Table 2
Summary of the detection rates of microarray from pregnancies with isolated ANH
Group
|
n
|
All CNVs detected by CMA
n (%)
|
Clinically significant
CNVs
n (%)
|
VOUS
n (%)
|
Benign CNVs
n (%)
|
Group A (APRPD 10–15 mm)
|
57
|
11(19.2%) a
|
1 + 2(5.2%) b
|
7
|
1
|
Group B (APRPD ≧
15 mm)
|
27
|
14(51.8%) a
|
2 + 5(25.9%) b
|
4
|
3
|
Total
|
84
|
26
|
3 + 7
|
11
|
4
|
Abbreviations: ANH: antenatal hydronephrosis; CMA, chromosomal microarray analysis; CNV, copy number variant; APRPD: anterior-posterior renal pelvic diameter; VOUS, variant of unknown significance. a All CNVs detectable by CMA in Group A versus Group B: p = 0.002 0.05 Pearson chi-square; b Clinically significant CNVs by CMA in Group A versus Group B: p = 0.018 0.05, Continuity correction in the chi-square test |
Fetuses with APRPD of 10–15 mm
In group A, CNVs were detected in 10.5% (6/57) cases, included three clinically significant CNVs, one benign CNV, and two VOUS. We compared the frequency of clinically significant CNVs with that in the control cohort in Chinese population [14]. The detected rate of clinically significant CNVs in group A was significantly higher than that in the control cohort (3/57 vs. 9/3748, P = 0.0). In case 2 (table3), the deleted region on chromosome15q11.2(0.47 Mb) overlapped with the 100% region of proximal 15q11.2 microdeletion/microduplication syndrome between BP1 and BP2, 10% CDS region of NIPA1 gene [OMIM: 608145] and 8.22% region of Prader-Willi syndrome (Type 1)/Angelman syndrome (Type 1). The mutation of NIPA1 gene [OMIM: 608145] is associated with spastic paraplegia 6 (SPG6) [OMIM: 600363], and SPG6 is autosomal dominant and imperfect inadequacy. The patient is mainly characterized by lower limb paralysis and sphincter disorders [PMID:25689425]; 15q11.2 BP1-BP2 deletion syndrome was with wide phenotypic variability and low penetrance, therefore, we assumed the deletion fragment was likely pathological. We detected a pathogenic deletion region on chromosome 17q12 in Case 6(table 3),involving 99.97% region of RCAD (renal cysts and diabetes)syndrome. The deletion fragment contains three single dose-sensitive genes: HNF1B、 ZNHIT3 gene [OMIM: 604500]and PIGW gene [OMIM: 610275]. The mutation in ZNHIT3 gene is associated with PEHO syndrome (PEHO) [OMIM: 260565], leading to tension decreased, mental retardation, optic atrophy, cerebellum and brain stem atrophy, myelination disorder etc; The mutation in PIGW gene is associated with mental responsive syndrome-5 (HPMRS5) [OMIM: 616025], leading to neonatal hypotonia, mental retardation, epilepsy, special face and so on.
Fetuses with APRPD of 15 mm or more
In Group B, CNVs were identified in 51.8% (14/27) cases(table 3), including seven clinically significant CNVs and four VOUS and three benign CNVs. Pathogenic CNVs were detected in Case 10 and case 3. Case 3 in table 3 had a 1.31 Mb deletion in chromosome 2q22.3q23.1 containing methyl-cp G-binding domain 5 (MBD5, MIM611472). Deletion in MBD5 is linked to 2q23.1 deletion syndrome characterized by moderate or severe mental retardation, seizures, skeletal abnormalities, sleep disturbance, significant speech impairment, and autistic-like behavioral problems. ORC4 gene in this deletion region is associated with Meier-Gorlin syndrome (MGS), MGS is a rare autosomal recessive primordial dwarfism disorder, characterized by microtia, patellar applasia/hypoplasia, and a proportionate short stature[15].In case 10(table 3), a de novo deletion fragment in 17q12 region covered 99.97% region of RCAD (renal cysts and diabetes) syndrome.
The genetic variants were not inherited from their parents in case 4, 5, 7 ,8 and case 9(table 3). Moreover, all overlapped with deletion/duplation syndromes or containing OMIM -morbid gene partly, but no definite pathogenic evidence had been reported. Hence, these disorders were classified as likely pathological. In case 4, a de novo deletion of 0.55 Mb was detected on 11p15.5. This repetitive fragment overlapped with 1.79% region of Homozygous 11p15-p14 Deletion syndrome [OMIM:606528], known as congenital hyperinsulinism (CHI) and profound hearing loss [16]. In Case 8, a de novo duplation in 15q13.3 region overlapped with 97.84% region of 15q13.3 recurrent region (D-CHRNA7 to BP5) (includes CHRNA7 and OTUD7A) duplication[ClinGen:ISCA-46295] and 33.26% region of 15q13.3 recurrent region (BP4-BP5) (includes CHRNA7) duplication[ClinGen:ISCA-37411]. In case 9, a de novo deletion fragment of 11p15.5 was shown to be overlap with 1.79% region of 11p15-p14 deletion syndrome (homozygous)[OMIM:606528],which contained 100.00% CDDS region in classical transcripts of CTSD gene [OMIM:116840], 100% CDS region in TNNI2 gene and 100% CDS region in H19. The mutation of CTSD gene is associated with neuronal ceroid lipofuscinosis-10 (CLN10)[OMIM:610127]༌which is autosomal recessive inheritance, is characterized by respiratory failure, vision loss, ataxia, microcephaly, mental retardation, etc. H19 gene is associated with Beckwith-Wiedemann syndrome.
Follow-up information
Eighteen cases were excluded for the following reasons: loss of follow-up (n = 7) and elective termination (n = 11) including 3 with chromosomal abnormalities, 6 with severe bilateral hydronephrosis, 1 with right ureteral atresia and 1 with congenital renal agenesis. Finally, 66 cases had a complete set of follow-ups during the prenatal and postnatal period. The total rate of normalization was 81.8% (54/66) in uterus or after birth. During postnatal follow-up period, 11 cases (16.6%, 11/66) were treated with surgery due to pelvic uretero junction obstruction (PUJO) (10/11) and ureter stricture (1/11). For all these children, the treatment of operation was effective, the postoperative renal morphology recovered significantly, and the renal function could be preserved, except one child was suspected to have a nephroblastoma at 8 months of age. None of the children had mental and growth retardation during the follow -up period.
Table 3
Summary of clinically significant CNVs, identified by CMA in 10 fetuses with isolated ANH
case
|
sex
|
gestational weeks
|
APRPD
(cm)
|
locus
|
Size
Mb
|
CNV
classification
|
Inheritance
|
Related syndrome
/OMIM gene
|
1
|
Male
|
26 + 5
|
Right 1.16 cm
Left 0.9 cm
|
del 3p26.3
60001-1,453,696
|
1.39
|
Likely path
|
Denovo
|
CNTN6
|
2
|
Male
|
23
|
Right 1.1 cm
Left 1.1 cm
|
del 15q11.2
22,754,322 − 23,221,689
|
0.46
|
Likely path
|
Denovo
|
15q11.2 recurrent region (BP1-BP2) deletion syndrome
|
3
|
Male
|
23 + 3
|
Right 2.1 cm
Left 1.65 cm
|
del 2q22.3q23.1
147,855,299 − 149,170,115
|
1.31
|
Pathogenic
|
Denovo
|
ACVR2A, ORC4
|
4
|
male
|
27
|
Right 2.4 cm
Left 1.7 cm
|
dup11p15.5
1,696,849-2,250,850
|
0.55
|
Likely path
|
Denovo
|
11p15-p14 deletion syndrome,
|
5
|
Female
|
27
|
Right 2.4 cm
|
del 3q22.3
136240085–138219078
|
1.9
|
Likely path
|
Denovo
|
CLDN18, DBR1, DZIP1L, ESYT3, IL20RB, MRAS, NCK1
A4GNT,ARMCEP70
,C8
|
6
|
male
|
26
|
Right 1.0
Left 1.1 cm
|
del17q12
34,815,551 − 36,347,393
|
1.53
|
Path
|
Denovo
|
RCAD (renal cysts and diabetes) syndrome
|
7
|
male
|
26
|
Left 1.5 cm
|
del17q11.2,
29396574–33259042
|
3.8
|
Likely path
|
Denovo
|
17q11.2 recurrent region duplication syndrome,
|
8
|
Female
|
27
|
Left 1.7 cm
|
dup15q13.3
32,028,804 − 32,515,681
|
0.484
|
Likely path
|
Denovo
|
15q13.3 recurrent region (D-CHRNA7 to BP5) (includes CHRNA7 and OTUD7A) duplication syndrome
|
9
|
male
|
25
|
Right 2.4 cm
Left 1.7 cm
|
dup11p15.5
1,696,849-2,250,850
|
0.554
|
Likely path
|
Denovo
|
KRTAP,IFITM10,CTSD,SYT8,TNNI2,LSP1,TNNT3,MRPL23,HOTS,H19,IGF2,INS-IGF2,INS,TH
|
10
|
female
|
27 + 3
|
Left 2.0 mm
Right 1.5 mm
|
Dele17q12
34,815,551 − 36,347,393
|
1.53
|
path
|
Denovo
|
RCAD (renal cysts and diabetes) syndrome
|
CNVs, copy number variants; ANH, antenatal hydronephrosis; dup, duplication; del, deletion; path: pathogenic; CMA: chromosomal microarray analysis; |