows high risk of chromosome 21
|
47,Xn,der(21 )t(2;21)(p22.2;q21.3),+21
|
Father karyotype normal, mother: 46,XX,t(2; 21) (p22.2; Q21.3)
|
dup(2)(p22.2p25.3) repeat 37.34Mb; dup(21)(q11.2q21.3) repeat 16Mb
|
Induction of Labour
|
6
|
Down's screening for chromosome 21 is high-risk
|
46,Xn,der(21)(18qter→18q12.3::21p13→21qter)
|
The father's karyotype was normal; The mother's karyotype was normal
|
dup(18)(q12.3q23) repeat 40.039Mb
|
Induction of Labour
|
7
|
Color ultrasound hint: NT thickening old age
|
46,Xn,der(4)del(4)(q35.2)dup(4)(q35.2q26)dn
|
The father's karyotype was normal; The mother's karyotype was normal
|
dup(4)(q26q35.2) repeat 71.762Mb; del(4)(q35.2) is missing 2.802Mb
|
Induction of Labour
|
8
|
NIPT showed fewer sex chromosomes
|
46,X,der(X)del(X)(p22.31)dup(X)(p22.31p11.1)dn
|
The father's karyotype was normal; The mother's karyotype was normal
|
dup(X)(p11.1p22.31) repeat 49.414Mb; del(X)(p22.31p22.33) is missing 8.872Mb
|
Induction of Labour
|