Genetic etiology analysis of 73 fetuses with ventriculomegaly

Genetic etiology analysis of 73 fetuses with ventriculomegaly | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Genetic etiology analysis of 73 fetuses with ventriculomegaly Zhao Chenyue, Xue Huiqin, Gao Jingbo, Guo Min, Yue Hao, Guo Rong, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4215892/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted 5 You are reading this latest preprint version Abstract Objective High-throughput sequencing was performed on 73 fetuses with ventriculomegaly (VM) to analyze the genetic causes, including chromosomal aberrations and genetic variations. Methods The clinical data from fetuses with lateral ventricular width greater than 10 mm in second and third trimester were collected from Shanxi Provincial Children's Hospital between 2020 and 2023. Patient samples included amniotic fluid or miscarriage tissue and were evaluated via copy number variation sequencing (CNV-seq), and those with negative CNV-seq result were further examined using whole exome sequencing (WES), with chromosomal aberrations and genetic variations counted. Statistical analysis was performed using SPSS 26.0, and pregnancy outcomes were followed. Results Of the 73 patients included in the study, 23 (31.5%) cases had chromosomal aberrations with 26 CNV fragments following CNV-seq, including 4 aneuploidies, 12 pathogenic variants, 2 likely pathogenic variants, and 8 variants of unknown significance. The detection rate of chromosomal aberrations was significantly higher in non-isolated VM relative to isolated VM. Negative CNV-seq results (n = 33) were further examined via WES, and a subset (n = 16, 48.48%) contained single-gene defects. These variants included SPATA5, PDHA1, TRIM71, PIK3R2, TUBB, CRB2, PIDD1, RTTN, FGFR3, AIMP1, POGZ, MYH7, CNOT3, MACF1 , and PURA , with 9 unreported variant loci also identified. Conclusion VM fetuses have complex developmental outcomes, and thus it is necessary to consider genetic etiology is VM. WES has the potential to provide a genetic diagnosis for VM fetuses without aneuploidy or CNVs, and can thereby increase the fetal VM diagnostic rate. Biological sciences/Genetics Biological sciences/Neuroscience Health sciences/Medical research fetal ventriculomegaly genetic causes chromosomal aberrations single gene genetic disease Figures Figure 1 Figure 2 INTRODUCTION During prenatal screenings, birth defects associated with the central nervous system (CNS) are of particular concern, with ventriculomegaly (VM) being the most common sonographic CNS abnormality detected. This condition is characterized by an enlargement of ventricles within the brain and is closely associated with cognitive and/or psychomotor skill developmental delays. To determine the presence of VM, lateral ventricular width measurements are obtained via prenatal ultrasonography, with a normal average lateral ventricular width during the second and third trimesters (14–40 weeks gestation) being 5.4–7.6 mm; while a width > 10 mm is classified as VM. Fetal VM is divided into three groups according to the ventricular diameter: mild (10–12 mm), moderate (12–15 mm), and severe (> 15 mm) 1,2 , and into two groups according to whether combined with other abnormal findings: isolated VM (IVM) and non-isolated VM (NIVM). There are three predominant causes of fetal VM, including brain parenchymal loss, cerebrospinal fluid obstruction, or excessive cerebrospinal fluid secretion. In some cases, the development of VM can be associated with genetic factors, such as chromosomal aberrations and genetic variations, or maternal factors, such as an infection with cytomegalovirus or toxoplasmosis during pregnancy 3 . VM has complex neurodevelopmental outcomes ranging from a normal physiology to serious complications that lead to death, with chromosomal abnormalities or single-gene defects (SGD) associated with a poor prognosis 4 . In addition to traditional non-invasive prenatal testing (NIPT), genetic screening is increasingly being utilized to detect abnormalities via karyotyping, copy number variation sequencing (CNV-seq), whole exome sequencing (WES), or by examining fetal and parental variations simultaneously using trio-WES 5 . Combining genetic examination with clinical and neurologic imaging findings can improve predictive outcomes, improve VM patient management, improve VM classification accuracies, predict neurocognitive outcomes, and stratify patients into treatment plans. Moreover, this combined approach may help identify possible VM genetic mutation sites, establish effective clinical management during pregnancy, provide meaningful guidance for prenatal counseling in affected families, reduce birth defects, and provide guidance for subsequent pregnancies. However, few studies have combined CNV-seq and WES in fetal VM. As such, the primary aim of this study was to examine the contributions of chromosomal and genetic abnormalities to the etiology of fetal VM while also assessing the genetic diagnostic capacity of WES in the VM fetal. RESULTS Of the patients that met the inclusion criteria (n = 73), 33 patients had no detectable CNVs following CNV-seq. Thus, this cohort underwent further evaluation via WES. Figure 1 shows the flow and results of the genetic analysis for the study cohort. Demographics, VM characteristics and sequencing information for the study cohort are summarized in Table 1 . The median maternal age was 29 (range, 22–42) years, and the fetuses were assessed at a median gestational age of 25 (range, 17–33) weeks. Table 1 Demographic and clinical characteristics and sequencing information for 73 fetuses with ventriculomegaly. Variable Value Maternal age (years) 29 (22–42) Gestational age at diagnosis (weeks) 25 (17–33) VM type Mild 45 Moderate-to-severe 28 IVM 36 NIVM 37 Genetic sequencing CNV-seq 73 WES 33 Data are given as median (range). VM, ventriculomegly; IVM, isolated VM; NIVM, non-isolated VM, CNV-seq, copy number variation sequencing; WES, whole exome sequencing. Results of CNV-seq Of the 73 fetal samples that underwent CNV-seq analysis, 23 (31.5%) had chromosomal abnormalities with 26 CNV fragments were detected, including aneuploidy (n = 4, 5.5%) and the AMCG classifications P (n = 12), LP (n = 2), and VOUS (n = 8). Of these, 3 patients presented with 2 CNV fragments, with classifications of P and VOUS for patients P11 and P65, and P and LP for patient P38. Relatively high aberration frequencies were noted in chromosomes 1, 15, 17 and 22 (Tables 2 and 3 ). Table 2 Aneuploidies identified by CNV-seq in the study cohort ID GA Aneuploidy Ultrasound/ MRI findings P37 20 Trisomy 21 Mild VM and NF 0.66 cm P53 30 Klinefelter syndrome (47, XXY) Mild VM P62 17 Triploidy (69, XXX) Mild VM, cerebellar morphology is irregular, clear septum not shown, poor spine and sacrum tail alignment, and oligohydramnios P73 20 Trisomy 18 Mild VM, ventricular septal defect and abnormal development of the left upper limb GA, gestational age; VM, ventriculomegly; NF, nuchal fold. Table 3 Positive results following CNV-seq analysis and their clinical phenotypes. ID GA Copy-number variant (hg19) Size (Mb) Classification Ultrasound/ MRI findings P9 30 del( 19 )(p13.2) chr19:g.12740000_13420000del 0.66 P Severe VM and club foot P10 25 del( 2 )(q36.3q37.3) chr2:g.229040000_243020000del 13.98 P Moderate VM, nasal bones not shown, single umbilical artery, and polyhydramnios P11 25 del( 22 )(q11.21q11.21) chr22:g.18880000_21480000del 2.60 P Moderate VM, right atrium and right ventricular enlargement, and micromandible dup( 3 )(p26.1p26.1) chr3:g.6120000_7240000dup 1.12 VOUS P16 20 del( 1 )(p32.1p31.3) chr1:g.59040000_67720000del 8.68 P Moderate VM P19 27 dup( 15 )(q23) chr15:g.67940001-68290000dup 0.35 VOUS Severe VM and oligohydramnios P21 31 dup(X)(q21.33) chrX:g.93880000_94520000dup 0.64 VOUS Severe VM P26 27 del( 15 )(q11.2) chr15:g.22740001_23060000del 0.32 VOUS Severe VM, polycystic kidney, and short right arm P27 31 del( 17 )(p13.3p13.3) chr17:g.20000_2740000del 2.72 P Moderate VM, narrow clear space, and lissencephaly P28 21 del( 22 )(q11.21q11.21) chr22:g.18772431_21350683del 2.58 P Moderate VM and hydropericardium P31 27 del( 12 )(q23.1q23.1) chr12:g.99789704_100215808del 0.42 VOUS Mild VM and callosal dysplasia P38 21 del( 18 )(q21.2q23) chr18:g.52600000_78020000del 25.42 P Mild VM dup( 8 )(q24.22q24.3) chr8:g.132680000_146300000dup 13.62 LP P39 28 dup( 9 )(q21.13q21.2) chr9:g77040000_79300000dup 2.26 VOUS Mild VM and polyhydramnios P47 28 del( 17 )(q21.2q21.2) chr17:g.38504567_40767059del 2.26 P Mild VM P52 27 del( 15 )(q11.2q13.1) chr15:g.23461770_28702646del 5.24 P Mild VM P57 31 del( 15 )(q13.2q13.3) chr15:g.30548906_32750325del 2.2 P Mild VM, wide extracerebral space, abnormal pituitary signals (Rathke's cleft cyst?), esophageal atresia, polyhydramnios, and single umbilical artery P64 24 dup( 1 )(q21.1q44)(mos) chr1:g.144000000_249220000dup 105.22 P Mild VM, micromandible, small ears, and polycystic kidney P65 19 dup( 5 )(q35.2q35.3) chr5:g.175780000_177440000dup 1.66 P Mild VM, NT 0.32 cm, and NF 0.63 cm del( 5 )(q14.2q14.3) chr5:g.81840000_83120000del 1.28 VOUS P67 29 del( 16 )(p13.3) chr16: g.854532_2080377del 1.226 LP Mild VM, ventricular septal defect, left temporoparietal extracerebral space is wide, abnormal pituitary morphology and signals, and adenohypophyseal protuberance P69 24 del( 2 )(q12.1q13) chr2:g.105300000_110880000del 5.58 VOUS Mild VM GA, gestational age; VM, ventriculomegly; P, pathogenic; LP, likely pathogenic; VOUS, variants of uncertain significance; NT, nuchal translucency; NF, nuchal fold. Results of WES Of the 33 pregnancies that underwent WES analysis, 16 (48.48%) had a positive result. In cases of identified SGD among 33 pregnancies, prenatal IVM samples (n = 6) revealed mutations in SPATA5 , PDHA1, TRIM71 , PIK3R2 , PIDD1 , and MACF1 genes. Of these, SPATA5 c.544delA(exon5), PDHA1 c.273(exon3)T > A, TRIM71 c.1799(exon4)G > A, PIDD1 c.1855(exon11)A > G, and MACF1 c.18597(exon74)_c.18600(exon74)delCAAA were novel variant loci not previously reported. Furthermore, prenatal NIVM (n = 10) samples revealed mutations in PDHA1, TUBB , CRB2 , FGFR3 , RTTN , AIMP1 , POGZ , MYH7 , CNOT3 , and PURA genes. Of these, CRB2 c.3078(exon10)_c.3093(exon10)delGGCGCGGCCCCGGCCC, AIMP1 c.187(exon3)A > T andc.110(exon3)delT, POGZ c.3406dupG, and MYH7 c.3133(exon25)C > A were novel variant loci not previously reported. Moreover, patients P14 (NIVM) and P18 (IVM) were found to have a pyruvate dehydrogenase E1-α deficiency (PDHAD) (Table 4 ). Table 4 Cases with a positive result following WES analysis and their clinical phenotypes ID GA Gene Variant Classification Disease, inheritance model Ultrasound/ MRI findings P8 25 SPATA5 c.544(exon5)delA, Het LP Neurodevelopmental disorder with hearing loss, seizures and brain abnormalities; NEDHSB (OMIM: 616577), AR Moderate VM and higher white matter T2W1 signals in the body of bilateral ventricles c.1678(exon9)G > A, Het VOUS P14 24 PDHA1 c.273(exon3)T > A, Het P Pyruvate dehydrogenase E1-α deficiency; PDHAD (OMIM: 312170), XD Severe VM and callosal dysplasia P15 26 TRIM71 c.1799(exon4)G > A, Het LP Hydrocephalus, congenital 4; HYC4 (OMIM:618667), AD Moderate VM P18 23 PDHA1 c.409(exon4)G > A, Het LP Pyruvate dehydrogenase E1-α deficiency; PDHAD (OMIM: 312170), XD Moderate VM P20 31 PIK3R2 c.1117(exon10)G > A P Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1; MPPH1 (OMIM: 603387), AD Severe VM P22 30 TUBB c.217(exon3)A > G, De novo , Het LP Complex cortical dysplasia with other brain malformations6, CDCBM6, (OMIM: #615771), AD Moderate VM and suboptimal lateral ventricular morphology. Low bilateral frontoparietal white matter T1W1 signal, high T2W1 signal, and high bilateral pallidal T1W1. Hemivertebral deformity with irregular morphology of the thoracic vertebrae at 8 and 9 and disc signal abnormalities. P24 30 CRB2 c.3078(exon10)_c.3093(exon10)delGGCGCGGCCCCGGCCC, Het LP Ventriculomegaly with cystic kidney disease; VMCKD (OMIM: 219730), AR Severe VM and birenal echo enhancement c.1960(exon8)G > C, Het VOUS P44 33 PIDD1 c.1855(exon11)A > G, Het VOUS Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly; MRT75 (OMIM: 619827), AR Mild VM c.103(exon2)G > A, Het VOUS P49 33 RTTN c.2101(exon16)C > T, Het LP microcephaly, short stature, and polymicrogyria with or without seizures; MSSP (OMIM: 614833), AR Mild VM, clear septal stenosis, and fetal development is 2 weeks less than GA c.2863(exon22)G > A, Het VOUS P51 28 FGFR3 c.1620(exon12)C > A, Het P Thanatophoric dysplasia, type I; TD1 (OMIM: #187600), AD Achondroplasia, ACH; (OMIM: #100800), AD Mild VM and long bones of limbs compared to small gestations P54 26 AIMP1 c.187(exon3)A > T, Het P Leukodystrophy, hypomyelinating 3; HLD3 (OMIM: 260600), AR Mild VM, atrial septal defect, and ventricular septal defect c.110(exon3)delT, Het P P60 19 POGZ c.3406dupG, Het LP White-Sutton syndrome; WHSUS (OMIM: 616364), AD Mild VM and club foot P61 21 MYH7 c.3133(exon25)C > A, Het LP Cardiomyopathy, dilated, 1S; CMD1S (OMIM: 613426), AD Mild VM, small chest, oligohydramnios, fetal development is 3 weeks less than GA, and membranaceous placenta P63 30 CNOT3 c.2248(exon18)C > T, Het LP Intellectual developmental disorder with speech delay, autism, and dysmorphic facies; IDDSADF (OMIM: 618672), AD Mild VM and callosal dysplasia P66 24 MACF1 c.18597(exon74)_c.18600(exon74)delCAAA, Het LP Lissencephaly 9 with complex brainstem malformation; LIS9 (OMIM: 618325), AD Mild VM P72 29 PURA c.367(exon1)C > T, Het P Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties; NEDRIHF (OMIM: 616158), AD Mild VM, suboptimal lateral ventricular morphology, and left frontal lobe T2W1 and FLAIR showed hypointense signals AD, autosomal dominant; AR, autosomal recessive; XD, X-linked dominant; Het, heterozygous; P, pathogenic; LP, likely pathogenic; VOUS, variants of uncertain significance. Chromosome aberrations and gene variations in different fetal VM groups When comparing the positive and negative results following CNV-seq and WES, the chromosomal aberration detection rates were comparable within groups with the exception of a positive result in the CNV-seq group. In this group, NIVM showed a significantly higher detection rate relative to IVM (43.2% vs. 19.4%, p < 0.05, Fig. 2 ). Next, NIVMs were examined within the positive and negative result CNV-seq and WES groups in conjunction with other abnormalities. The results showed that 58.3% (7/12) of chromosomal aberrations and 55.6% (5/9) of genetic variants are present in combination with skeletal system abnormalities (Table 5 ). Table 5 Chromosomal aberrations and genetic variation in NIVM. CNV-seq (n = 37) WES (n = 20) Total positive negative Total positive negative Single system 23 7 16 14 6 8 ≥ 2 systems 14 9 5 6 4 2 CNS 11 5 6 10 5 5 cardiovascular system 10 5 5 2 1 1 Digestive system 2 1 1 2 1 1 Urinary system 4 2 2 1 1 0 Skeletal system 12 7 5 9 5 4 Others 11 5 6 3 1 2 Others include thickened nuchal fold, nuchal fold thickening, wide eyelids, polyhydramnios, and oligohydramnios. Follow-up outcomes Postnatal follow-ups were performed for 3 months to 3 years after pregnancy. Of the patients with a positive result following CNV-seq, 16 chose to terminate the pregnancy and 7 delivered alive. Of the live births, 6 had postpartum developmental delays and 1 had Klinefelter syndrome, which presented with wide eyelids, external ear malformation, hearing impairment and cryptorchidism. Of patients with a positive result following WES, 9 chose to terminate the pregnancy and 7 delivered alive. These gradually exhibited the clinical phenotype associated with their corresponding SGD at postnatal follow-ups. For patients that had a negative result following CNV-seq, 17 also had a negative result following WES, and 17 declined further testing following CNV-seq. Of these patients, 10 selected to terminate pregnancy and 24 delivered alive without incident. Even in patients who tested negative for both CNV-seq and WES, there were 5 cases with a poor postnatal outcome, including 1 case of premature death and 4 cases of developmental delay. DISCUSSION The aim of this study was to further evaluate the contribution of genetic etiology in fetal VM. When evaluating the entire VM cohort (n = 73), a chromosomal aberration rate of 31.5%(23/73) was observed, with 12 of those cases belonging to the P classification within the positive result following CNV-seq (12/23). Furthermore, relatively high aberration frequencies were noted in chromosomes 1, 15, 17 and 22, including 1q21.1 recurrent deletion, Prader-Willi syndrome, Koolen-de Vries syndrome, and 22q11.2 deletion syndrome. For the children diagnosed with 22q11.2 deletion syndrome (P11 and P28), both presented with moderate VM and cardiac abnormalities, which is consistent phenotype based on previous reports 6 . In 22q11.2 deletion syndrome (also known as DiGeorge syndrome and Velocardiofacial syndrome), multiple genes are affected, including the critically important TBX1 and DGCR8 genes. The TBX1 gene encodes the transcription factor T-box and the DGCR8 gene mediates miRNA biogenesis and plays a critical role in the normal development of multiple organ systems. During the development of the nervous system, a loss or mutation of these genes leads to aberrant neural progenitor proliferation and differentiation, with subsequent neuronal defects affecting the development and morphology of the fetal lateral ventricle to results in the development of VM 7–9 . It is still unclear whether there are differences in chromosomal aberration detection rates when comparing mild, moderate, or severe fetal VM, but NIVMs have been shown to be more commonly associated with chromosomal abnormalities relative to IVMs (9.5–36% vs. 1.5–12.0%) 10–13 . Consistent with previous studies, the rate of chromosomal aberration was significantly higher in NIVM than in IVM, thus further confirming that NIVM comes with an increased risk of chromosomal aberrations. We found 58.3% (7/12) of chromosomal aberrations of NIVMs were associated with skeletal system abnormalities, thus, we should note the possibility of chromosomal aberrations in fetal VM with multiple malformations, especially skeletal system. However, when comparing chromosome aberration detection rates between mild and moderate-to-severe VM, no significant difference was determined. These findings indicate that regardless of the extent of the widening, patients should be informed of the risk of chromosome aberration and further prenatal diagnostics advised. Recently, several studies have strongly suggested an increasingly closer relationship between VM and gene mutations 14,15 . This has in part been due to the rapid development of second-generation sequencing technologies that have enabled the diagnostic process to transition from low-depth CNV-seq analysis to WES. Furthermore, ACMG guidelines suggest that exome or genome sequencing be considered as a primary or secondary diagnostic tool in patients with congenital anomalies 16 . WES, a high-throughput genetic platform, allows the simultaneous detection of coding regions from thousands of genes, and can comprehensively and rapidly identify potential genetic variants associated with fetal VM; thus providing a more accurate clinical diagnosis and enabling a more informed genetic counseling 17,18 . While using WES to assess fetal structural abnormalities isn’t new, most fetal VM studies have been limited to SGD case reports or cohort studies examining karyotypes and CNVs. The strength of this study is that we combined a negative CNV with WES while categorizing the patients. This approach enabled a further diagnostic assessment and the ability to identify genes associated with ventricular widening, examine VM in conjunction with other structural abnormalities, and assess the contribution of SGD to fetal VM. Herein, WES was shown to effectively improve the chromosomal abnormality detection rate in VM fetuses, with 48.5% of SGD identified independent of CNV-seq. Fetal VM is seen as an indicator of other genetic syndromes in the majority of cases, while SGDs causing IVM is uncommon, L1CAM , AP1S2 , MPDZ and CCDC88C genes have been previously recognized as causally related to VM; while TRIM71 , SMARCC1 , PIK3CA , PTEN , MTOR , FOXJ1 , FMN2, PTCH1 and FXYD2 have been identified as VM risk genes 14 . Herein, within the 16 WES-positive cases, SGDs were the main manifestation, with SPATA5 , TRIM71 , PIK3R2 , PIDD1 , MACF1 and PDHA1 variations discovered in the IVM group and TUBB , CRB2 , FGFR3 , RTTN , AIMP1 , POGZ , MYH7 , CNOT3 , PURA and PDHA1 discovered in the NIVM group. Few previous reports have focused on the prenatal diagnosis of these genetic variant-related disorders, and our study confirms that VM can serve as an indicator for prenatal phenotypic examination. Meanwhile, the present study discovered 9 previously unreported gene variant loci, thus expanding the variant spectrum of relevant genes. Furthermore, WES-positive NIVM cases were predominantly associated with CNS and skeletal system abnormalities, while there was no significant difference in the detection rate when comparing the different VM degrees. Moreover, even when considering the CNV-seq results, the possibility of a chromosomal or genetic abnormality appears to be independent of the VM degree. Additionally, in the 2 patients with PDHAD (P14 and P18), one had moderate IVM and the other had severe VM combined with callosal dysplasia. While a PDHAD prenatal diagnosis is less commonly reported, 91.7% of these patients have been found to have prenatal manifestations 19 . Thus, it is possible that VM may be a predominant prenatal manifestation of PDHAD, and that the PDHA1 gene may also be a candidate gene for VM risk. But this would require further examination. Prenatal WES can identify potential SGD and facilitate perinatal decision-making and management, but it also presents new challenges in data interpretation and genetic heterogeneity analysis. Furthermore, the presence of VOUS also poses problems in prenatal counseling, particularly due to nonspecific fetal phenotypes, and can increase the uncertainty in clinical management and cause severe parental anxiety. While this study has provided some helpful insights, it has several limitations, including a relatively small sample size and the absence of a systematic evaluation for parents included in the study. Furthermore, fetal ultrasounds often fail to identify subtle abnormalities, therefore certain phenotypes cannot be identified during a conventional prenatal screening. In some cases, it is also difficult to detect neurological developmental abnormalities in children due to insufficient follow-up exams. In the future, we will attempt to recruit patients where a longer follow-up time can be achieved to more fully characterize fetal VM outcomes. In conclusion, our study highlights the importance of genetic etiology in fetal VM, and shows WES can effectively improve the diagnostic rate of fetal VM and associated abnormalities. Moreover, this study shows that genetic and imaging findings, when combined with a multidisciplinary evaluation, are essential for providing effective clinical management of VM fetuses during pregnancy. METHODS Samples Second and third trimester fetuses with a lateral ventricular width ≥ 10 mm, as determined via ultrasound or fetal cranial MRI, were selected from the Shanxi Provincial Children's Hospital, Taiyuan, China between 2020 and 2023. This study underwent a medical ethics review of Shanxi Children's Hospital of China (IRB-KYHZ-2019-006). Informed consent for testing was obtained from the patient's parents. All research was performed in accordance with the guidelines and regulations of the review board and the publisher to ensure the scientific and reliability of the research methodology. Fetuses with VM that could be associated with environmental factors such as infection, drug toxicity, environmental radiation, or chemical exposure were excluded. Clinical data for the selected cohort (n = 73) were obtained, and amniotic fluid (20 ml) or miscarriage tissue, either fetal skin-muscle (2 cm length) or umbilical cord (3 cm length) were collected. The samples were subjected to QF-PCR, and maternal contamination was excluded by detection of genetically marked short tandem repeats (STRs) Patients were divided into mild VM (10–12 mm) and moderate-to-severe VM (> 12 mm) groups, and further divided into IVM and NIVM. Patient samples were screened via CNV-seq and those with negative results were subsequently screened via WES. The pregnancy outcomes were followed by telephone, including whether the child was born and whether there were any abnormal findings after birth. Ultrasound examination and MRI According to the guidelines of the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) 20 , the ultrasound physician performed a prenatal ultrasound scan using a 2.5–5 MHz transabdominal transducer and a color doppler ultrasound instrument (GE Voluson E8, GE Healthcare, USA) to determine the presence of VM. Fetal MRIs were performed by an experienced operator using a 3.0T scanner (Ingenia, Philips Medical Systems, Netherlands), with the transverse diameter of the ventricular triangle on both sides measured in addition to examining the CNS for other abnormalities. Extraction of genomic DNA and genomic DNA library preparation TIANamp Micro DNA Kit (DP316, TIANGENBIOTECH, China) was used to extract DNA from fetal amniotic fluid or miscarried fetal tissues according to the manufacturer's protocol. DNA purity and concentration were evaluated using Qubit 2.0 fluorimeter (Thermo Fisher Scientific, USA) and electrophoresis with 0.8% agarose gel. A OD 260 /OD 280 ratio of 1.8–2.0 was deemed pure and concentrations were determined to be between 50–100 ng/L. DNA library preparation was performed according to Supplementary Material 1 using Chigene Library Prep Kitas (Beijing Chigene, China) and prepared library should meet the following requirements: concentration (Qubit 2.0: 25 uL, > 15 ng/uL); effective molecular concentration (q-PCP: 25 uL, > 10 nM); DNA fragment (Agilent 2100 detection: main peak 430bp, range 300-600bp). Copy-number variation sequencing (CNV-seq) Sequencing was performed using DNBSEQ-T7 sequencer (PE150, MGI Techdocs, China) and approximately 5 million sequencing reads per sample were mapped to the NCBI Human Reference Genome (hg19 / GRCh37) by Burrows-Wheeler Aligner (BWA) tool and then assigned to a 20 kb sequencing bin for sliding at 5 kb. CNV fragments were then analyzed and annotated using Decipher, OMIM, and ClinVar, with frequencies evaluated based on DGVs. CNV pathogenicity was then determined based on the American College of Medical Genetics and Genomics (ACMG) guidelines using the following classifications: pathogenic (P), likely pathogenic (LP), variants of uncertain significance (VOUS), LB (Likely benign), and B (Benign) 21 . Whole-exome sequencing (WES) Protein-coding exome enrichment was performed using xGen Exome Research Panel v2.0(IDT, Iowa, USA) that consists of 429,826 individually synthesized and quality-controlled probes, which targets 39 Mb protein-coding region (19,396 genes) of the human genome and covers 39 Mb of end-to-end tiled probe space. High-throughput two-end sequencing was performed using DNBSEQ-T7 sequencer with 150 bp paired-end reads, and not less than 99% of target sequence were sequenced. The raw data (fq/vcf format data) was imported through the Chigene Genetic Diseases Analysis Cloud platform, combined with major databases (dbSNP, ExAC, ESP, OMIM, HGMD, and ClinVar, etc.) for interpretation, then analyzed using Provean, SIFT, PolyPhen and Mutationtaster to predict loss- or gain-of-function. Gene loci with higher combined scores were then classified according to the 2015 ACMG guidelines as described above 21 . Follow-up of pregnancy outcomes A multidisciplinary team of sonologists, prenatal diagnostic departments, and pediatric neurology comprehensively assessed the prognosis of fetuses with CNS abnormalities to inform parents. Postnatal patient outcomes were tracked for 3 months to 3 years by telephone and electronic medical record systems. Statistical analyses Statistical analysis was performed using Statistical Package for the Social Sciences version 23 (SPSS Inc, Chicago, IL, USA). Categorical variables are expressed as frequencies (percentages) and compared using the Pearson χ test or the Fisher’s exact test, with p < 0.05 deemed statistically significant. Declarations Financial support. Research Project Supported by Shanxi Scholarship Council of China(2023-180); Medical Genetics Research Committee Key Laboratory of Shanxi Province “2021 “Four Batch” Science and Technology Innovation Program”(2021SYS24); Shanxi Province Health and Wellness Committee Funded Project(2023016). Potential conflicts of interest. All authors declare no competing interests. Author Contributions. Zhao Chenyue conducted design research methods, experimental design, writing articles, etc. Xue Huiqin is responsible for the overall supervision and coordination of the study to ensure the integrity and accuracy of the study. Gao Jingbo conducted experimental design, writing articles, etc. Guo Min assisted in data collection. Yue Hao assisted with article typesetting. Guo Rong assisted in data collection, processing and analysis. Cao Guizhi assisted in data collection. Sun Xiayu assisted in data analysis. Wu Jianrui assisted in data analysis. Data availability statement. The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request. Ethics statement. This study underwent a medical ethics review of Shanxi Children's Hospital of China (IRB-KYHZ-2019-006). Informed consent for testing was obtained from the patient's parents. References Society for Maternal-Fetal, M. et al. Fetal ventriculomegaly. Am J. Obstet Gynecol . 223 , B30-B33 (2020). Mirsky, D. M., Stence, N. V., Powers, A. M., Dingman, A. L. & Neuberger, I. Imaging of fetal ventriculomegaly. Pediatr Radiol. 50 , 1948-1958 (2020). Pisapia, J. M., Sinha, S., Zarnow, D. M., Johnson, M. P. & Heuer, G. G. Fetal ventriculomegaly: Diagnosis, treatment, and future directions. Childs Nerv Syst . 33 , 1113-1123 (2017). Ryan, G. A. et al. Prenatal findings and associated survival rates in fetal ventriculomegaly: A prospective observational study. Int J. Gynaecol Obstet . 159 , 891-897 (2022). Shreeve, N. et al. Incremental yield of whole‐genome sequencing over chromosomal microarray analysis and exome sequencing for congenital anomalies in prenatal period and infancy: systematic review and meta‐analysis. Ultrasound Obstet Gynecol . 63 , 15-23 (2024). Blagowidow, N. et al. Prenatal screening and diagnostic considerations for 22q11.2 microdeletions. Genes . 14 , 160 (2023). Hiramoto, T. et al. Tbx1, a gene encoded in 22q11.2 copy number variant, is a link between alterations in fimbria myelination and cognitive speed in mice. Mol Psychiatry . 27 , 929-938 (2022). Merico, D. et al. MicroRNA dysregulation, gene networks, and risk for schizophrenia in 22q11.2 deletion syndrome. Front Neurol . 5 , 238 (2014). Zinkstok, J. R. et al. Neurobiological perspective of 22q11.2 deletion syndrome. The Lancet Psychiatry . 6 , 951-960 (2019). Duan, H. L. et al. The application of chromosomal microarray analysis to the prenatal diagnosis of isolated mild ventriculomegaly. Taiwan J. Obstet Gynecol . 58 , 251-254 (2019). Santirocco, M. et al . Chromosomal microarray analysis in fetuses with central nervous system anomalies: An 8-year long observational study from a tertiary care university hospital. Prenat Diagn . 41 , 123-135 (2021). Gezer, C. et al. Chromosome abnormality incidence in fetuses with cerebral ventriculomegaly. J. Obstet Gynaecol. 34 , 387-391 (2014). Lok, W. Y. et al. Chromosomal abnormalities and neurological outcomes in fetal cerebral ventriculomegaly: a retrospective cohort analysis. Hong Kong Med J . 27 , 428-436 (2021). Jin, S. C. et al. Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus. Nat Med . 26 , 1754-1765 (2020). Hale, A. T. et al. The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact. Fluids Barriers CNS . 21 , 24 (2024). Manickam, K. et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med . 23 , 2029-2037 (2021). Giorgione, V., Haratz, K. K., Constantini, S., Birnbaum, R. & Malinger, G. Fetal cerebral ventriculomegaly: What do we tell the prospective parents? Prenat Diagn . 42 , 1674-1681 (2022). Baptiste, C. et al. Fetal central nervous system anomalies: When should we offer exome sequencing? Prenat Diagn . 42 , 736-743 (2022). Jiao, J. et al . Prenatal diagnosis of pyruvate dehydrogenase E1-α deficiency: a case report. Chin J. Perinat Med . 26 , 246-249 (2023). Salomon, L. J. et al. ISUOG Practice Guidelines (updated): performance of the routine mid‐trimester fetal ultrasound scan. Ultrasound Obstet Gynecol . 59 , 840-856 (2022). Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med . 17 , 405-424 (2015). Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial.docx Cite Share Download PDF Status: Published Journal Publication published 02 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 08 Jul, 2024 Editor assigned by journal 25 Jun, 2024 Editor invited by journal 11 Apr, 2024 Submission checks completed at journal 11 Apr, 2024 First submitted to journal 04 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4215892","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":291516403,"identity":"fa25d60e-6755-48e8-8277-3ae2ae579fba","order_by":0,"name":"Zhao Chenyue","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhao","middleName":"","lastName":"Chenyue","suffix":""},{"id":291516404,"identity":"5b4fb847-b7c5-4d1c-81aa-27847dd7e3c9","order_by":1,"name":"Xue Huiqin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIie3RPQrCMBTA8SeFZHmoY6SCV2gptAhFr6IU6hKcFQcHwakHUPQcnVsKutS9bn6Akw5eQEy72SHt6JD/lpAfySMAKtV/RgBmDHs0KFbYrEdSt2sGKUAkCKlFGmvfhYwXBCqJw7h9eZIEG9tXfH/zQZeAdr1lEtLf+BNzjwlSfeoZceiJhxHL4hJiZN5BRyZu2XGbxaEmCBJdTsZrHY0E4ZzmZFmH5LeMfIQMc5JUk37w8Dv7yEUz4JZxCo9ItIpZHCpGeH3YsEdT8zIPF8MWXV3v0oe1R+L7frY0yfGCtKIyUalUKlWpL+qLRFDJzgxNAAAAAElFTkSuQmCC","orcid":"","institution":"Children’s Hospital of Shanxi, Women Health Center of Shanxi","correspondingAuthor":true,"prefix":"","firstName":"Xue","middleName":"","lastName":"Huiqin","suffix":""},{"id":291516405,"identity":"6e6e91e9-b696-4776-80e6-fe4ec52f1d3d","order_by":2,"name":"Gao Jingbo","email":"","orcid":"","institution":"Children’s Hospital of Shanxi, Women Health Center of Shanxi","correspondingAuthor":false,"prefix":"","firstName":"Gao","middleName":"","lastName":"Jingbo","suffix":""},{"id":291516406,"identity":"7b2ab018-5abb-4ffb-b8cd-e71938a39316","order_by":3,"name":"Guo Min","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Guo","middleName":"","lastName":"Min","suffix":""},{"id":291516407,"identity":"8fc2f662-17d0-4814-b312-4dd84d5d3742","order_by":4,"name":"Yue Hao","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Hao","suffix":""},{"id":291516408,"identity":"80224bda-5257-4ed5-9706-571b4254833e","order_by":5,"name":"Guo Rong","email":"","orcid":"","institution":"Children’s Hospital of Shanxi, Women Health Center of Shanxi","correspondingAuthor":false,"prefix":"","firstName":"Guo","middleName":"","lastName":"Rong","suffix":""},{"id":291516409,"identity":"4fc33238-58bf-4036-8be8-9055e343dd43","order_by":6,"name":"Cao Guizhi","email":"","orcid":"","institution":"Children’s Hospital of Shanxi, Women Health Center of Shanxi","correspondingAuthor":false,"prefix":"","firstName":"Cao","middleName":"","lastName":"Guizhi","suffix":""},{"id":291516410,"identity":"e539af4a-f685-46db-b6bf-47a224d3e801","order_by":7,"name":"Sun Xiayu","email":"","orcid":"","institution":"Children’s Hospital of Shanxi, Women Health Center of Shanxi","correspondingAuthor":false,"prefix":"","firstName":"Sun","middleName":"","lastName":"Xiayu","suffix":""},{"id":291516411,"identity":"61af3050-7fc4-4705-b19f-8f4240774f34","order_by":8,"name":"Wu Jianrui","email":"","orcid":"","institution":"Children’s Hospital of Shanxi, Women Health Center of Shanxi","correspondingAuthor":false,"prefix":"","firstName":"Wu","middleName":"","lastName":"Jianrui","suffix":""}],"badges":[],"createdAt":"2024-04-04 06:12:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4215892/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4215892/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-06714-2","type":"published","date":"2025-07-02T15:57:28+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":54997807,"identity":"a3aaa47d-02da-49eb-9a4e-17d401a93722","added_by":"auto","created_at":"2024-04-19 18:14:14","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":27470,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of imaging diagnosis pathway\u003c/p\u003e\n\u003cp\u003ePathogenic (P), likely pathogenic (LP), and variants of uncertain significance (VOUS).\u003c/p\u003e","description":"","filename":"Picture42.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4215892/v1/d4c87fc8f41cbc8613c58d50.jpg"},{"id":54997808,"identity":"df1c2ee8-7595-43d9-a0db-242d384cd4f2","added_by":"auto","created_at":"2024-04-19 18:14:14","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":23553,"visible":true,"origin":"","legend":"\u003cp\u003eResults of genetic tests for different fetal VM types.\u003c/p\u003e","description":"","filename":"Picture43.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4215892/v1/8495b0416a0cb2aefc730778.jpg"},{"id":86179715,"identity":"6788abd1-7a06-49e1-b5c9-51cccbd89557","added_by":"auto","created_at":"2025-07-07 16:18:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1083736,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4215892/v1/705f3e99-7a27-4e3c-8615-3a3cca7e735a.pdf"},{"id":54997809,"identity":"9a68075b-e335-460b-ac77-19ce6a4d2a1d","added_by":"auto","created_at":"2024-04-19 18:14:14","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":121604,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4215892/v1/e77cdcf57797cd81f7e49b7e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Genetic etiology analysis of 73 fetuses with ventriculomegaly","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eDuring prenatal screenings, birth defects associated with the central nervous system (CNS) are of particular concern, with ventriculomegaly (VM) being the most common sonographic CNS abnormality detected. This condition is characterized by an enlargement of ventricles within the brain and is closely associated with cognitive and/or psychomotor skill developmental delays. To determine the presence of VM, lateral ventricular width measurements are obtained via prenatal ultrasonography, with a normal average lateral ventricular width during the second and third trimesters (14\u0026ndash;40 weeks gestation) being 5.4\u0026ndash;7.6 mm; while a width\u0026thinsp;\u0026gt;\u0026thinsp;10 mm is classified as VM. Fetal VM is divided into three groups according to the ventricular diameter: mild (10\u0026ndash;12 mm), moderate (12\u0026ndash;15 mm), and severe (\u0026gt;\u0026thinsp;15 mm)\u003csup\u003e1,2\u003c/sup\u003e, and into two groups according to whether combined with other abnormal findings: isolated VM (IVM) and non-isolated VM (NIVM). There are three predominant causes of fetal VM, including brain parenchymal loss, cerebrospinal fluid obstruction, or excessive cerebrospinal fluid secretion. In some cases, the development of VM can be associated with genetic factors, such as chromosomal aberrations and genetic variations, or maternal factors, such as an infection with cytomegalovirus or toxoplasmosis during pregnancy\u003csup\u003e3\u003c/sup\u003e. VM has complex neurodevelopmental outcomes ranging from a normal physiology to serious complications that lead to death, with chromosomal abnormalities or single-gene defects (SGD) associated with a poor prognosis\u003csup\u003e4\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn addition to traditional non-invasive prenatal testing (NIPT), genetic screening is increasingly being utilized to detect abnormalities via karyotyping, copy number variation sequencing (CNV-seq), whole exome sequencing (WES), or by examining fetal and parental variations simultaneously using trio-WES\u003csup\u003e5\u003c/sup\u003e. Combining genetic examination with clinical and neurologic imaging findings can improve predictive outcomes, improve VM patient management, improve VM classification accuracies, predict neurocognitive outcomes, and stratify patients into treatment plans. Moreover, this combined approach may help identify possible VM genetic mutation sites, establish effective clinical management during pregnancy, provide meaningful guidance for prenatal counseling in affected families, reduce birth defects, and provide guidance for subsequent pregnancies. However, few studies have combined CNV-seq and WES in fetal VM. As such, the primary aim of this study was to examine the contributions of chromosomal and genetic abnormalities to the etiology of fetal VM while also assessing the genetic diagnostic capacity of WES in the VM fetal.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eOf the patients that met the inclusion criteria (n\u0026thinsp;=\u0026thinsp;73), 33 patients had no detectable CNVs following CNV-seq.\u0026nbsp;Thus, this cohort underwent further evaluation via WES. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the flow and results of the genetic analysis for the study cohort.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDemographics, VM characteristics and sequencing information for the study cohort are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median maternal age was 29 (range, 22\u0026ndash;42) years, and the fetuses were assessed at a median gestational age of 25 (range, 17\u0026ndash;33) weeks.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and clinical characteristics and sequencing information for 73 fetuses with ventriculomegaly.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal age (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (22\u0026ndash;42)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age at diagnosis (weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (17\u0026ndash;33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eVM type\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate-to-severe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNIVM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eGenetic sequencing\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCNV-seq\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eData are given as median (range). VM, ventriculomegly; IVM, isolated VM; NIVM, non-isolated VM, CNV-seq, copy number variation sequencing; WES, whole exome sequencing.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eResults of CNV-seq\u003c/h3\u003e\n\u003cp\u003eOf the 73 fetal samples that underwent CNV-seq analysis, 23 (31.5%) had chromosomal abnormalities with 26 CNV fragments were detected, including aneuploidy (n\u0026thinsp;=\u0026thinsp;4, 5.5%) and the AMCG classifications P (n\u0026thinsp;=\u0026thinsp;12), LP (n\u0026thinsp;=\u0026thinsp;2), and VOUS (n\u0026thinsp;=\u0026thinsp;8). Of these, 3 patients presented with 2 CNV fragments, with classifications of P and VOUS for patients P11 and P65, and P and LP for patient P38. Relatively high aberration frequencies were noted in chromosomes 1, 15, 17 and 22 (Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAneuploidies identified by CNV-seq in the study cohort\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eID\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAneuploidy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUltrasound/ MRI findings\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTrisomy 21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMild VM and NF 0.66 cm\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eKlinefelter syndrome (47, XXY)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMild VM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTriploidy (69, XXX)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMild VM, cerebellar morphology is irregular, clear septum not shown, poor spine and sacrum tail alignment, and oligohydramnios\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTrisomy 18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMild VM, ventricular septal defect and abnormal development of the left upper limb\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eGA, gestational age; VM, ventriculomegly; NF, nuchal fold.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePositive results following CNV-seq analysis and their clinical phenotypes.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eID\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCopy-number variant (hg19)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSize (Mb)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClassification\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUltrasound/ MRI findings\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)(p13.2)\u003c/p\u003e \u003cp\u003echr19:g.12740000_13420000del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSevere VM and club foot\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)(q36.3q37.3)\u003c/p\u003e \u003cp\u003echr2:g.229040000_243020000del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eModerate VM, nasal bones not shown, single umbilical artery, and polyhydramnios\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)(q11.21q11.21)\u003c/p\u003e \u003cp\u003echr22:g.18880000_21480000del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eModerate VM, right atrium and right ventricular enlargement, and micromandible\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edup(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)(p26.1p26.1)\u003c/p\u003e \u003cp\u003echr3:g.6120000_7240000dup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVOUS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)(p32.1p31.3)\u003c/p\u003e \u003cp\u003echr1:g.59040000_67720000del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eModerate VM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edup(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)(q23)\u003c/p\u003e \u003cp\u003echr15:g.67940001-68290000dup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVOUS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSevere VM and oligohydramnios\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edup(X)(q21.33)\u003c/p\u003e \u003cp\u003echrX:g.93880000_94520000dup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVOUS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSevere VM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)(q11.2)\u003c/p\u003e \u003cp\u003echr15:g.22740001_23060000del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVOUS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSevere VM, polycystic kidney, and short right arm\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)(p13.3p13.3)\u003c/p\u003e \u003cp\u003echr17:g.20000_2740000del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eModerate VM, narrow clear space, and lissencephaly\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)(q11.21q11.21)\u003c/p\u003e \u003cp\u003echr22:g.18772431_21350683del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eModerate VM and hydropericardium\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)(q23.1q23.1)\u003c/p\u003e \u003cp\u003echr12:g.99789704_100215808del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVOUS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMild VM and callosal dysplasia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)(q21.2q23)\u003c/p\u003e \u003cp\u003echr18:g.52600000_78020000del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMild VM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edup(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)(q24.22q24.3)\u003c/p\u003e \u003cp\u003echr8:g.132680000_146300000dup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edup(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)(q21.13q21.2)\u003c/p\u003e \u003cp\u003echr9:g77040000_79300000dup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVOUS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMild VM and polyhydramnios\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)(q21.2q21.2)\u003c/p\u003e \u003cp\u003echr17:g.38504567_40767059del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMild VM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)(q11.2q13.1)\u003c/p\u003e \u003cp\u003echr15:g.23461770_28702646del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMild VM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)(q13.2q13.3)\u003c/p\u003e \u003cp\u003echr15:g.30548906_32750325del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMild VM, wide extracerebral space, abnormal pituitary signals (Rathke's cleft cyst?), esophageal atresia, polyhydramnios, and single umbilical artery\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edup(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)(q21.1q44)(mos)\u003c/p\u003e \u003cp\u003echr1:g.144000000_249220000dup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e105.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMild VM, micromandible, small ears, and polycystic kidney\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edup(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)(q35.2q35.3)\u003c/p\u003e \u003cp\u003echr5:g.175780000_177440000dup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMild VM, NT 0.32 cm, and NF 0.63 cm\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)(q14.2q14.3)\u003c/p\u003e \u003cp\u003echr5:g.81840000_83120000del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVOUS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)(p13.3)\u003c/p\u003e \u003cp\u003echr16: g.854532_2080377del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.226\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMild VM, ventricular septal defect, left temporoparietal extracerebral space is wide, abnormal pituitary morphology and signals, and adenohypophyseal protuberance\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edel(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)(q12.1q13)\u003c/p\u003e \u003cp\u003echr2:g.105300000_110880000del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVOUS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMild VM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eGA, gestational age; VM, ventriculomegly; P, pathogenic; LP, likely pathogenic; VOUS, variants of uncertain significance; NT, nuchal translucency; NF, nuchal fold.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eResults of WES\u003c/h3\u003e\n\u003cp\u003eOf the 33 pregnancies that underwent WES analysis, 16 (48.48%) had a positive result. In cases of identified SGD among 33 pregnancies, prenatal IVM samples (n\u0026thinsp;=\u0026thinsp;6) revealed mutations in \u003cem\u003eSPATA5\u003c/em\u003e, \u003cem\u003ePDHA1, TRIM71\u003c/em\u003e, \u003cem\u003ePIK3R2\u003c/em\u003e, \u003cem\u003ePIDD1\u003c/em\u003e, and \u003cem\u003eMACF1\u003c/em\u003e genes. Of these, \u003cem\u003eSPATA5\u003c/em\u003e c.544delA(exon5), \u003cem\u003ePDHA1\u003c/em\u003e c.273(exon3)T\u0026thinsp;\u0026gt;\u0026thinsp;A, \u003cem\u003eTRIM71\u003c/em\u003e c.1799(exon4)G\u0026thinsp;\u0026gt;\u0026thinsp;A, \u003cem\u003ePIDD1\u003c/em\u003e c.1855(exon11)A\u0026thinsp;\u0026gt;\u0026thinsp;G, and \u003cem\u003eMACF1\u003c/em\u003e c.18597(exon74)_c.18600(exon74)delCAAA were novel variant loci not previously reported. Furthermore, prenatal NIVM (n\u0026thinsp;=\u0026thinsp;10) samples revealed mutations in \u003cem\u003ePDHA1, TUBB\u003c/em\u003e, \u003cem\u003eCRB2\u003c/em\u003e, \u003cem\u003eFGFR3\u003c/em\u003e, \u003cem\u003eRTTN\u003c/em\u003e, \u003cem\u003eAIMP1\u003c/em\u003e, \u003cem\u003ePOGZ\u003c/em\u003e, \u003cem\u003eMYH7\u003c/em\u003e, \u003cem\u003eCNOT3\u003c/em\u003e, \u003cem\u003eand PURA\u003c/em\u003e genes. Of these, \u003cem\u003eCRB2\u003c/em\u003e c.3078(exon10)_c.3093(exon10)delGGCGCGGCCCCGGCCC, \u003cem\u003eAIMP1\u003c/em\u003e c.187(exon3)A\u0026thinsp;\u0026gt;\u0026thinsp;T andc.110(exon3)delT, \u003cem\u003ePOGZ\u003c/em\u003e c.3406dupG, and \u003cem\u003eMYH7\u003c/em\u003e c.3133(exon25)C\u0026thinsp;\u0026gt;\u0026thinsp;A were novel variant loci not previously reported. Moreover, patients P14 (NIVM) and P18 (IVM) were found to have a pyruvate dehydrogenase E1-α deficiency (PDHAD) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCases with a positive result following WES analysis and their clinical phenotypes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eID\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClassification\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDisease, inheritance model\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUltrasound/ MRI findings\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eSPATA5\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.544(exon5)delA, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNeurodevelopmental disorder with hearing loss, seizures and brain abnormalities; NEDHSB (OMIM: 616577), AR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eModerate VM and higher white matter T2W1 signals in the body of bilateral ventricles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.1678(exon9)G\u0026thinsp;\u0026gt;\u0026thinsp;A, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVOUS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ePDHA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.273(exon3)T\u0026thinsp;\u0026gt;\u0026thinsp;A, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePyruvate dehydrogenase E1-α deficiency; PDHAD (OMIM: 312170), XD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSevere VM and callosal dysplasia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eTRIM71\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.1799(exon4)G\u0026thinsp;\u0026gt;\u0026thinsp;A, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHydrocephalus, congenital 4; HYC4 (OMIM:618667), AD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eModerate VM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ePDHA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.409(exon4)G\u0026thinsp;\u0026gt;\u0026thinsp;A, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePyruvate dehydrogenase E1-α deficiency; PDHAD (OMIM: 312170), XD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eModerate VM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ePIK3R2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.1117(exon10)G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMegalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1; MPPH1 (OMIM: 603387), AD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSevere VM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eTUBB\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.217(exon3)A\u0026thinsp;\u0026gt;\u0026thinsp;G, \u003cem\u003eDe novo\u003c/em\u003e, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eComplex cortical dysplasia with other brain malformations6, CDCBM6, (OMIM: #615771), AD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eModerate VM and suboptimal lateral ventricular morphology. Low bilateral frontoparietal white matter T1W1 signal, high T2W1 signal, and high bilateral pallidal T1W1. Hemivertebral deformity with irregular morphology of the thoracic vertebrae at 8 and 9 and disc signal abnormalities.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eCRB2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.3078(exon10)_c.3093(exon10)delGGCGCGGCCCCGGCCC, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVentriculomegaly with cystic kidney disease; VMCKD (OMIM: 219730), AR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSevere VM and birenal echo enhancement\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.1960(exon8)G\u0026thinsp;\u0026gt;\u0026thinsp;C, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVOUS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003ePIDD1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.1855(exon11)A\u0026thinsp;\u0026gt;\u0026thinsp;G, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVOUS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIntellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly; MRT75 (OMIM: 619827), AR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMild VM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.103(exon2)G\u0026thinsp;\u0026gt;\u0026thinsp;A, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVOUS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eRTTN\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.2101(exon16)C\u0026thinsp;\u0026gt;\u0026thinsp;T, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003emicrocephaly, short stature, and polymicrogyria with or without seizures; MSSP (OMIM: 614833), AR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMild VM, clear septal stenosis, and fetal development is 2 weeks less than GA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.2863(exon22)G\u0026thinsp;\u0026gt;\u0026thinsp;A, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVOUS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eFGFR3\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.1620(exon12)C\u0026thinsp;\u0026gt;\u0026thinsp;A, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eThanatophoric dysplasia, type I; TD1 (OMIM: #187600), AD\u003c/p\u003e \u003cp\u003eAchondroplasia, ACH; (OMIM: #100800), AD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMild VM and long bones of limbs compared to small gestations\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eAIMP1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.187(exon3)A\u0026thinsp;\u0026gt;\u0026thinsp;T, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLeukodystrophy, hypomyelinating 3; HLD3 (OMIM: 260600), AR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMild VM, atrial septal defect, and ventricular septal defect\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.110(exon3)delT, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ePOGZ\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.3406dupG, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eWhite-Sutton syndrome; WHSUS (OMIM: 616364), AD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMild VM and club foot\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eMYH7\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.3133(exon25)C\u0026thinsp;\u0026gt;\u0026thinsp;A, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCardiomyopathy, dilated, 1S; CMD1S (OMIM: 613426), AD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMild VM, small chest, oligohydramnios, fetal development is 3 weeks less than GA, and membranaceous placenta\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eCNOT3\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.2248(exon18)C\u0026thinsp;\u0026gt;\u0026thinsp;T, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIntellectual developmental disorder with speech delay, autism, and dysmorphic facies; IDDSADF (OMIM: 618672), AD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMild VM and callosal dysplasia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eMACF1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.18597(exon74)_c.18600(exon74)delCAAA, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLissencephaly 9 with complex brainstem malformation; LIS9 (OMIM: 618325), AD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMild VM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ePURA\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec.367(exon1)C\u0026thinsp;\u0026gt;\u0026thinsp;T, Het\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNeurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties; NEDRIHF (OMIM: 616158), AD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMild VM, suboptimal lateral ventricular morphology, and left frontal lobe T2W1 and FLAIR showed hypointense signals\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAD, autosomal dominant; AR, autosomal recessive; XD, X-linked dominant; Het, heterozygous; P, pathogenic; LP, likely pathogenic; VOUS, variants of uncertain significance.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eChromosome aberrations and gene variations in different fetal VM groups\u003c/h2\u003e \u003cp\u003eWhen comparing the positive and negative results following CNV-seq and WES, the chromosomal aberration detection rates were comparable within groups with the exception of a positive result in the CNV-seq group. In this group, NIVM showed a significantly higher detection rate relative to IVM (43.2% vs. 19.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Next, NIVMs were examined within the positive and negative result CNV-seq and WES groups in conjunction with other abnormalities. The results showed that 58.3% (7/12) of chromosomal aberrations and 55.6% (5/9) of genetic variants are present in combination with skeletal system abnormalities (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChromosomal aberrations and genetic variation in NIVM.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eCNV-seq (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eWES (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003epositive\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003enegative\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003epositive\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003enegative\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;2 systems\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecardiovascular system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDigestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkeletal system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eOthers include thickened nuchal fold, nuchal fold thickening, wide eyelids, polyhydramnios, and oligohydramnios.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up outcomes\u003c/h2\u003e \u003cp\u003ePostnatal follow-ups were performed for 3 months to 3 years after pregnancy. Of the patients with a positive result following CNV-seq, 16 chose to terminate the pregnancy and 7 delivered alive. Of the live births, 6 had postpartum developmental delays and 1 had Klinefelter syndrome, which presented with wide eyelids, external ear malformation, hearing impairment and cryptorchidism. Of patients with a positive result following WES, 9 chose to terminate the pregnancy and 7 delivered alive. These gradually exhibited the clinical phenotype associated with their corresponding SGD at postnatal follow-ups. For patients that had a negative result following CNV-seq, 17 also had a negative result following WES, and 17 declined further testing following CNV-seq.\u0026nbsp;Of these patients, 10 selected to terminate pregnancy and 24 delivered alive without incident. Even in patients who tested negative for both CNV-seq and WES, there were 5 cases with a poor postnatal outcome, including 1 case of premature death and 4 cases of developmental delay.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe aim of this study was to further evaluate the contribution of genetic etiology in fetal VM. When evaluating the entire VM cohort (n\u0026thinsp;=\u0026thinsp;73), a chromosomal aberration rate of 31.5%(23/73) was observed, with 12 of those cases belonging to the P classification within the positive result following CNV-seq (12/23). Furthermore, relatively high aberration frequencies were noted in chromosomes 1, 15, 17 and 22, including 1q21.1 recurrent deletion, Prader-Willi syndrome, Koolen-de Vries syndrome, and 22q11.2 deletion syndrome. For the children diagnosed with 22q11.2 deletion syndrome (P11 and P28), both presented with moderate VM and cardiac abnormalities, which is consistent phenotype based on previous reports\u003csup\u003e6\u003c/sup\u003e. In 22q11.2 deletion syndrome (also known as DiGeorge syndrome and Velocardiofacial syndrome), multiple genes are affected, including the critically important \u003cem\u003eTBX1\u003c/em\u003e and \u003cem\u003eDGCR8\u003c/em\u003e genes. The \u003cem\u003eTBX1\u003c/em\u003e gene encodes the transcription factor T-box and the \u003cem\u003eDGCR8\u003c/em\u003e gene mediates miRNA biogenesis and plays a critical role in the normal development of multiple organ systems. During the development of the nervous system, a loss or mutation of these genes leads to aberrant neural progenitor proliferation and differentiation, with subsequent neuronal defects affecting the development and morphology of the fetal lateral ventricle to results in the development of VM\u003csup\u003e7\u0026ndash;9\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIt is still unclear whether there are differences in chromosomal aberration detection rates when comparing mild, moderate, or severe fetal VM, but NIVMs have been shown to be more commonly associated with chromosomal abnormalities relative to IVMs (9.5\u0026ndash;36% vs. 1.5\u0026ndash;12.0%)\u003csup\u003e10\u0026ndash;13\u003c/sup\u003e. Consistent with previous studies, the rate of chromosomal aberration was significantly higher in NIVM than in IVM, thus further confirming that NIVM comes with an increased risk of chromosomal aberrations. We found 58.3% (7/12) of chromosomal aberrations of NIVMs were associated with skeletal system abnormalities, thus, we should note the possibility of chromosomal aberrations in fetal VM with multiple malformations, especially skeletal system. However, when comparing chromosome aberration detection rates between mild and moderate-to-severe VM, no significant difference was determined. These findings indicate that regardless of the extent of the widening, patients should be informed of the risk of chromosome aberration and further prenatal diagnostics advised.\u003c/p\u003e \u003cp\u003eRecently, several studies have strongly suggested an increasingly closer relationship between VM and gene mutations\u003csup\u003e14,15\u003c/sup\u003e. This has in part been due to the rapid development of second-generation sequencing technologies that have enabled the diagnostic process to transition from low-depth CNV-seq analysis to WES. Furthermore, ACMG guidelines suggest that exome or genome sequencing be considered as a primary or secondary diagnostic tool in patients with congenital anomalies\u003csup\u003e16\u003c/sup\u003e. WES, a high-throughput genetic platform, allows the simultaneous detection of coding regions from thousands of genes, and can comprehensively and rapidly identify potential genetic variants associated with fetal VM; thus providing a more accurate clinical diagnosis and enabling a more informed genetic counseling\u003csup\u003e17,18\u003c/sup\u003e. While using WES to assess fetal structural abnormalities isn\u0026rsquo;t new, most fetal VM studies have been limited to SGD case reports or cohort studies examining karyotypes and CNVs. The strength of this study is that we combined a negative CNV with WES while categorizing the patients. This approach enabled a further diagnostic assessment and the ability to identify genes associated with ventricular widening, examine VM in conjunction with other structural abnormalities, and assess the contribution of SGD to fetal VM.\u003c/p\u003e \u003cp\u003eHerein, WES was shown to effectively improve the chromosomal abnormality detection rate in VM fetuses, with 48.5% of SGD identified independent of CNV-seq.\u0026nbsp;Fetal VM is seen as an indicator of other genetic syndromes in the majority of cases, while SGDs causing IVM is uncommon, \u003cem\u003eL1CAM\u003c/em\u003e, \u003cem\u003eAP1S2\u003c/em\u003e, \u003cem\u003eMPDZ\u003c/em\u003e and \u003cem\u003eCCDC88C\u003c/em\u003e genes have been previously recognized as causally related to VM; while \u003cem\u003eTRIM71\u003c/em\u003e, \u003cem\u003eSMARCC1\u003c/em\u003e, \u003cem\u003ePIK3CA\u003c/em\u003e, \u003cem\u003ePTEN\u003c/em\u003e, \u003cem\u003eMTOR\u003c/em\u003e, \u003cem\u003eFOXJ1\u003c/em\u003e, \u003cem\u003eFMN2, PTCH1\u003c/em\u003e and \u003cem\u003eFXYD2\u003c/em\u003e have been identified as VM risk genes\u003csup\u003e14\u003c/sup\u003e. Herein, within the 16 WES-positive cases, SGDs were the main manifestation, with \u003cem\u003eSPATA5\u003c/em\u003e, \u003cem\u003eTRIM71\u003c/em\u003e, \u003cem\u003ePIK3R2\u003c/em\u003e, \u003cem\u003ePIDD1\u003c/em\u003e, \u003cem\u003eMACF1\u003c/em\u003e and \u003cem\u003ePDHA1\u003c/em\u003e variations discovered in the IVM group and \u003cem\u003eTUBB\u003c/em\u003e, \u003cem\u003eCRB2\u003c/em\u003e, \u003cem\u003eFGFR3\u003c/em\u003e, \u003cem\u003eRTTN\u003c/em\u003e, \u003cem\u003eAIMP1\u003c/em\u003e, \u003cem\u003ePOGZ\u003c/em\u003e, \u003cem\u003eMYH7\u003c/em\u003e, \u003cem\u003eCNOT3\u003c/em\u003e, \u003cem\u003ePURA\u003c/em\u003e and \u003cem\u003ePDHA1\u003c/em\u003e discovered in the NIVM group. Few previous reports have focused on the prenatal diagnosis of these genetic variant-related disorders, and our study confirms that VM can serve as an indicator for prenatal phenotypic examination. Meanwhile, the present study discovered 9 previously unreported gene variant loci, thus expanding the variant spectrum of relevant genes. Furthermore, WES-positive NIVM cases were predominantly associated with CNS and skeletal system abnormalities, while there was no significant difference in the detection rate when comparing the different VM degrees. Moreover, even when considering the CNV-seq results, the possibility of a chromosomal or genetic abnormality appears to be independent of the VM degree. Additionally, in the 2 patients with PDHAD (P14 and P18), one had moderate IVM and the other had severe VM combined with callosal dysplasia. While a PDHAD prenatal diagnosis is less commonly reported, 91.7% of these patients have been found to have prenatal manifestations\u003csup\u003e19\u003c/sup\u003e. Thus, it is possible that VM may be a predominant prenatal manifestation of PDHAD, and that the \u003cem\u003ePDHA1\u003c/em\u003e gene may also be a candidate gene for VM risk. But this would require further examination.\u003c/p\u003e \u003cp\u003ePrenatal WES can identify potential SGD and facilitate perinatal decision-making and management, but it also presents new challenges in data interpretation and genetic heterogeneity analysis. Furthermore, the presence of VOUS also poses problems in prenatal counseling, particularly due to nonspecific fetal phenotypes, and can increase the uncertainty in clinical management and cause severe parental anxiety. While this study has provided some helpful insights, it has several limitations, including a relatively small sample size and the absence of a systematic evaluation for parents included in the study. Furthermore, fetal ultrasounds often fail to identify subtle abnormalities, therefore certain phenotypes cannot be identified during a conventional prenatal screening. In some cases, it is also difficult to detect neurological developmental abnormalities in children due to insufficient follow-up exams. In the future, we will attempt to recruit patients where a longer follow-up time can be achieved to more fully characterize fetal VM outcomes.\u003c/p\u003e \u003cp\u003eIn conclusion, our study highlights the importance of genetic etiology in fetal VM, and shows WES can effectively improve the diagnostic rate of fetal VM and associated abnormalities. Moreover, this study shows that genetic and imaging findings, when combined with a multidisciplinary evaluation, are essential for providing effective clinical management of VM fetuses during pregnancy.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSamples\u003c/h2\u003e \u003cp\u003eSecond and third trimester fetuses with a lateral ventricular width\u0026thinsp;\u0026ge;\u0026thinsp;10 mm, as determined via ultrasound or fetal cranial MRI, were selected from the Shanxi Provincial Children's Hospital, Taiyuan, China between 2020 and 2023. This study underwent a medical ethics review of Shanxi Children's Hospital of China (IRB-KYHZ-2019-006). Informed consent for testing was obtained from the patient's parents. All research was performed in accordance with the guidelines and regulations of the review board and the publisher to ensure the scientific and reliability of the research methodology. Fetuses with VM that could be associated with environmental factors such as infection, drug toxicity, environmental radiation, or chemical exposure were excluded. Clinical data for the selected cohort (n\u0026thinsp;=\u0026thinsp;73) were obtained, and amniotic fluid (20 ml) or miscarriage tissue, either fetal skin-muscle (2 cm length) or umbilical cord (3 cm length) were collected. The samples were subjected to QF-PCR, and maternal contamination was excluded by detection of genetically marked short tandem repeats (STRs)\u003c/p\u003e \u003cp\u003ePatients were divided into mild VM (10\u0026ndash;12 mm) and moderate-to-severe VM (\u0026gt;\u0026thinsp;12 mm) groups, and further divided into IVM and NIVM. Patient samples were screened via CNV-seq and those with negative results were subsequently screened via WES. The pregnancy outcomes were followed by telephone, including whether the child was born and whether there were any abnormal findings after birth.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eUltrasound examination and MRI\u003c/h2\u003e \u003cp\u003eAccording to the guidelines of the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG)\u003csup\u003e20\u003c/sup\u003e, the ultrasound physician performed a prenatal ultrasound scan using a 2.5\u0026ndash;5 MHz transabdominal transducer and a color doppler ultrasound instrument (GE Voluson E8, GE Healthcare, USA) to determine the presence of VM. Fetal MRIs were performed by an experienced operator using a 3.0T scanner (Ingenia, Philips Medical Systems, Netherlands), with the transverse diameter of the ventricular triangle on both sides measured in addition to examining the CNS for other abnormalities.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eExtraction of genomic DNA and genomic DNA library preparation\u003c/h2\u003e \u003cp\u003eTIANamp Micro DNA Kit (DP316, TIANGENBIOTECH, China) was used to extract DNA from fetal amniotic fluid or miscarried fetal tissues according to the manufacturer's protocol. DNA purity and concentration were evaluated using Qubit 2.0 fluorimeter (Thermo Fisher Scientific, USA) and electrophoresis with 0.8% agarose gel. A OD\u003csub\u003e260\u003c/sub\u003e/OD\u003csub\u003e280\u003c/sub\u003e ratio of 1.8\u0026ndash;2.0 was deemed pure and concentrations were determined to be between 50\u0026ndash;100 ng/L.\u003c/p\u003e \u003cp\u003eDNA library preparation was performed according to Supplementary Material 1 using Chigene Library Prep Kitas (Beijing Chigene, China) and prepared library should meet the following requirements: concentration (Qubit 2.0: 25 uL, \u0026gt; 15 ng/uL); effective molecular concentration (q-PCP: 25 uL, \u0026gt; 10 nM); DNA fragment (Agilent 2100 detection: main peak 430bp, range 300-600bp).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCopy-number variation sequencing (CNV-seq)\u003c/h2\u003e \u003cp\u003eSequencing was performed using DNBSEQ-T7 sequencer (PE150, MGI Techdocs, China) and approximately 5\u0026nbsp;million sequencing reads per sample were mapped to the NCBI Human Reference Genome (hg19 / GRCh37) by Burrows-Wheeler Aligner (BWA) tool and then assigned to a 20 kb sequencing bin for sliding at 5 kb. CNV fragments were then analyzed and annotated using Decipher, OMIM, and ClinVar, with frequencies evaluated based on DGVs. CNV pathogenicity was then determined based on the American College of Medical Genetics and Genomics (ACMG) guidelines using the following classifications: pathogenic (P), likely pathogenic (LP), variants of uncertain significance (VOUS), LB (Likely benign), and B (Benign) \u003csup\u003e21\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eWhole-exome sequencing (WES)\u003c/h2\u003e \u003cp\u003eProtein-coding exome enrichment was performed using xGen Exome Research Panel v2.0(IDT, Iowa, USA) that consists of 429,826 individually synthesized and quality-controlled probes, which targets 39 Mb protein-coding region (19,396 genes) of the human genome and covers 39 Mb of end-to-end tiled probe space. High-throughput two-end sequencing was performed using DNBSEQ-T7 sequencer with 150 bp paired-end reads, and not less than 99% of target sequence were sequenced. The raw data (fq/vcf format data) was imported through the Chigene Genetic Diseases Analysis Cloud platform, combined with major databases (dbSNP, ExAC, ESP, OMIM, HGMD, and ClinVar, etc.) for interpretation, then analyzed using Provean, SIFT, PolyPhen and Mutationtaster to predict loss- or gain-of-function. Gene loci with higher combined scores were then classified according to the 2015 ACMG guidelines as described above\u003csup\u003e21\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up of pregnancy outcomes\u003c/h2\u003e \u003cp\u003eA multidisciplinary team of sonologists, prenatal diagnostic departments, and pediatric neurology comprehensively assessed the prognosis of fetuses with CNS abnormalities to inform parents. Postnatal patient outcomes were tracked for 3 months to 3 years by telephone and electronic medical record systems.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using Statistical Package for the Social Sciences version 23 (SPSS Inc, Chicago, IL, USA). Categorical variables are expressed as frequencies (percentages) and compared using the Pearson χ test or the Fisher\u0026rsquo;s exact test, with \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 deemed statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFinancial support.\u0026nbsp;\u003c/strong\u003eResearch Project Supported by Shanxi Scholarship Council of China(2023-180); Medical Genetics Research Committee Key Laboratory of Shanxi Province \u0026ldquo;2021 \u0026ldquo;Four Batch\u0026rdquo; Science and Technology Innovation Program\u0026rdquo;(2021SYS24); Shanxi Province Health and Wellness Committee Funded Project(2023016).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePotential conflicts of interest.\u003c/strong\u003e All authors\u0026nbsp;declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZhao Chenyue conducted design research methods, experimental design, writing articles, etc.\u003c/p\u003e\n\u003cp\u003eXue Huiqin is responsible for the overall supervision and coordination of the study to ensure the integrity and accuracy of the study.\u003c/p\u003e\n\u003cp\u003eGao Jingbo conducted experimental design, writing articles, etc.\u003c/p\u003e\n\u003cp\u003eGuo Min assisted in data collection.\u003c/p\u003e\n\u003cp\u003eYue Hao assisted with article typesetting.\u003c/p\u003e\n\u003cp\u003eGuo Rong assisted in data collection, processing and analysis.\u003c/p\u003e\n\u003cp\u003eCao Guizhi assisted in data collection.\u003c/p\u003e\n\u003cp\u003eSun Xiayu assisted in data analysis.\u003c/p\u003e\n\u003cp\u003eWu Jianrui assisted in data analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement.\u0026nbsp;\u003c/strong\u003eThe datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics\u003c/strong\u003e \u003cstrong\u003estatement.\u003c/strong\u003e This study underwent a medical ethics review\u0026nbsp;of Shanxi Children\u0026apos;s Hospital of China (IRB-KYHZ-2019-006). Informed consent for testing was obtained from the patient\u0026apos;s parents.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSociety for Maternal-Fetal, M.\u003cem\u003e et al.\u003c/em\u003e Fetal ventriculomegaly. \u003cem\u003eAm J. Obstet Gynecol\u003c/em\u003e . \u003cstrong\u003e223\u003c/strong\u003e, B30-B33 (2020).\u003c/li\u003e\n\u003cli\u003eMirsky, D. M., Stence, N. V., Powers, A. M., Dingman, A. L. \u0026amp; Neuberger, I. Imaging of fetal ventriculomegaly. \u003cem\u003ePediatr Radiol. \u003c/em\u003e\u003cstrong\u003e50\u003c/strong\u003e, 1948-1958 (2020).\u003c/li\u003e\n\u003cli\u003ePisapia, J. M., Sinha, S., Zarnow, D. M., Johnson, M. P. \u0026amp; Heuer, G. G. Fetal ventriculomegaly: Diagnosis, treatment, and future directions. \u003cem\u003eChilds Nerv Syst\u003c/em\u003e. \u003cstrong\u003e33\u003c/strong\u003e, 1113-1123 (2017).\u003c/li\u003e\n\u003cli\u003eRyan, G. A.\u003cem\u003e et al.\u003c/em\u003e Prenatal findings and associated survival rates in fetal ventriculomegaly: A prospective observational study. \u003cem\u003eInt J. Gynaecol Obstet\u003c/em\u003e. \u003cstrong\u003e159\u003c/strong\u003e, 891-897 (2022).\u003c/li\u003e\n\u003cli\u003eShreeve, N.\u003cem\u003e et al.\u003c/em\u003e Incremental yield of whole‐genome sequencing over chromosomal microarray analysis and exome sequencing for congenital anomalies in prenatal period and infancy: systematic review and meta‐analysis. \u003cem\u003eUltrasound Obstet Gynecol\u003c/em\u003e. \u003cstrong\u003e63\u003c/strong\u003e, 15-23 (2024).\u003c/li\u003e\n\u003cli\u003eBlagowidow, N.\u003cem\u003e et al.\u003c/em\u003e Prenatal screening and diagnostic considerations for 22q11.2 microdeletions. \u003cem\u003eGenes\u003c/em\u003e. \u003cstrong\u003e14\u003c/strong\u003e, 160 (2023).\u003c/li\u003e\n\u003cli\u003eHiramoto, T.\u003cem\u003e et al.\u003c/em\u003e Tbx1, a gene encoded in 22q11.2 copy number variant, is a link between alterations in fimbria myelination and cognitive speed in mice. \u003cem\u003eMol Psychiatry\u003c/em\u003e. \u003cstrong\u003e27\u003c/strong\u003e, 929-938 (2022).\u003c/li\u003e\n\u003cli\u003eMerico, D.\u003cem\u003e et al.\u003c/em\u003e MicroRNA dysregulation, gene networks, and risk for schizophrenia in 22q11.2 deletion syndrome. \u003cem\u003eFront Neurol\u003c/em\u003e. \u003cstrong\u003e5\u003c/strong\u003e, 238 (2014).\u003c/li\u003e\n\u003cli\u003eZinkstok, J. R.\u003cem\u003e et al.\u003c/em\u003e Neurobiological perspective of 22q11.2 deletion syndrome. \u003cem\u003eThe Lancet Psychiatry\u003c/em\u003e. \u003cstrong\u003e6\u003c/strong\u003e, 951-960 (2019).\u003c/li\u003e\n\u003cli\u003eDuan, H. L.\u003cem\u003e et al.\u003c/em\u003e The application of chromosomal microarray analysis to the prenatal diagnosis of isolated mild ventriculomegaly. \u003cem\u003eTaiwan J. Obstet Gynecol\u003c/em\u003e. \u003cstrong\u003e58\u003c/strong\u003e, 251-254 (2019).\u003c/li\u003e\n\u003cli\u003eSantirocco, M. \u003cem\u003eet al\u003c/em\u003e. Chromosomal microarray analysis in fetuses with central nervous system anomalies: An 8-year long observational study from a tertiary care university hospital. \u003cem\u003ePrenat Diagn\u003c/em\u003e. \u003cstrong\u003e41\u003c/strong\u003e, 123-135 (2021).\u003c/li\u003e\n\u003cli\u003eGezer, C.\u003cem\u003e et al.\u003c/em\u003e Chromosome abnormality incidence in fetuses with cerebral ventriculomegaly. \u003cem\u003eJ. Obstet Gynaecol.\u003c/em\u003e \u003cstrong\u003e34\u003c/strong\u003e, 387-391 (2014).\u003c/li\u003e\n\u003cli\u003eLok, W. Y.\u003cem\u003e et al.\u003c/em\u003e Chromosomal abnormalities and neurological outcomes in fetal cerebral ventriculomegaly: a retrospective cohort analysis. \u003cem\u003eHong Kong Med J\u003c/em\u003e. \u003cstrong\u003e27\u003c/strong\u003e, 428-436 (2021).\u003c/li\u003e\n\u003cli\u003eJin, S. C.\u003cem\u003e et al.\u003c/em\u003e Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus. \u003cem\u003eNat Med\u003c/em\u003e. \u003cstrong\u003e26\u003c/strong\u003e, 1754-1765 (2020).\u003c/li\u003e\n\u003cli\u003eHale, A. T.\u003cem\u003e et al.\u003c/em\u003e The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact. \u003cem\u003eFluids Barriers CNS\u003c/em\u003e. \u003cstrong\u003e21\u003c/strong\u003e, 24 (2024).\u003c/li\u003e\n\u003cli\u003eManickam, K.\u003cem\u003e et al.\u003c/em\u003e Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). \u003cem\u003eGenet Med\u003c/em\u003e. \u003cstrong\u003e23\u003c/strong\u003e, 2029-2037 (2021).\u003c/li\u003e\n\u003cli\u003eGiorgione, V., Haratz, K. K., Constantini, S., Birnbaum, R. \u0026amp; Malinger, G. Fetal cerebral ventriculomegaly: What do we tell the prospective parents? \u003cem\u003ePrenat Diagn\u003c/em\u003e. \u003cstrong\u003e42\u003c/strong\u003e, 1674-1681 (2022).\u003c/li\u003e\n\u003cli\u003eBaptiste, C.\u003cem\u003e et al.\u003c/em\u003e Fetal central nervous system anomalies: When should we offer exome sequencing? \u003cem\u003ePrenat Diagn\u003c/em\u003e. \u003cstrong\u003e42\u003c/strong\u003e, 736-743 (2022).\u003c/li\u003e\n\u003cli\u003eJiao, J. \u003cem\u003eet al\u003c/em\u003e. Prenatal diagnosis of pyruvate dehydrogenase E1-\u0026alpha; deficiency: a case report. \u003cem\u003eChin J. Perinat Med\u003c/em\u003e. \u003cstrong\u003e26\u003c/strong\u003e, 246-249 (2023).\u003c/li\u003e\n\u003cli\u003eSalomon, L. J.\u003cem\u003e et al.\u003c/em\u003e ISUOG Practice Guidelines (updated): performance of the routine mid‐trimester fetal ultrasound scan. \u003cem\u003eUltrasound Obstet Gynecol\u003c/em\u003e. \u003cstrong\u003e59\u003c/strong\u003e, 840-856 (2022).\u003c/li\u003e\n\u003cli\u003eRichards, S.\u003cem\u003e et al.\u003c/em\u003e Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. \u003cem\u003eGenet Med\u003c/em\u003e. \u003cstrong\u003e17\u003c/strong\u003e, 405-424 (2015).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"fetal ventriculomegaly, genetic causes, chromosomal aberrations, single gene genetic disease","lastPublishedDoi":"10.21203/rs.3.rs-4215892/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4215892/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjective\u003c/b\u003e\u003c/p\u003e \u003cp\u003eHigh-throughput sequencing was performed on 73 fetuses with ventriculomegaly (VM) to analyze the genetic causes, including chromosomal aberrations and genetic variations.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe clinical data from fetuses with lateral ventricular width greater than 10 mm in second and third trimester were collected from Shanxi Provincial Children's Hospital between 2020 and 2023. Patient samples included amniotic fluid or miscarriage tissue and were evaluated via copy number variation sequencing (CNV-seq), and those with negative CNV-seq result were further examined using whole exome sequencing (WES), with chromosomal aberrations and genetic variations counted. Statistical analysis was performed using SPSS 26.0, and pregnancy outcomes were followed.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eOf the 73 patients included in the study, 23 (31.5%) cases had chromosomal aberrations with 26 CNV fragments following CNV-seq, including 4 aneuploidies, 12 pathogenic variants, 2 likely pathogenic variants, and 8 variants of unknown significance. The detection rate of chromosomal aberrations was significantly higher in non-isolated VM relative to isolated VM. Negative CNV-seq results (n\u0026thinsp;=\u0026thinsp;33) were further examined via WES, and a subset (n\u0026thinsp;=\u0026thinsp;16, 48.48%) contained single-gene defects. These variants included \u003cem\u003eSPATA5, PDHA1, TRIM71, PIK3R2, TUBB, CRB2, PIDD1, RTTN, FGFR3, AIMP1, POGZ, MYH7, CNOT3, MACF1\u003c/em\u003e, and \u003cem\u003ePURA\u003c/em\u003e, with 9 unreported variant loci also identified.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eVM fetuses have complex developmental outcomes, and thus it is necessary to consider genetic etiology is VM. WES has the potential to provide a genetic diagnosis for VM fetuses without aneuploidy or CNVs, and can thereby increase the fetal VM diagnostic rate.\u003c/p\u003e","manuscriptTitle":"Genetic etiology analysis of 73 fetuses with ventriculomegaly","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-19 18:14:09","doi":"10.21203/rs.3.rs-4215892/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-08T17:30:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-25T09:41:56+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-04-11T16:31:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-11T16:10:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-04-04T06:10:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"befc86e1-1bcb-465f-8145-90777241e7c3","owner":[],"postedDate":"April 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":30709766,"name":"Biological sciences/Genetics"},{"id":30709767,"name":"Biological sciences/Neuroscience"},{"id":30709768,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-07-07T16:09:12+00:00","versionOfRecord":{"articleIdentity":"rs-4215892","link":"https://doi.org/10.1038/s41598-025-06714-2","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-07-02 15:57:28","publishedOnDateReadable":"July 2nd, 2025"},"versionCreatedAt":"2024-04-19 18:14:09","video":"","vorDoi":"10.1038/s41598-025-06714-2","vorDoiUrl":"https://doi.org/10.1038/s41598-025-06714-2","workflowStages":[]},"version":"v1","identity":"rs-4215892","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4215892","identity":"rs-4215892","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}