Perinatal outcomes of fetuses with pathogenic copy number variants (pCNVs) and confirmed parental inheritance patterns: A retrospective study at a single institution

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Nevertheless, evidence regarding the clinical outcomes of fetuses with pathogenic copy number variants(pCNVs) remains limited, with few studies specifically addressing this outcome. This study aimed to retrospectively evaluate the perinatal outcomes of fetuses with pathogenic copy number variations (pCNVs) with confirmed parental inheritance patterns. Methods From 2019 to 2024, 587 pCNVs were identified, with 91 cases subjected to parental analysis. Maternal information, anomaly scans, and pregnancy complications were documented as part of our comprehensive prenatal assessment. Follow-up data regarding pregnancy outcomes and neonatal health (up to 18 months post-partum) were collected. Results In 91 patients, 25 (27.5%) exhibited inherited pCNVs with a median length of 2.7 ± 3.5 Mb, whereas 66 (72.5%) presented de novo pCNVs with a median length of 5.7 ± 7.2 Mb, indicating a significant difference in length between the two groups ( P = 0.011). Parental inheritance occurred in 34% of pCNVs < 6.2 Mb. Among the 60 de novo cases with follow-up data, 58 (96.7%) opted for termination (TOP). Among the 23 inherited cases, 9 (39.1%) chose TOP. The 14 surviving term fetuses presented no developmental delay or structural anomalies. Conclusion When pCNVs are detected in prenatal diagnosis, parental inheritance information should be provided, especially in cases where the fragment length is less than 6.2 Mb. Parental origin verification has been shown to significantly improve the survival rate of fetuses with pCNVs. Prenatal diagnosis Pathogenic chromosomal copy number variants (pCNVs) Parental inheritance Introduction Chromosomal microarray analysis (CMA) is a high-resolution genomic technique used to detect deletions (losses) or duplications (gains) of DNA segments across the entire genome[1]. In recent years, CMA has been widely used in prenatal diagnosis because of its less stringent sample quality requirements and significantly higher resolution[2], which allows for a notably increased detection rate of clinically significant copy number variants (CNVs), particularly in cases with fetal structural anomalies[3]. Recent studies and expert consensus have established that compared with traditional karyotyping methods, CMA provides an additional diagnostic rate of 10% [4]. However, it has also been revealed that some pathogenic chromosomal microdeletions or duplications are inherited from one of parents[5]. Matthen Hoi Kin Chau et al.[5] conducted an extensive literature review of published prenatal chromosomal microarray data, assembling a large cohort comprising 23,865 fetuses. In the study of 311 positive cases with available parental inheritance data, 107 (34.4%) were identified as being inherited from one of the parents. This high proportion presents more challenges and decision-making dilemmas for genetic counseling and prenatal consultation. In this retrospective study, we analyzed the outcomes of prenatally diagnosed cases of pathogenic copy number variations (pCNVs) with confirmed parental origin over the past five years. Subjects and methods 1.1 Subjects This retrospective study was performed between January 2019 and December 2024. At our institute, CMA and karyotyping were applied for all prenatal samples. The indications for invasive procedures mainly include the following: 1, high risk of Down syndrome screening; 2, fetal increased nuchal translucency (NT ≥ 3.0 mm); 3, fetal ultrasound structural abnormalities or fetal growth retardation (FGR); 4, high risk of NIPT; and 5, a history of poor reproduction, such as a history of induced labor due to fetuses with microdeletions or microduplications. When pCNVs were detected, the pregnancies were referred to our clinic for detailed genetic counseling, and parental CMA was suggested under the following conditions: 1, incomplete penetrance of pCNVs; 2, morphology scan via ultrasound was normal. 3, Requested by the couples. This study was approved by the Ethics Committee of Longgang Maternity & Child Healthcare Hospital (No. LGFYYXLLL-2020-002). Written informed consent was obtained from all the participants. 1.2 Copy number variation sequencing CMA was carried out in accordance with the manufacturer’s instructions. In brief, total genomic DNA was extracted from tissue samples via the Amp Genomic DNA Kit (TIANGEN Biotech, Beijing, China). After the genomic DNA was sheared to an average size of 200 bp, 2.5 ng of the fragmented DNA was used to create the sequencing library. Eight-base pair (8-bp) bar-coded sequencing adaptors were ligated to the DNA fragments, and PCR was performed to amplify the ligation products. The generated libraries were then pooled and sequenced on a NextSeq CN 500 high-throughput platform at approximately 1× depth after purification of the PCR product via mag- netic beads. For each sample, 8–10 million 35-bp single-end raw reads were produced. Short reads were aligned to the human reference genome (hg19) via the BWA aligner after sequencing quality control and trimming. Each reference chromosome was divided equally by a 100-kb window, and the number of uniquely mapped reads in each window of each chromosome was counted. The LOWESS model was used to adjust the GC bias per window read count. The corrected read counts were contrasted with an internal reference database created from a collection of 100 samples with a normal karyotype that was verified via G-banded karyotype analysis. A full description of the algorithms employed for the bioinformatics analysis was provided in the previous literature [ 7 ] . CNVs detected by the platform had an effective minimum resolution of 100 kb. 1.3 Evaluation of CNVs Databases include DGV ( http://dgv.tcag.ca/dgv/app/home ), DECIPHER ( https://decipher.sanger.ac.uk/ ), OMIM ( https://www.ncbi.nlm.nih.gov/omim/ ), UCSC ( http://genome.ucsc.edu/ ), GeneReviews ( https://www.ncbi.nlm.nih.gov/books/NBK1116/ ), and the ClinGen Dosage Sensitivity Map ( https://www.ncbi.nlm.nih.gov/ucsc.edu/ ). projects/dbvar/clingen/index.shtml) and PubMed ( http://www.ncbi.nlm.gov/pubmed ) were used to analyze the suspected pathogenic regions. The pathogenicity of CNVs was evaluated according to the American College of Medical Genetics (ACMG) guidelines [ 8 – 9 ] . CNVs are classified into three major categories: pathogenic, variants of uncertain significance (VOUS), and benign. Only pathogenic CNVs and VOUS were reported in this study. 1.4 Follow-up outcomes The follow-up was carried out through a combination of hospital record review and structured telephone interviews via customized questionnaires by our center’s follow-up staff. The specific follow-up data included pregnancy outcomes (miscarriages or births), gestational ages at delivery, sex, birth weight/length, and ultrasound findings during pregnancy (nervous system, cardiovascular system, craniofacial growth, respiratory system, abdominal abnormalities, urinary system, alimentary system, musculoskeletal system and others) and postnatal health conditions (congenital defects, developmental details and so on). 1.5 Statistical analysis SPSS software (version 22.0) was used for the data analysis. SPSS software (version 22.0) was used for the data analysis. The quantitative data are expressed as the means ± standard deviations (X ± S), and comparisons between groups were performed via t tests. Qualitative data are represented as the number of cases (percentages), and comparisons between groups were performed via the paired chi-square test. Statistical significance was determined when the p value was less than 0.05, indicating that the observed differences were unlikely to be due to chance alone. Results A total of 2.1 4.5% of fetal pCNVs were detected, and a parent-of-origin test was performed in 91 cases. From January 2020 to December 2024, CMA was performed on 13162 prenatal samples. Chromosomal abnormalities were detected in 1151 cases (8.7%), among which common aneuploidies were identified in 564 cases (4.3%), including 254 cases of trisomy 21 (45.0%), 50 cases of trisomy 18 (8.8%), 13 cases of trisomy 13 (2.3%) and 247 cases of sex chromosomal abnormalities (43.8%). pCNVs were detected in 587 cases (4.5%), of which the parent-of-origin test was performed in only 91 cases. Among these 91 patients, the median maternal age and gestational age were 30.0 (range, 27.1–33.8) years and 18.0 (range, 12.0–33.0) weeks, respectively. The clinical indications for invasive procedures are presented in Table 1 . Table 1 Parental Inheritance and Pregnant Outcomes of 91 fetuses with Pathogenic Copy Number Variants (pCNVs) Chromosomal aberration pCNAs Median Size (Mb) Parental Inheritance Indications for prenatal diagnosis TOP Loss to follow up Location Number of cases Deletion Duplication Maternal Paternal de no vo YES NO 22 16 8 8 2.82(1.39–3.16) 2 2 12 Congenital heart disease (9) 13 2 1 Increased NT (4) Absence of NB (1) Talipes equinovarus (1) Adverse obstetric history (1) X 14 12 2 8.39(1.69–39.9) 4 0 10 high risk of NIPT(8) 9 4 1 Short limbs (1) Omphalocele (1) Tethered spinal cord (1) Increased NT (1) Absence of NB with right umbilical vein(1) high risk of Down syndrome (1) 17 13 10 3 1.52(1.34–11.5) 3 1 9 Congenital kidney development anomaly(7) 11 1 1 Duodenal stenosis and atresia with bilateral microtia and malformation (1) Congenital heart disease (1) Increased NT (1) Lateral ventricle widening with short limbs(1) Ependymal cyst(1) Adverse obstetric history (1) 16 12 5 7 1.31(0.6–6.9) 2 1 9 Lateral ventricle widening(1) 8 2 2 Hemivertebra(1) Ependymal cyst(1) High risk of Down syndrome (1) Fetal right pulmonary adenoma(1) Omphalocele(1) Congenital disease(1) Left renal hydronephrosis with lateral ventricle expansion(1) Bilateral renal dysplasia(1) Polydactyly(1) High risk of NIPT(1) Increased NT (1) 15 10 7 3 3.83(0.5–6.19) 2 3 5 NIPT high risk (5) 5 4 1 Increased NT (2) Fetal cleft lip and palate(2) High risk of Down syndrome screening(1) 2 6 5 1 9.2(0.19–23.2) 0 2 4 Increased NT (2) 5 1 0 High risk of Down syndrome (1) Fetal clubfoot(1) One of the twins in MCDA stopped developing(1) High risk in NIPT (1) 1 5 3 2 1.85(1.74–33.9) 1 1 3 Duodenal atresia with widened lateral ventricles (1) 4 1 0 FGR(2) Adverse obstetric history(1) Congenital heart disease (1) 4 2 2 0 7.54,11.7 0 0 2 Cleft lip and palate(1) 1 0 1 Absence of the nasal bone with single umbilical artery(1) 10 2 2 0 7.68,12.86 0 0 2 Bilateral renal agenesis with bilateral pulmonary hypoplasia and oligohydramnios(1) 2 0 0 Adverse obstetric history(1) 11 2 1 1 2.36,3.4 0 0 2 Ventricular septal defect with increased NT 2 0 0 Agenesis of the corpus callosum 18 2 2 0 6.32,11.5 0 0 2 Congenital heart disease (1) 2 0 0 High risk in NIPT (1) 5 1 1 0 5.09 1 0 0 High risk in NIPT(1) 1 0 0 6 1 1 0 2.36 0 0 1 High risk in NIPT (1) 0 0 1 7 1 1 0 1.43 0 0 1 Right kidney polycystic (1) 1 0 0 9 1 1 0 5.54 0 0 1 High risk in NIPT(1) 1 0 0 14 1 1 0 1.63 0 0 1 High risk in NIPT(1) 1 0 0 19 1 0 1 8.31 0 0 1 Right kidney polycystic(1) 1 0 0 Y 1 1 0 3.18 0 0 1 High risk of Down syndrome (1) 1 0 0 2.2 Parental inheritance was identified in 27.5% of the cases. Among the 91 cases, inheritance from parents was observed in 25 (27.5%) cases, with maternal inheritance accounting for 60.0% (15/25) and paternal inheritance accounting for 40% (10–25). The remaining 72.5% of cases (66/90) were identified de novo. The incidences of parental inheritance of pCNVs on chromosomes 15, 16, 17, 22 and X are 50.0%, 25.0%, 30.8%, 25.0% and 28.5%, respectively. There was no statistically significant difference in the incidence of parental inheritance among these different chromosome loci ( P = 0.698). 2.3 When pCNVs are shorter than 6.2 Mb, paternal inheritance is observed in 34.3% of cases Among the 25 patients with paternally inherited pCNVs, the median fragment length was 2.7 ± 3.5 Mb. In contrast, the 66 de novo pCNVs presented a significantly greater median length of 5.7 ± 7.2 Mb. Statistical analysis confirmed that paternally inherited pCNVs had significantly shorter fragment lengths than did de novo variants ( P = 0.011). When a 6.2 Mb cutoff was used to stratify all cases, 70 cases had pCNVs shorter than 6.2 Mb, of which paternal inheritance was identified in 24 cases (34.3%). In contrast, among the 21 patients with pCNVs longer than 6.2 Mb, only 1 patient (4.7%) exhibited paternal inheritance. 2.4 TOP was identified in 96.7% of patients with de novo pCNVs but only in 39.1% of patients with paternally inherited CNVs. Among the 91 patients included in this perinatal outcome analysis, eight patients were lost to follow-up. Among the 83 cases with complete data, termination of pregnancy (TOP) was carried out in 67 cases (80.7%). In the subgroup of 60 patients with de novo pCNVs, the TOP was selected in 58 patients (96.7%). The two surviving fetuses (3.3%) presented a deletion in the Xq27 region and a duplication at the 16p11.2 locus. Among the 23 patients with inherited pCNVs, the TOP was chosen in nine patients (39.1%). Among the 14 fetuses (60.8%) that survived to term, the median follow-up duration was 8.6 months (range 5–18). Extended neonatal follow-up, including serial pediatric evaluations, revealed no clinical evidence of developmental delay or congenital structural anomalies. (See Table 2 ) Table 2 Clinical follow-up assessment of 16 delivery cases with pCNVs after prenatal diagnosis Case No. Prenatal Indications Chromosomal Location Size (Mb) Parental Inheritance Follow-up time(months) Other 4 Congenital heart disease 1q21 1.75 Paternal 6 Favorable neonatal outcome 8 Fetal clubfoot 2q13 1.73 Paternal 5 Surgical treatment of varus foot was performed one month after birth. 23 High risk in NIPT 15q11 5.7 Maternal 8 Favorable neonatal outcome 24 Fetal cleft lip and palate 15q11 0.52 Paternal 11 Cleft lip and palate surgery 6 months after birth 25 Increased NT 15q11 0.5 Maternal 10 Favorable neonatal outcome 26 High risk in NIPT 15q11 6.16 Paternal 9 Favorable neonatal outcome 28 High risk in NIPT 15q11 0.56 Paternal 18 Favorable neonatal outcome 38 Omphalocele 16p11 0.58 de no vo 7 Surgical treatment after birth 43 High risk in NIPT 16p13 2.8 Maternal 9 Favorable neonatal outcome 54 Right kidney hydronephrosis with ureter dilation 17p12 1.39 Maternal 7 Favorable neonatal outcome 69 Increased NT 22q11 2.82 Paternal 6 Favorable neonatal outcome 74 High risk in NIPT 22q11 3.15 Maternal 10 Favorable neonatal outcome 77 High risk in NIPT XP22 1.69 Maternal 8 Favorable neonatal outcome 82 High risk in NIPT Xq26.3 17.8 Maternal 7 Favorable neonatal outcome 87 High risk in NIPT Xq27.3q28 11.8 de no vo 8 Favorable neonatal outcome 89 Developmental deficiency of nasal bones; persistent right umbilical vein Xp22 1.69 Maternal 9 Favorable neonatal outcome Discussion CMA has several advantages in prenatal diagnosis, such as high resolution, comprehensive detection, no need for cell culture and improved diagnostic yield. CNVs are associated with an increased risk of developmental disorders, congenital anomalies, and various health complications. Research has identified specific CNVs linked to developmental delay, such as those found in the 1q21.1, 3q29, and 15q11.2 regions, and has shown that approximately 1/200 children may carry neurodevelopmental disorder (NDD)-related CNVs. Additionally, CNVs on the X chromosome have been detected in approximately 2.8% of patients with neurodevelopmental disorders, with males potentially exhibiting more severe symptoms. However, CMA has also identified a subset of pathogenic microdeletions or duplications that are inherited from one of the parents. Such inherited copy number variants may have variable expressivity or incomplete penetrance, underscoring the importance of parental studies in risk assessment. In our study, 27.5% (25/91) of pCNVs were inherited from parents. This result is consistent with the findings of the study performed by Matthen Hoi Kin Chau et al.[5], who reported that parental inheritance was present in 34.4% (107/311) of cases. This conclusion raises a crucial question: when pCNVs are detected during prenatal diagnosis, should we perform a parent-of-origin test for each patient, and if we can confirm the parental origin, how does this information influence genetic counseling and risk assessment for the fetus? In this study, we compared the locus and length of pCNVs between patients whose pCNVs were inherited from parents and those whose pCNVs were inherited de novo, and there was no statistically significant difference in the incidence of parental inheritance among different chromosome loci. However, the length of pCNVs inherited from parents is significantly shorter than that of pCNVs inherited de novo. To make this more practical, we set the 95th percentile length of pCNVs inherited from parents as the cutoff and found that parental inheritance occurred in 34.4% of the cases when the length of pCNVs was shorter than 6.2 Mb. In contrast, when the length of pCNVs exceeded 6.2 Mb, only one case (4.7%) exhibited paternal inheritance. This threshold provides practical guidelines for clinical decision-making, particularly in cases where the origin of pCNVs remains ambiguous. Given that shorter pCNVs are more likely to be inherited and thus associated with milder or variable phenotypes, distinguishing parental origin can significantly refine risk assessment and genetic counseling. In contrast, longer pCNVs, especially those exceeding 6.2 Mb, are predominantly de novo and are often linked to more severe clinical outcomes, reinforcing the need for vigilant monitoring and comprehensive evaluation. This study further evaluated the perinatal outcomes of fetuses diagnosed with pCNVs. Among the 83 patients whose complete follow-up data were available, 80.7% of the pregnancies were terminated by a TOP. Subgroup analysis revealed a TOP rate of 96.7% in the 60 patients with de novo pCNVs, whereas it was 39.1% in the 23 patients with inherited pCNVs. This striking difference in termination rates underscores the profound impact of inheritance status on parental decision-making, with de novo variants perceived as higher risk. The absence of adverse clinical outcomes in inherited pCNVs further supports their potential benignity or reduced penetrance. Genetic counseling that incorporates inheritance patterns and variant size enables more accurate prognosis estimation. As prenatal detection of pCNVs becomes more common through expanded genomic screening, integrating these factors will be essential for guiding families toward informed, personalized decisions. On the basis of the available follow-up data, no clinical evidence of developmental delay or congenital structural anomalies was observed for the 16 live births. These findings suggest that the inheritance pattern of pCNVs plays a critical role in parental decision-making and clinical prognosis. However, the absence of adverse outcomes in live-born infants, although encouraging, must be interpreted cautiously because of the limited follow-up period and small sample size. Long-term neurodevelopmental monitoring is essential to fully ascertain the phenotypic spectrum, especially for inherited pCNVs where late-onset manifestations may not yet be apparent. Genetic counseling should therefore integrate origin, size, inheritance, and family-specific context to support informed decisions. The clinical manifestations of 22q11 microeletion/duplication include developmental delay, cardiovascular defects, autistic behavior, and various minor birth defects. However, the penetrance of the 22q11 microdeletion/duplication is estimated to be approximately 20–30% [ 10 – 11 ] . Recurrent 17q12 duplication is inherited in an autosomal dominant manner, with approximately 10% of duplications occurring de novo and approximately 90% being inherited from a parent who is often minimally affected or phenotypically normal [ 11 ] . Patients with the 15q11.2 BP1-BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances, psychiatric problems, autism, seizures, schizophrenia and mild dysmorphic features, which are less common. The 15q11.2 BP1–BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, NIPA1, and NIPA2) is emerging as a recognized syndrome with a prevalence ranging from 0.57%-1.27% of patients presented for microarray analysis, which is a two- to fourfold increase compared with that of controls. The latest research shows that the penetrance of this fragment is very low, at only 2% [ 12 ] . 16p11.2 microdeletions or microduplications are found in 0.6–1% of isolated children with autism, but there are no descriptions of more clinical phenotypes being studied [ 13 – 14 ] . Interestingly, through a cohort study of the American Autism Genetic Resource database (Autism Genetic Resource Exchange, AGRE), we found that not all family members with autism have 16p11.2CNVs, and not all 16p11.2CNVs show autism. Therefore, further clinical research is needed to explain the correlation between 16p11.2CNVs and autism [ 15 – 17 ] . In conclusion, in cases where prenatal diagnosis identifies pCNVs, it is imperative to obtain parental inheritance information, particularly when the detected fragment size is under 6.2 Mb, to facilitate comprehensive genetic counseling and assess the potential risks to the fetus. Verification of parental origin can significantly increase the survival rate of fetuses with pCNVs. Abbreviations pCNVs pathogenic copy number variations CMA Chromosomal Microarray Analysis FGR fetal growth retardation NT Nuchal Translucency TOP termination of pregnancy Declarations Ethical approval statement Ethical approval for this study was obtained from the Ethics Committee of Longgang District Maternity & Child Healthcare Hospital, Shenzhen. The approval date was August 31, 2020, with the reference number LGFYYXLLL-2020-002. All procedures were conducted in accordance with the committee's guidelines and regulations. Consent for publication All participants provided written informed consent for the publication of anonymized data and any accompanying images, ensuring confidentiality and compliance with privacy regulations. The study adheres to the principles of the Declaration of Helsinki, ensuring respect for the dignity, rights, and welfare of all participants. Availability of data and materials The data that support the findings of this study are available on reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.The authors confirm that all materials used in this study are available upon reasonable request and in compliance with institutional guidelines. No part of this work has been previously published or submitted elsewhere, ensuring originality and integrity in reporting. Competing interests The authors declare that they have no conflicts of interest. Fundings This study was supported (or partially supported) by the Shenzhen Longgang District Science and Technology Innovation Bureau (LGKCYLWS2023016) and the Shenzhen Longgang District Science and Technology Innovation Bureau (LGWJ2024-46). Authors' contributions FeiFei Chen, SiQi Wu, LiPing Wu: data collection and follow-up. RuChun Huang, WeiQiang Liu: Laboratory operations and CMA. XiaoYi Cong: pCNV interpretation. Xin Yang@Tu Xinzhi: study design, supervision, manuscript drafting. All the authors reviewed and approved the final version. Acknowledgments We would like to express our sincere gratitude to all the participants and their families who generously contributed to this study. Their trust and cooperation were essential to the completion of this research. We appreciate the valuable insights and suggestions from colleagues in the field of prenatal genetics, which helped improve the quality of this manuscript. References Society for Maternal-Fetal Medicine (SMFM). Electronic address: [email protected] ; Dugoff L, Norton ME, Kuller JA. The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016 Oct;215(4):B2-9. doi: 10.1016/j.ajog.2016.07.016. Epub 2016 Jul 15. Erratum in: Am J Obstet Gynecol. 2017 Feb;216(2):180. doi: 10.1016/j.ajog.2016.11.1031. PMID: 27427470. Shi X, Huang W, Lu J, He W, Liu Q, Wu J. 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A case of Friedreich ataxia in an adolescent with 16p11.2 microdeletion syndrome. Neurol Sci. 2020 Mar;41(3):721-722. doi: 10.1007/s10072-019-04075-z. Epub 2019 Oct 2. PMID: 31578651. Flejter WL, Bennett-Baker P, Barcroft CL, Kiousis S, Chamberlain JS. Region-specific cosmids and STRPs identified by chromosome microdissection and FISH. Genomics. 1995 Jan 20;25(2):413-20. doi: 10.1016/0888-7543(95)80041-j. PMID: 7789975. Genovese A, Butler MG. The Autism Spectrum: Behavioral, Psychiatric and Genetic Associations. Genes (Basel). 2023 Mar 9;14(3):677. doi: 10.3390/genes14030677. PMID: 36980949; PMCID: PMC10048473. Varghese M, Keshav N, Jacot-Descombes S, Warda T, Wicinski B, Dickstein DL, Harony-Nicolas H, De Rubeis S, Drapeau E, Buxbaum JD, Hof PR. Autism spectrum disorder: neuropathology and animal models. Acta Neuropathol. 2017 Oct;134(4):537-566. doi: 10.1007/s00401-017-1736-4. Epub 2017 Jun 5. PMID: 28584888; PMCID: PMC5693718. Rein B, Yan Z. 16p11.2 Copy Number Variations and Neurodevelopmental Disorders. Trends Neurosci. 2020 Nov;43(11):886-901. doi: 10.1016/j.tins.2020.09.001. Epub 2020 Sep 28. PMID: 32993859; PMCID: PMC7606557. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7739350","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":549321443,"identity":"e0d20bef-8e89-49e2-a8c9-7e9b08689394","order_by":0,"name":"Feifei Chen","email":"","orcid":"","institution":"Shantou University Medical College","correspondingAuthor":false,"prefix":"","firstName":"Feifei","middleName":"","lastName":"Chen","suffix":""},{"id":549321444,"identity":"5c98e37b-8e8d-48c8-9ea8-bf60748a8132","order_by":1,"name":"Siqi Wu","email":"","orcid":"","institution":"Shantou University Medical College","correspondingAuthor":false,"prefix":"","firstName":"Siqi","middleName":"","lastName":"Wu","suffix":""},{"id":549321445,"identity":"6c498734-a7c0-4cb3-b878-26c7d6dd71b9","order_by":2,"name":"Liping Wu","email":"","orcid":"","institution":"Shantou University Medical College","correspondingAuthor":false,"prefix":"","firstName":"Liping","middleName":"","lastName":"Wu","suffix":""},{"id":549321446,"identity":"90b19dd2-3f6a-424e-915d-8a5086c2456f","order_by":3,"name":"Ruchun Huang","email":"","orcid":"","institution":"Shantou University Medical College","correspondingAuthor":false,"prefix":"","firstName":"Ruchun","middleName":"","lastName":"Huang","suffix":""},{"id":549321447,"identity":"94aa11b2-bb64-4131-89f0-5b87c73eefe6","order_by":4,"name":"Xiaoyi Cong","email":"","orcid":"","institution":"Shantou University Medical College","correspondingAuthor":false,"prefix":"","firstName":"Xiaoyi","middleName":"","lastName":"Cong","suffix":""},{"id":549321448,"identity":"cd12c770-4b3c-462d-bb88-9ee3b1022b6b","order_by":5,"name":"Xin Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYDADNgYGxgcJFTWkaWE2eHDmGIkWST5sYSaszOD42cMvf7bdyefjP3ysIrGBjYG/vTsBv5YzeWnWvG3PLNsk0tJuJO6QYZA4c3YDfi0HcsyMGdsOG7BJ8JjdSDzDxmAgkUtAy/k3ZoY/QVr4z38rSGxjJkLLjRzjB7wgLQw5bAxEaZG88caMmeccyGFpxhIJZ47xEPQL3/kc448/yg4byPcffvjxR0WNHH97L34tCgcY2CSQBXjwKgcB+QYG5g8EVY2CUTAKRsHIBgD0AEmeZPlmQQAAAABJRU5ErkJggg==","orcid":"","institution":"Shantou University Medical College","correspondingAuthor":true,"prefix":"","firstName":"Xin","middleName":"","lastName":"Yang","suffix":""},{"id":549321451,"identity":"675ae85e-50c5-43c7-892f-3c49904411ea","order_by":6,"name":"Xinzhi Tu","email":"","orcid":"","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xinzhi","middleName":"","lastName":"Tu","suffix":""}],"badges":[],"createdAt":"2025-09-29 07:53:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7739350/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7739350/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":96611189,"identity":"06123acf-c497-4b1b-b742-7a23d311ddd5","added_by":"auto","created_at":"2025-11-24 09:33:01","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38740,"visible":true,"origin":"","legend":"","description":"","filename":"reviewed0928manuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-7739350/v1/4319ae1623ac347482f95198.docx"},{"id":96611248,"identity":"71b9d661-6b01-4630-83be-c57403a48355","added_by":"auto","created_at":"2025-11-24 09:33:22","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":33321,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7739350/v1/1de8dcfb097e9332bc01121a.docx"},{"id":96611204,"identity":"a1b9a912-168b-4b15-8834-46c342706ce4","added_by":"auto","created_at":"2025-11-24 09:33:10","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":14461,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7739350/v1/3c7ca8b9d7a59ee82e1cb739.docx"},{"id":96611249,"identity":"0d09a74c-33e8-4a58-8949-9a88c6d5ec66","added_by":"auto","created_at":"2025-11-24 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09:33:30","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":104052,"visible":true,"origin":"","legend":"","description":"","filename":"7ad45617cd574f8ba8e29d2ee89391691structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7739350/v1/87c95a5cd4f96a6c9360383b.xml"},{"id":96611251,"identity":"dc96e0fb-5911-4484-92bb-519888701fc3","added_by":"auto","created_at":"2025-11-24 09:33:25","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":113866,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7739350/v1/016326731522225fc9d38727.html"},{"id":100628237,"identity":"2bcdcc66-e784-422b-a1b2-2bbad83488d6","added_by":"auto","created_at":"2026-01-19 20:27:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1677633,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7739350/v1/25af9ad9-df6a-4691-8a49-f369b0816786.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Perinatal outcomes of fetuses with pathogenic copy number variants (pCNVs) and confirmed parental inheritance patterns: A retrospective study at a single institution","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChromosomal microarray analysis (CMA) is a high-resolution genomic technique used to detect deletions (losses) or duplications (gains) of DNA segments across the entire genome[1]. In recent years, CMA has been widely used in prenatal diagnosis because of its less stringent sample quality requirements and significantly higher resolution[2], which allows for a notably increased detection rate of clinically significant copy number variants (CNVs), particularly in cases with fetal structural anomalies[3]. Recent studies and expert consensus have established that compared with traditional karyotyping methods, CMA provides an additional diagnostic rate of 10% [4]. However, it has also been revealed that some pathogenic chromosomal microdeletions or duplications are inherited from one of parents[5]. Matthen Hoi Kin Chau et al.[5] conducted an extensive literature review of published prenatal chromosomal microarray data, assembling a large cohort comprising 23,865 fetuses. In the study of 311 positive cases with available parental inheritance data, 107 (34.4%) were identified as being inherited from one of the parents. This high proportion presents more challenges and decision-making dilemmas for genetic counseling and prenatal consultation.\u003c/p\u003e\u003cp\u003eIn this retrospective study, we analyzed the outcomes of prenatally diagnosed cases of pathogenic copy number variations (pCNVs) with confirmed parental origin over the past five years.\u003c/p\u003e"},{"header":"Subjects and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e1.1 Subjects\u003c/h2\u003e\u003cp\u003eThis retrospective study was performed between January 2019 and December 2024. At our institute, CMA and karyotyping were applied for all prenatal samples. The indications for invasive procedures mainly include the following: 1, high risk of Down syndrome screening; 2, fetal increased nuchal translucency (NT\u0026thinsp;\u0026ge;\u0026thinsp;3.0 mm); 3, fetal ultrasound structural abnormalities or fetal growth retardation (FGR); 4, high risk of NIPT; and 5, a history of poor reproduction, such as a history of induced labor due to fetuses with microdeletions or microduplications. When pCNVs were detected, the pregnancies were referred to our clinic for detailed genetic counseling, and parental CMA was suggested under the following conditions: 1, incomplete penetrance of pCNVs; 2, morphology scan via ultrasound was normal. 3, Requested by the couples.\u003c/p\u003e\u003cp\u003eThis study was approved by the Ethics Committee of Longgang Maternity \u0026amp; Child Healthcare Hospital (No. LGFYYXLLL-2020-002). Written informed consent was obtained from all the participants.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e1.2 Copy number variation sequencing\u003c/h2\u003e\u003cp\u003eCMA was carried out in accordance with the manufacturer\u0026rsquo;s instructions. In brief, total genomic DNA was extracted from tissue samples via the Amp Genomic\u003c/p\u003e\u003cp\u003eDNA Kit (TIANGEN Biotech, Beijing, China). After the genomic DNA was sheared to an average size of 200 bp, 2.5 ng of the fragmented DNA was used to create the sequencing library. Eight-base pair (8-bp) bar-coded sequencing adaptors were ligated to the DNA fragments, and PCR was performed to amplify the ligation products. The generated libraries were then pooled and sequenced on a NextSeq CN 500 high-throughput platform at approximately 1\u0026times; depth after purification of the PCR product via mag-\u003c/p\u003e\u003cp\u003enetic beads. For each sample, 8\u0026ndash;10\u0026nbsp;million 35-bp single-end raw reads were produced. Short reads were aligned to the human reference genome (hg19) via the\u003c/p\u003e\u003cp\u003eBWA aligner after sequencing quality control and trimming. Each reference chromosome was divided equally by a 100-kb window, and the number of uniquely mapped reads in each window of each chromosome was counted. The LOWESS model was used to adjust the GC bias per window read count. The corrected read counts were contrasted with an internal reference database created from a collection of 100 samples with a normal karyotype that was verified via G-banded karyotype analysis. A full description of the algorithms employed for the bioinformatics analysis was provided in the previous literature\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. CNVs detected by the platform had an effective minimum resolution of 100 kb.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e1.3 Evaluation of CNVs\u003c/h2\u003e\u003cp\u003eDatabases include DGV (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dgv.tcag.ca/dgv/app/home\u003c/span\u003e\u003cspan address=\"http://dgv.tcag.ca/dgv/app/home\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), DECIPHER (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://decipher.sanger.ac.uk/\u003c/span\u003e\u003cspan address=\"https://decipher.sanger.ac.uk/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), OMIM (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/omim/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/omim/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), UCSC (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://genome.ucsc.edu/\u003c/span\u003e\u003cspan address=\"http://genome.ucsc.edu/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), GeneReviews (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/books/NBK1116/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/books/NBK1116/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), and the ClinGen Dosage Sensitivity Map (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/ucsc.edu/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/ucsc.edu/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eprojects/dbvar/clingen/index.shtml) and PubMed (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.gov/pubmed\u003c/span\u003e\u003cspan address=\"http://www.ncbi.nlm.gov/pubmed\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) were used to analyze the suspected pathogenic regions. The pathogenicity of CNVs was evaluated according to the American College of Medical Genetics (ACMG) guidelines\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. CNVs are classified into three major categories: pathogenic, variants of uncertain significance (VOUS), and benign. Only pathogenic CNVs and VOUS were reported in this study.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e1.4 Follow-up outcomes\u003c/h2\u003e\u003cp\u003eThe follow-up was carried out through a combination of hospital record review and structured telephone interviews via customized questionnaires by our center\u0026rsquo;s follow-up staff. The specific follow-up data included pregnancy outcomes (miscarriages or births), gestational ages at delivery, sex, birth weight/length, and ultrasound findings during pregnancy (nervous system, cardiovascular system, craniofacial growth, respiratory system, abdominal abnormalities, urinary system, alimentary system, musculoskeletal system and others) and postnatal health conditions (congenital defects, developmental details and so on).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e1.5 Statistical analysis\u003c/h2\u003e\u003cp\u003eSPSS software (version 22.0) was used for the data analysis. SPSS software (version 22.0) was used for the data analysis. The quantitative data are expressed as the means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations (X\u0026thinsp;\u0026plusmn;\u0026thinsp;S), and comparisons between groups were performed via t tests. Qualitative data are represented as the number of cases (percentages), and comparisons between groups were performed via the paired chi-square test. Statistical significance was determined when the p value was less than 0.05, indicating that the observed differences were unlikely to be due to chance alone.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eA total of 2.1 4.5% of fetal pCNVs were detected, and a parent-of-origin test was performed in 91 cases.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFrom January 2020 to December 2024, CMA was performed on 13162 prenatal samples. Chromosomal abnormalities were detected in 1151 cases (8.7%), among which common aneuploidies were identified in 564 cases (4.3%), including 254 cases of trisomy 21 (45.0%), 50 cases of trisomy 18 (8.8%), 13 cases of trisomy 13 (2.3%) and 247 cases of sex chromosomal abnormalities (43.8%). pCNVs were detected in 587 cases (4.5%), of which the parent-of-origin test was performed in only 91 cases. Among these 91 patients, the median maternal age and gestational age were 30.0 (range, 27.1\u0026ndash;33.8) years and 18.0 (range, 12.0\u0026ndash;33.0) weeks, respectively. The clinical indications for invasive procedures are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\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\u003eParental Inheritance and Pregnant Outcomes of 91 fetuses with Pathogenic Copy Number Variants (pCNVs)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"12\"\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\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eChromosomal aberration\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003epCNAs\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eMedian Size (Mb)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u003cp\u003eParental Inheritance\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eIndications for prenatal diagnosis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003eTOP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eLoss to follow up\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLocation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of cases\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDeletion\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDuplication\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePaternal\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003ede no vo\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eYES\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eNO\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e2.82(1.39\u0026ndash;3.16)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCongenital heart disease (9)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIncreased NT (4)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAbsence of NB (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eTalipes equinovarus (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAdverse obstetric history (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003eX\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e8.39(1.69\u0026ndash;39.9)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003ehigh risk of NIPT(8)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eShort limbs (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eOmphalocele (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eTethered spinal cord (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIncreased NT (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAbsence of NB with right umbilical vein(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003ehigh risk of Down syndrome (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e1.52(1.34\u0026ndash;11.5)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCongenital kidney development anomaly(7)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eDuodenal stenosis and atresia with bilateral microtia and malformation (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCongenital heart disease (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIncreased NT (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eLateral ventricle widening with short limbs(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eEpendymal cyst(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAdverse obstetric history (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"11\" rowspan=\"12\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"11\" rowspan=\"12\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"11\" rowspan=\"12\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"11\" rowspan=\"12\"\u003e\u003cp\u003e1.31(0.6\u0026ndash;6.9)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"11\" rowspan=\"12\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"11\" rowspan=\"12\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"11\" rowspan=\"12\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eLateral ventricle widening(1)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"11\" rowspan=\"12\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\" morerows=\"11\" rowspan=\"12\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\" morerows=\"11\" rowspan=\"12\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHemivertebra(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eEpendymal cyst(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHigh risk of Down syndrome (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFetal right pulmonary adenoma(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eOmphalocele(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCongenital disease(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eLeft renal hydronephrosis with lateral ventricle expansion(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eBilateral renal dysplasia(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePolydactyly(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHigh risk of NIPT(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIncreased NT (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e3.83(0.5\u0026ndash;6.19)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNIPT high risk (5)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIncreased NT (2)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFetal cleft lip and palate(2)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHigh risk of Down syndrome screening(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e9.2(0.19\u0026ndash;23.2)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIncreased NT (2)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHigh risk of Down syndrome (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFetal clubfoot(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eOne of the twins in MCDA stopped developing(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHigh risk in NIPT (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e1.85(1.74\u0026ndash;33.9)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eDuodenal atresia with widened lateral ventricles (1)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFGR(2)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAdverse obstetric history(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCongenital heart disease (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e7.54,11.7\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCleft lip and palate(1)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAbsence of the nasal bone with single umbilical artery(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e7.68,12.86\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eBilateral renal agenesis with bilateral pulmonary hypoplasia and oligohydramnios(1)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAdverse obstetric history(1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e2.36,3.4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eVentricular septal defect with increased NT\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAgenesis of the corpus callosum\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e6.32,11.5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCongenital heart disease (1)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHigh risk in NIPT (1)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\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\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e5.09\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\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHigh risk in NIPT(1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\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\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHigh risk in NIPT (1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\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\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eRight kidney polycystic (1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\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\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e5.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHigh risk in NIPT(1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\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\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHigh risk in NIPT(1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0\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\u003e8.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eRight kidney polycystic(1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eY\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\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\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHigh risk of Down syndrome (1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Parental inheritance was identified in 27.5% of the cases.\u003c/h2\u003e\u003cp\u003eAmong the 91 cases, inheritance from parents was observed in 25 (27.5%) cases, with maternal inheritance accounting for 60.0% (15/25) and paternal inheritance accounting for 40% (10\u0026ndash;25). The remaining 72.5% of cases (66/90) were identified de novo. The incidences of parental inheritance of pCNVs on chromosomes 15, 16, 17, 22 and X are 50.0%, 25.0%, 30.8%, 25.0% and 28.5%, respectively. There was no statistically significant difference in the incidence of parental inheritance among these different chromosome loci (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.698).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e2.3 When pCNVs are shorter than 6.2 Mb, paternal inheritance is observed in 34.3% of cases\u003c/h2\u003e\u003cp\u003eAmong the 25 patients with paternally inherited pCNVs, the median fragment length was 2.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5 Mb. In contrast, the 66 de novo pCNVs presented a significantly greater median length of 5.7\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2 Mb. Statistical analysis confirmed that paternally inherited pCNVs had significantly shorter fragment lengths than did de novo variants (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011). When a 6.2 Mb cutoff was used to stratify all cases, 70 cases had pCNVs shorter than 6.2 Mb, of which paternal inheritance was identified in 24 cases (34.3%). In contrast, among the 21 patients with pCNVs longer than 6.2 Mb, only 1 patient (4.7%) exhibited paternal inheritance.\u003c/p\u003e\u003cp\u003e\u003cb\u003e2.4 TOP was identified in 96.7% of patients with de novo pCNVs but only in 39.1% of patients with paternally inherited CNVs.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAmong the 91 patients included in this perinatal outcome analysis, eight patients were lost to follow-up. Among the 83 cases with complete data, termination of pregnancy (TOP) was carried out in 67 cases (80.7%). In the subgroup of 60 patients with de novo pCNVs, the TOP was selected in 58 patients (96.7%). The two surviving fetuses (3.3%) presented a deletion in the Xq27 region and a duplication at the 16p11.2 locus. Among the 23 patients with inherited pCNVs, the TOP was chosen in nine patients (39.1%). Among the 14 fetuses (60.8%) that survived to term, the median follow-up duration was 8.6 months (range 5\u0026ndash;18). Extended neonatal follow-up, including serial pediatric evaluations, revealed no clinical evidence of developmental delay or congenital structural anomalies. (See Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\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\u003eClinical follow-up assessment of 16 delivery cases with pCNVs after prenatal diagnosis\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=\"left\" 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=\"char\" char=\".\" 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\u003eCase No.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePrenatal Indications\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eChromosomal Location\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\u003eParental Inheritance\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFollow-up time(months)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCongenital heart disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1q21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePaternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFavorable neonatal outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFetal clubfoot\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2q13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePaternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSurgical treatment of varus foot was performed one month after birth.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh risk in NIPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15q11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFavorable neonatal outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFetal cleft lip and palate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15q11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePaternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCleft lip and palate surgery 6 months after birth\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIncreased NT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15q11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFavorable neonatal outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh risk in NIPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15q11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePaternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFavorable neonatal outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh risk in NIPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15q11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePaternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFavorable neonatal outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOmphalocele\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16p11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ede no vo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSurgical treatment after birth\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh risk in NIPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16p13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFavorable neonatal outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRight kidney hydronephrosis with ureter dilation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17p12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFavorable neonatal outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIncreased NT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22q11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePaternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFavorable neonatal outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh risk in NIPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22q11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFavorable neonatal outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh risk in NIPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eXP22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFavorable neonatal outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh risk in NIPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eXq26.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e17.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFavorable neonatal outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh risk in NIPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eXq27.3q28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e11.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ede no vo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFavorable neonatal outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDevelopmental deficiency of nasal bones; persistent right umbilical vein\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eXp22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFavorable neonatal outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eCMA has several advantages in prenatal diagnosis, such as high resolution, comprehensive detection, no need for cell culture and improved diagnostic yield. CNVs are associated with an increased risk of developmental disorders, congenital anomalies, and various health complications. Research has identified specific CNVs linked to developmental delay, such as those found in the 1q21.1, 3q29, and 15q11.2 regions, and has shown that approximately 1/200 children may carry neurodevelopmental disorder (NDD)-related CNVs. Additionally, CNVs on the X chromosome have been detected in approximately 2.8% of patients with neurodevelopmental disorders, with males potentially exhibiting more severe symptoms. However, CMA has also identified a subset of pathogenic microdeletions or duplications that are inherited from one of the parents. Such inherited copy number variants may have variable expressivity or incomplete penetrance, underscoring the importance of parental studies in risk assessment.\u003c/p\u003e\u003cp\u003e In our study, 27.5% (25/91) of pCNVs were inherited from parents. This result is consistent with the findings of the study performed by Matthen Hoi Kin Chau et al.[5], who reported that parental inheritance was present in 34.4% (107/311) of cases. This conclusion raises a crucial question: when pCNVs are detected during prenatal diagnosis, should we perform a parent-of-origin test for each patient, and if we can confirm the parental origin, how does this information influence genetic counseling and risk assessment for the fetus?\u003c/p\u003e\u003cp\u003eIn this study, we compared the locus and length of pCNVs between patients whose pCNVs were inherited from parents and those whose pCNVs were inherited de novo, and there was no statistically significant difference in the incidence of parental inheritance among different chromosome loci. However, the length of pCNVs inherited from parents is significantly shorter than that of pCNVs inherited de novo. To make this more practical, we set the 95th percentile length of pCNVs inherited from parents as the cutoff and found that parental inheritance occurred in 34.4% of the cases when the length of pCNVs was shorter than 6.2 Mb. In contrast, when the length of pCNVs exceeded 6.2 Mb, only one case (4.7%) exhibited paternal inheritance. This threshold provides practical guidelines for clinical decision-making, particularly in cases where the origin of pCNVs remains ambiguous. Given that shorter pCNVs are more likely to be inherited and thus associated with milder or variable phenotypes, distinguishing parental origin can significantly refine risk assessment and genetic counseling. In contrast, longer pCNVs, especially those exceeding 6.2 Mb, are predominantly de novo and are often linked to more severe clinical outcomes, reinforcing the need for vigilant monitoring and comprehensive evaluation.\u003c/p\u003e\u003cp\u003eThis study further evaluated the perinatal outcomes of fetuses diagnosed with pCNVs. Among the 83 patients whose complete follow-up data were available, 80.7% of the pregnancies were terminated by a TOP. Subgroup analysis revealed a TOP rate of 96.7% in the 60 patients with de novo pCNVs, whereas it was 39.1% in the 23 patients with inherited pCNVs. This striking difference in termination rates underscores the profound impact of inheritance status on parental decision-making, with de novo variants perceived as higher risk. The absence of adverse clinical outcomes in inherited pCNVs further supports their potential benignity or reduced penetrance. Genetic counseling that incorporates inheritance patterns and variant size enables more accurate prognosis estimation. As prenatal detection of pCNVs becomes more common through expanded genomic screening, integrating these factors will be essential for guiding families toward informed, personalized decisions.\u003c/p\u003e\u003cp\u003eOn the basis of the available follow-up data, no clinical evidence of developmental delay or congenital structural anomalies was observed for the 16 live births. These findings suggest that the inheritance pattern of pCNVs plays a critical role in parental decision-making and clinical prognosis. However, the absence of adverse outcomes in live-born infants, although encouraging, must be interpreted cautiously because of the limited follow-up period and small sample size. Long-term neurodevelopmental monitoring is essential to fully ascertain the phenotypic spectrum, especially for inherited pCNVs where late-onset manifestations may not yet be apparent. Genetic counseling should therefore integrate origin, size, inheritance, and family-specific context to support informed decisions.\u003c/p\u003e\u003cp\u003eThe clinical manifestations of 22q11 microeletion/duplication include developmental delay, cardiovascular defects, autistic behavior, and various minor birth defects. However, the penetrance of the 22q11 microdeletion/duplication is estimated to be approximately 20\u0026ndash;30%\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Recurrent 17q12 duplication is inherited in an autosomal dominant manner, with approximately 10% of duplications occurring de novo and approximately 90% being inherited from a parent who is often minimally affected or phenotypically normal\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Patients with the 15q11.2 BP1-BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances, psychiatric problems, autism, seizures, schizophrenia and mild dysmorphic features, which are less common. The 15q11.2 BP1\u0026ndash;BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, NIPA1, and NIPA2) is emerging as a recognized syndrome with a prevalence ranging from 0.57%-1.27% of patients presented for microarray analysis, which is a two- to fourfold increase compared with that of controls. The latest research shows that the penetrance of this fragment is very low, at only 2%\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. 16p11.2 microdeletions or microduplications are found in 0.6\u0026ndash;1% of isolated children with autism, but there are no descriptions of more clinical phenotypes being studied\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Interestingly, through a cohort study of the American Autism Genetic Resource database (Autism Genetic Resource Exchange, AGRE), we found that not all family members with autism have 16p11.2CNVs, and not all 16p11.2CNVs show autism. Therefore, further clinical research is needed to explain the correlation between 16p11.2CNVs and autism\u003csup\u003e[\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn conclusion, in cases where prenatal diagnosis identifies pCNVs, it is imperative to obtain parental inheritance information, particularly when the detected fragment size is under 6.2 Mb, to facilitate comprehensive genetic counseling and assess the potential risks to the fetus. Verification of parental origin can significantly increase the survival rate of fetuses with pCNVs.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003epCNVs pathogenic copy number variations\u003c/p\u003e\n\u003cp\u003eCMA Chromosomal Microarray Analysis\u003c/p\u003e\n\u003cp\u003eFGR fetal growth retardation \u003c/p\u003e\n\u003cp\u003eNT Nuchal Translucency\u003c/p\u003e\n\u003cp\u003eTOP termination of pregnancy\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for this study was obtained from the Ethics Committee of Longgang District Maternity \u0026amp; Child Healthcare Hospital, Shenzhen. The approval date was August 31, 2020, with the reference number LGFYYXLLL-2020-002. All procedures were conducted in accordance with the committee's guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll participants provided written informed consent for the publication of anonymized data and any accompanying images, ensuring confidentiality and compliance with privacy regulations. The study adheres to the principles of the Declaration of Helsinki, ensuring respect for the dignity, rights, and welfare of all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.The authors confirm that all materials used in this study are available upon reasonable request and in compliance with institutional guidelines. No part of this work has been previously published or submitted elsewhere, ensuring originality and integrity in reporting. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFundings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported (or partially supported) by the Shenzhen Longgang District Science and Technology Innovation Bureau (LGKCYLWS2023016) and the Shenzhen Longgang District Science and Technology Innovation Bureau (LGWJ2024-46).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003cbr\u003e\u003c/strong\u003eFeiFei Chen, SiQi Wu, LiPing Wu: data collection and follow-up. RuChun Huang, WeiQiang Liu: Laboratory operations and CMA. XiaoYi Cong: pCNV interpretation. Xin Yang@Tu Xinzhi: study design, supervision, manuscript drafting. All the authors reviewed and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to express our sincere gratitude to all the participants and their families who generously contributed to this study. Their trust and cooperation were essential to the completion of this research. We appreciate the valuable insights and suggestions from colleagues in the field of prenatal genetics, which helped improve the quality of this manuscript.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSociety for Maternal-Fetal Medicine (SMFM). Electronic address: [email protected]; Dugoff L, Norton ME, Kuller JA. The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016 Oct;215(4):B2-9. doi: 10.1016/j.ajog.2016.07.016. Epub 2016 Jul 15. Erratum in: Am J Obstet Gynecol. 2017 Feb;216(2):180. doi: 10.1016/j.ajog.2016.11.1031. PMID: 27427470.\u003c/li\u003e\n\u003cli\u003eShi X, Huang W, Lu J, He W, Liu Q, Wu J. Prenatal diagnosis of Miller-Dieker syndrome by chromosomal microarray. Ann Hum Genet. 2021 Mar;85(2):92-96. doi: 10.1111/ahg.12407. Epub 2020 Oct 7. PMID: 33026665.\u003c/li\u003e\n\u003cli\u003eWapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, Savage M, Platt LD, Saltzman D, Grobman WA, Klugman S, Scholl T, Simpson JL, McCall K, Aggarwal VS, Bunke B, Nahum O, Patel A, Lamb AN, Thom EA, Beaudet AL, Ledbetter DH, Shaffer LG, Jackson L. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012 Dec 6;367(23):2175-84. doi: 10.1056/NEJMoa1203382. PMID: 23215555; PMCID: PMC3549418.\u003c/li\u003e\n\u003cli\u003eWapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, Savage M, Platt LD, Saltzman D, Grobman WA, Klugman S, Scholl T, Simpson JL, McCall K, Aggarwal VS, Bunke B, Nahum O, Patel A, Lamb AN, Thom EA, Beaudet AL, Ledbetter DH, Shaffer LG, Jackson L. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012 Dec 6;367(23):2175-84. doi: 10.1056/NEJMoa1203382. PMID: 23215555; PMCID: PMC3549418.\u003c/li\u003e\n\u003cli\u003eLan L, Luo D, Lian J, She L, Zhang B, Zhong H, Wang H, Wu H. Chromosomal Abnormalities Detected by Chromosomal Microarray Analysis and Karyotype in Fetuses with Ultrasound Abnormalities. Int J Gen Med. 2024 Oct 14;17:4645-4658. doi: 10.2147/IJGM.S483290. PMID: 39429961; PMCID: PMC11488349.\u003c/li\u003e\n\u003cli\u003eChau MHK, Cao Y, Kwok YKY, Chan S, Chan YM, Wang H, Yang Z, Wong HK, Leung TY, Choy KW. Characteristics and mode of inheritance of pathogenic copy number variants in prenatal diagnosis. Am J Obstet Gynecol. 2019 Nov;221(5):493.e1-493.e11. doi: 10.1016/j.ajog.2019.06.007. Epub 2019 Jun 14. PMID: 31207233.\u003c/li\u003e\n\u003cli\u003eHuang R, Fu F, Zhou H, Zhang L, Lei T, Cheng K, Yan S, Guo F, Wang Y, Ma C, Li R, Yu Q, Deng Q, Li L, Yang X, Han J, Li D, Liao C. Prenatal diagnosis in the fetal hyperechogenic kidneys: assessment using chromosomal microarray analysis and exome sequencing. Hum Genet. 2023 Jun;142(6):835-847. doi: 10.1007/s00439-023-02545-1. Epub 2023 Apr 24. PMID: 37095353.\u003c/li\u003e\n\u003cli\u003eKearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST; Working Group of the American College of Medical Genetics Laboratory Quality Assurance Committee. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011 Jul;13(7):680-5. doi: 10.1097/GIM.0b013e3182217a3a. PMID: 21681106.\u003c/li\u003e\n\u003cli\u003eSouth ST, Lee C, Lamb AN, Higgins AW, Kearney HM; Working Group for the American College of Medical Genetics and Genomics Laboratory Quality Assurance Committee. ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. 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PMID: 32993859; PMCID: PMC7606557.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Prenatal diagnosis, Pathogenic chromosomal copy number variants (pCNVs), Parental inheritance","lastPublishedDoi":"10.21203/rs.3.rs-7739350/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7739350/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eIn prenatal diagnosis, chromosomal microarray(CMA) demonstrates a significantly higher diagnostic yield than conventional karyotyping. Nevertheless, evidence regarding the clinical outcomes of fetuses with pathogenic copy number variants(pCNVs) remains limited, with few studies specifically addressing this outcome. This study aimed to retrospectively evaluate the perinatal outcomes of fetuses with pathogenic copy number variations (pCNVs) with confirmed parental inheritance patterns.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eFrom 2019 to 2024, 587 pCNVs were identified, with 91 cases subjected to parental analysis. Maternal information, anomaly scans, and pregnancy complications were documented as part of our comprehensive prenatal assessment. Follow-up data regarding pregnancy outcomes and neonatal health (up to 18 months post-partum) were collected.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eIn 91 patients, 25 (27.5%) exhibited inherited pCNVs with a median length of 2.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5 Mb, whereas 66 (72.5%) presented de novo pCNVs with a median length of 5.7\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2 Mb, indicating a significant difference in length between the two groups (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.011). Parental inheritance occurred in 34% of pCNVs\u0026thinsp;\u0026lt;\u0026thinsp;6.2 Mb. Among the 60 de novo cases with follow-up data, 58 (96.7%) opted for termination (TOP). Among the 23 inherited cases, 9 (39.1%) chose TOP. The 14 surviving term fetuses presented no developmental delay or structural anomalies.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eWhen pCNVs are detected in prenatal diagnosis, parental inheritance information should be provided, especially in cases where the fragment length is less than 6.2 Mb. Parental origin verification has been shown to significantly improve the survival rate of fetuses with pCNVs.\u003c/p\u003e","manuscriptTitle":"Perinatal outcomes of fetuses with pathogenic copy number variants (pCNVs) and confirmed parental inheritance patterns: A retrospective study at a single institution","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-24 09:30:47","doi":"10.21203/rs.3.rs-7739350/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"24ca8bc5-5520-46b4-973b-d49cad60a957","owner":[],"postedDate":"November 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T20:25:59+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-24 09:30:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7739350","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7739350","identity":"rs-7739350","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}