Prenatal diagnosis, ultrasound characteristics and pregnancy outcomes of 16p11.2 deletion and duplication syndromes

Prenatal diagnosis, ultrasound characteristics and pregnancy outcomes of 16p11.2 deletion and duplication syndromes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prenatal diagnosis, ultrasound characteristics and pregnancy outcomes of 16p11.2 deletion and duplication syndromes Xiaoyi Cong, Guanhua Duan, Tong Zhang, Xiaojin Luo, Hongyan Niu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8402789/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background Recurrent copy number variations (CNVs) in the 16p11.2 region are a prevalent cause of neurodevelopmental disorders. This study aims to investigate the prenatal phenotypic characteristics of 19 fetuses with 16p11.2 deletion/duplication syndromes and the results of single nucleotide polymorphism array (SNP-array) analysis. Methods We retrospectively analyzed 9671 pregnant women who underwent amniocentesis in Longgang Maternal and Child Health Hospital in Shenzhen from November 2018 to August 2025. SNP-array and G-banding karyotyping were performed on amniotic fluid samples from those pregnant women. The fetuses with 16p11.2 deletion/duplication detected by SNP-array were followed up. Results Out of the 9671 cases, 19 were diagnosed with 16p11.2 deletion/duplication, yielding a detection rate of 0.2%(19/9671). Among these cases, eleven fetuses exhibited a 16p11.2 deletion, while eight fetuses demonstrated a 16p11.2 duplication. Of these, eight deletions encompassed the proximal 16p11.2 region (BP4-BP5), while three deletions involved the distal 16p11.2 region (BP2-BP3). Among the eightidentified duplications, five encompassed the BP4-BP5 region, and two involved the BP2-BP3 region. Another case exhibited both proximal and distal duplications (BP2-BP5). Among the 19 cases diagnosed with 16p11.2 deletion or duplication, six cases exhibited structural abnormalities in different systems, includingtwo caseswith cardiovascular abnormalities, one case with cerebral abnormalities. Additionally, one fetus demonstrated pulmonary abnormalities, one presented clubfeet and another one presented with cleft lip and palate. Various ultrasound soft marker abnormalities were observed in five cases, including nuchal translucency thickening, lateral ventricular enlargement, single umbilical artery, and choroid plexus cyst. Eight cases showed no significant ultrasound abnormalities. Conclusions Fetuses possessing a 16p11.2 deletion or duplication demonstrate a broad spectrum of clinical features, characterized by incomplete penetrance and variable expressivity. In comparison to 16p11.2 duplication, individuals with a 16p11.2 deletion/duplication single nucleotide polymorphism microarray technology(SNP-array) prenatal phenotypes copy number variation(CNV) abnormal ultrasound findings Figures Figure 1 Figure 2 Introduction With the widespread application of chromosomal microarray analysis (CMA) in prenatal diagnostics, there has been an increasing identification of fetal diseases and abnormal phenotypes associated with copy number variations (CNVs). The CNV at chromosome 16p11.2 is a prevalent contributor to neurodevelopmental disorders. Approximately 71% of proximal 16p11.2 deletions occur de novo, with an incidence rate of approximately 1 in 2,000 individuals (0.05%). In contrast, the occurrence of 16p11.2 duplication is approximately 3 in 10,000 (0.03%), with approximately 70% of these duplications inherited from parental carriers [ 1 – 2 ] . Chromosome 16p11.2 encompasses a cluster of low-copy repeats (LCRs) that facilitate meiotic non-allelic homologous recombination, leading to either deletions or duplications within this region. Copy number variations (CNVs) in the 16p11.2 region predominantly involve two core susceptible areas: one is a CNV in the proximal region encompassing TBX6 (chr16:29.6Mb-30.2Mb), and the other is in the distal region containing SH2B1 (chr16:28.8Mb-29.0Mb). Clinical phenotypes associated with proximal deletions of 16p11.2 include abnormalities of the skeletal and cardiovascular systems, neurodevelopmental disorders, and autism spectrum disorder [ 3 ] . Some fetuses exhibited structural malformations or various soft marker abnormalities on ultrasonography, whereas others displayed no discernible aberrant phenotypes. Previous research has predominantly concentrated on the phenotypes observed in postpartum cases, resulting in a paucity of clinical data concerning prenatal fetuses. Furthermore, there is a lack of systematic descriptions of their clinical features, pregnancy outcomes, and prognosis. Moreover, the diverse phenotypes and incomplete penetrance of these conditions present great challenges to clinical genetic counseling. Therefore, there is an urgent need for additional prenatal case data to further investigate the genotype-phenotype mechanisms influencing the penetrance and expressivity of this syndrome. This study retrospectively analyzed the molecular genetic characteristics and abnormal ultrasound findings of 19 fetuses with 16p11.2 deletion or duplication, and enriched the phenotypic spectrum of this syndrome. Materials and methods Subjects Between November 2018 to August 2025, a cohort of 19 pregnant women who underwent amniocentesis at Longgang Maternal and Child Health Hospital in Shenzhen was selected as participants for this study. These individuals were identified as having a 16p11.2 deletion or duplication through SNP-array analysis. The primary indications for prenatal diagnosis in these cases included congenital structural anomalies, abnormal ultrasound markers, advanced maternal age, and high risk of serological screening. The study was approved by the Medical Ethics Committee (LGFYKYXMLL-2024-39), and written informed consent was obtained from all participants before testing. Amniotic fluid collection and DNA extraction Amniocentesis was conducted on cases identified as high-risk, during which 5 mL of amniotic fluid was collected. Subsequently, DNA was extracted from the collected amniotic fluid using the QIAamp DNA Blood Mini Kit (No. 51106, Qiagen, Germany), in accordance with the manufacturer's protocol. Single nucleotide polymorphism array analysis (SNP-array) SNP-array was conducted using the Affymetrix Cytoscan 750K chip (Thermo Fisher, CA, USA). DNA samples were prepared in accordance with the manufacturer's protocol, encompassing steps such as digestion, ligation, PCR amplification, purification, fragmentation, and labeling for hybridization and chip scanning. The short tandem repeat (STR) method was employed to detect any maternal blood contamination, and confirm that there was no contamination. Data analysis was performed using the Chromosome Analysis Suite(ChAS 4.3) software. CNV results were filtered using a threshold of 100 kilobase pairs (Kb) and a minimum of 50 probe markers. Databases, including the UCSC Genome Browser, DECIPHER, DGV, and ClinGen, were consulted for the classification and interpretation of CNVs. Subsequently, the results were categorized into five classifications: pathogenic, likely pathogenic, of undetermined significance, likely benign, and benign. Classification of 16p11.2 copy number variations The 16p11.2 CNVs can be categorized into two primary susceptible regions based on distinct breakpoints: the proximal deletion, also referred to as the typical deletion (BP4-BP5, ISCA-37400), which encompasses the TBX6 gene; and the distal deletion (BP2-BP3, ISCA-37486), which includes the SH2B1 gene. Karyotype analysis Twenty milliliters of amniotic fluid were inoculated into two sterile cell culture flasks and incubated at 37°C with 5% CO2 for a duration of 6 to 8 days, contingent upon the growth status of the cultures. Chromosome preparations were conducted using conventional methods, including harvesting, titration, and banding. Partial karyotypes were scanned using Leica automated karyotyping systems, and only well-distributed banded karyotypes were selected for further analysis. The karyotypes were interpreted in accordance with the 2020 International System for Human Cytogenetic Nomenclature (ISCN2020). Pregnancy outcome follow-up All cases with 16p11.2 deletions or duplications detected by SNP array were followed up after birth. Results SNP array results During the study period, a total of 9671 fetuses underwent SNP array testing. Among these, eleven fetuses were identified with 16p11.2 deletions, and eight fetuses exhibited 16p11.2 duplications. The median maternal age was 32 ± 6 years, ranging from 22 to 44 years. The median gestational age at the time of prenatal diagnosis was 21 ± 5 weeks, with a range spanning from 13 to 31 weeks. Among the eleven cases exhibiting 16p11.2 deletions, cases 1 to case 8 presented with proximal deletions ranging from 500 to 900 kb, encompassing OMIM genes including PRRT2, TBX6, SEZ6L2, KCTD13, ALDOA, KIF22, and TLCD3B. In contrast, case 9 to case11 exhibited a distal deletion, primarily involving OMIM genes such as SH2B1, SPNS1, TUFM, and CD19. Among the eight cases identified with 16p11.2 duplications through SNP-array analysis, five cases exhibited proximal duplications ranging from 700 kb to 900 kb, one case presented with both proximal and distal duplications measuring 1863kb, and the other two cases demonstrated distal duplications of 200 kb to 400 kb(Fig. 1 ). Subsequent familial verification revealed that three of these cases involved de novo mutations, one case inherited from the father. whereas the remaining four cases were not eligible for verification. Karyotype analysis conducted on all 19 fetuses did not reveal any abnormalities. Pathogenicity analysis of CNV The proximal deletions span from 500 to 900 Kb, encompassing the 16p11.2 recurrent region (BP4-BP5, including TBX6). According to the ClinGen database, this region has a Haploinsufficiency Score of 3, indicating it is a well-established region of haploinsufficiency sensitivity. Case 9 and case11 involve the 16p11.2 distal recurrent region (BP2-BP3, including SH2B1), which also has a Haploinsufficiency Score of 3, confirming its status as a recognized haploinsufficiency sensitivity region. Case 10 did not fully encompass the 16p11.2 distal recurrent region. This deletion was classified as a CNV of unclear clinical significance. Most of the proximal duplications detected via SNP-array analysis fully encompass the recurrent 16p11.2 region (proximal, BP4-BP5), which includes the TBX6 gene. This region has a triplosensitivity score of 3, and according to the ACMG scoring standards, these CNVs were classified as pathogenic. While the duplication observed in case 12 is considered a likely pathogenic CNV. Although it does not entirely cover the recurrent 16p11.2 region, it includes the TBX6 gene, which is a critical gene within this region. Case 14 also fully encompasses the 16p11.2 recurrent region (BP2-BP5) and is similarly classified as a pathogenic CNV. The another two cases encompass the 16p11.2 distal recurrent region (BP2-BP3), which includes the SH2B1 gene and has a triplosensitivity score of 1. Currently, there is insufficient evidence to establish the pathogenicity of this distal region. According to CNV evaluation criteria, these two distal duplications are classified as CNVs of uncertain clinical significance. Ultrasonic results Among the 19 instances of 16p11.2 deletion or duplication syndrome, ultrasound abnormalities were observed in 7 deletion cases (63.6%, 7/11) and in 3 duplication cases(37.5%, 3/8), as detailed in Table 1 and Table 2 . Notably, two of these deletion cases demonstrated the cardiovascular system abnormalities: one involving complex congenital heart disease and another characterized by a single umbilical artery. Furthermore, three cases demonstrated craniocerebral abnormalities: one case showed the absence of the corpus callosum accompanied by bilateral lateral ventricle enlargement, one presented with a midsagittal chamber and nuchal translucency (NT) thickening, while another case showed bilateral lateral ventricle dilation combined with posterior cranial fossa cistern dilation. There was also a case that showed clubfeet. An additional case was characterized by isolated NT thickening. Among the eight fetuses with 16p11.2 duplications, one was diagnosed with pulmonary cystadenoma (refer to Fig. 2 ), and one showed subependymal cyst in the left lateral ventricle combined with tricuspid regurgitation. Another case showed cleft lip and palate. Whereas the remaining five did not display any discernible abnormalities. Table 1 Prenatal ultrasound features of fetuses with 16p11.2 deletions Ultrasound findings cases Percent (%) Abnormal cardiovascular system Complex congenital heart disease Single umbilical artery Abnormal craniocerebral Absence of corpus callosum Lateral ventricle widening Midsail chamber Posterior cranial fossa cistern widening Abnormalities of the skeletal system clubfoot NT thicken 2 1 1 5 1 2 1 1 1 1 2 20 10 10 50 10 20 10 10 10 10 20 Total 10 NT: thickness of the transparent layer of the neck Table 2 Detailed information of 12 cases with 16p11.2 deletion/duplication Case No. Age GA (wk) Indications for prenatal diagnosis CMA CNV Size Region Ultrasound findings Outcome 1 22 25 + 4 Unclear venous catheter arr[GRCh37] 16p11.2(29351827_30176508)x1 825Kb BP4-BP5 Single umbilical artery; unclear venous catheter TOP 2 44 26 + 4 High risk of prenatal serological screening arr[GRCh37] 16p11.2(29580021_30371223)x1 791Kb BP4-BP5 Double aortic arch; the left superior vena cava was persistent CHD 3 31 25 + 2 Abnormal Ultrasound Findings arr[GRCh37] 16p11.2(29343462_30190029)x1 846Kb BP4-BP5 The corpus callosum was absent; placenta rotunda; the right lateral ventricle hydrops; the lateral ventricles were widened bilaterally, with the left side 1.3 cm and the right side 2.2 cm TOP 4 29 16 + 6 Abnormal Ultrasound Findings arr[GRCh37] 16p11.2(29,580,021_30,190,029)x1 610Kb BP4-BP5 NT 3.0mm; the middle velum of the fetus(0.77*0.44cm) Live birth with underheight and underweight 5 29 13 + 5 Abnormal Ultrasound Findings arr[GRCh37] 16p11.2(29,580,021_30,176,508)x1 596Kb BP4-BP5 NT thickening(4.2mm) TOP 6 37 17 High risk of prenatal serological screening arr[GRCh37] 16p11.2(29,580,021_30,177,916)x1 598Kb BP4-BP5 Normal TOP 7 40 19 + 3 Senior age, History of adverse pregnancy and childbirth arr[GRCh37] 16p11.2(29,580,021_30,190,029)x1 610Kb BP4-BP5 Normal TOP 8 30 16 + 6 Abnormal Ultrasound Findings arr[GRCh37] 16p11.2(29,580,021_30,176,508)x1 596Kb BP4-BP5 Normal TOP 9 42 18 + 2 High risk of prenatal serological screening, advanced age arr[GRCh37] 16p11.2(28,852,776_29,032,280)x1 180Kb BP2-BP3 Normal TOP 10 30 27 + 3 Abnormal Ultrasound Findings arr[GRCh37] 16p11.2(28,852,776_29,032,280)x1 180Kb BP2-BP3 The lateral ventricles were widened bilaterally, with the left side of 1.08 cm and the right side of 1.33 cm; Posterior cranial fossa cistern widening Live birth 11 30 25 Abnormal Ultrasound Findings arr[hg19] 16p11.2(28,371,467 − 29,428,532)x1 1.06Mb BP2-BP3 clubfoot TOP 12 25 19 + 4 High risk of prenatal serological screening arr[GRCh37] 16p11.2(29,428,532_30,190,029)x3 761Kb BP4-BP5 Normal TOP 13 30 17 + 3 High risk of sex chromosome screening by NIPT arr(X)×2,(Y)×1 arr[GRCh37] 16p11.2(29,591,327_30,339,365)x3 748Kb BP4-BP5 Normal TOP 14 30 20 Abnormal Ultrasound Findings arr[GRCh37] 16p11.2(28,488,011_30,350,748)x3 1863Kb BP2-BP5 Right choroid plexus cyst; Pulmonary cystadenoma TOP 15 30 31 + 3 Abnormal Ultrasound Findings arr[GRCh37] 16p11.2(29,428,532_30,350,748)x3 922Kb BP4-BP5 Subependymal cyst in the left lateral ventricle; tricuspid regurgitation Live birth 16 34 18 Abnormal Ultrasound Findings arr[GRCh37]4p16.3p16.1(68,346_7,453,158)x1 arr[GRCh37]11q22.3(104,328,778_105,959,082)x3 arr[GRCh37] 16p11.2(29,428,532_30,330,881)x3 902Kb BP4-BP5 Fetal cleft lip and palate TOP 17 26 26 NIPT indicates an increase in the number of chromosome 7 arr[hg19] 16p11.2(29,580,020–30,190,029)x3 610Kb BP4-BP5 Normal Live birth 18 37 17 + 4 High risk of prenatal serological screening, advanced age arr[GRCh37] 16p11.2(28810325_29032280)x3 222Kb BP2-BP3 Normal Live birth with underweight 19 30 17 + 5 High risk of prenatal serological screening arr[GRCh37] 16p11.2(28,708,187_29,043,863)x3 336Kb BP2-BP3 Normal Loss to follow-up 20 2 / Speech and language delay, Poor self-care ability in daily life (Clinical manifestations during childhood) arr[GRCh37] 16p11.2(29580021_30339365)x3 759Kb BP4-BP5 Normal Language development delay and poor social interaction skills GA : gestational age; wk:weeks; TOP: terminate of pregnancy; CHD: congenital heart disease. Pregnancy outcomes and follow-up Among the 19 pregnant women with SNP-array results showing CNVs in the 16p11.2 region, 7 cases with deletions and 4 with duplications opted for termination after genetic counseling. One case (case 5) resulted in spontaneous abortion at 20 weeks due to premature rupture of membranes. Case 2 was delivered via cesarean section at 40 weeks, weighing 3800g, with an Apgar score of 10, but had complex congenital heart disease. The fetus of cases 4 was delivered at 39 + 6 weeks with normal phenotypes. When he was 30 months old, his height and weight status was classified as underheight (<-2SD) and underweight (<-2SD) with no other abnormal conditions. The 16p11.2 deletion CNV of case 10 was inherited from the mother and the fetus was delivered without any abnormal phenotypes. Case15 and case17 give birth to healthy female infants without any abnormal phenotypes. The fetus of case18 was delivered at 39 weeks, weighing 3130g, with an Apgar score of 10. When he was 32 months old, his weight status was classified as underweight (<-1SD) with no other abnormal conditions. Case 19 was lost to follow-up. In this study, in addition to the prenatal cases, we also included a 2-year-old child who carried a proximal duplication in the 16p11.2 region(case20). His main clinical manifestations include delayed language development, poor self-care ability and interpersonal communication skills(Table 2 ). Discussion A 99.5% sequence-homologous low-copy repeat, approximately 147 Kb in length, flanks each side of the 16p11.2 core susceptibility region, making it susceptible to nonallelic homologous recombination (NAHR) during cell division. Consequently, daughter cells exhibit a propensity for CNVs within the 16p11.2 region [ 4 ] . In this study, 11cases of 16p11.2 deletion, identified through SNP-array analysis, displayed variability in size. The differing sizes and locations of these CNVs result in variations in the number and types of genes encompassed, leading to diverse clinical phenotypes. GeneReviews provided a detailed update on the clinical phenotypes of 16p11.2 deletion in 2021. The conditions observed encompassed a range of developmental delays and mental and behavioral disorders, affecting over 90% of the population studied. Speech disorders were present in 80%–90% of individuals, while obesity was observed in 75%. Motor coordination difficulties affected 60% of the cohort, and autism spectrum disorders were identified in 20%–25%. Epilepsy was diagnosed in 25% of cases, and vertebral malformations were present in 21%. Hearing loss was observed in less than 11% of individuals, paroxysmal dyskinesia in up to 9%, and cardiac malformations in 6% [ 5 ] . The literature on 16p11.2 duplication is limited. Clinical manifestations associated with proximal 16p11.2 duplication, particularly involving the TBX6 gene, encompass developmental delays, intellectual disabilities, seizures, behavioral issues, autism spectrum disorders, microcephaly, and various other congenital anomalies [ 6 – 7 ] . Neuropsychiatric symptoms are the most prevalent phenotypes observed in carriers recruited by the 16p11.2, followed by malformations of the skeletal and cardiovascular systems. Due to the challenges in accurately assessing fetal intelligence, language development, and other aspects of nervous system development prenatally, the identification of this syndrome relies heavily on medical imaging techniques such as ultrasound. Given the extensive use of ultrasound in prenatal diagnostics and its efficacy in detecting abnormalities in the cardiovascular and spinal systems, the identification of prenatal phenotypes associated with 16p11.2 is likely to focus primarily on these two systems. In this study, among the 11instances of 16p11.2 deletion identified, 3 cases exhibited structural malformations as determined by ultrasound examination. These structural malformations mainly distributed in the skeletal system, the cardiovascular system and the central nervous system. Among the 9 cases with 16p11.2 duplication, two cases with proximal duplications were noted to have abnormalities of the respiratory system and the cardiovascular system. Wang et al. [ 8 ] reported that skeleton and cardiovascular system abnormalities were the two most common structural malformations associated with the 16p11.2 deletion. Li et al. [ 9 ] documented a case involving monozygotic twins with a 16p11.2 distal deletion. Fetus A exhibited aortic coarctation, left ventricular noncompaction, an atrial septal defect, pericardial effusion, and left hydronephrosis, whereas fetus B presented with a single umbilical artery. Both fetuses experienced intrauterine growth restriction; however, postnatally, fetus A demonstrated moderate delays in speech and psychomotor development, in contrast to fetus B, who exhibited normal cognitive and behavioral development. Recent findings have further corroborated the presence of variability in the penetrance and expressivity of clinical phenotypes among individuals harboring distinct 16p11.2 deletions. The etiological factors contributing to discordant phenotypes in monozygotic twins primarily encompass epigenetic modifications, environmental influences, asymmetric embryonic division, differential cellular differentiation, and aberrant placental blood flow. In instances where ultrasound imaging reveals congenital cardiac structural anomalies in the fetus, it is imperative to conduct a thorough investigation to exclude the presence of copy number variations in the 16p11.2 region. Carriers of the 16p11.2 copy number variant exhibit a range of neurological symptoms, predominantly including autism spectrum disorder, intellectual disability, epilepsy, and behavioral abnormalities [ 10 ] . In this study, case 3 exhibited structural abnormalities in the central nervous system as detected by ultrasound. The deleted regions in this instance primarily involve genes such as PRRT2 and SEZ6L2. The precise mechanisms by which these gene deletions result in abnormal phenotypes in patients remain poorly understood. Current research suggests that the PRRT2 gene encodes a transmembrane protein and is recognized a well-defined haploinsufficiency-sensitive gene. Mutations in this gene have been linked to conditions such as episodic kinesigenic dyskinesia 1, benign familial infantile epilepsy type 2, migraine, and complex neurodevelopmental disorders [ 11 – 12 ] . It has been reported that individuals harboring loss-of-function variants in the PRRT2 gene exhibit clinical phenotypes, including epilepsy and paroxysmal kinesigenic dyskinesia [ 13 – 14 ] . Similarly, deletions in the SEZ6L2 gene may be linked to phenotypes such as abnormal behavior and autism [ 15 – 16 ] . Due to our inability to obtain clinical phenotypic data of the fetal nervous system, and the subsequent decision by the pregnant woman to terminate the pregnancy following the SNP array results, an in-depth investigation into the genotype–phenotype correlation in these instances were not feasible. Case 20 has a duplication in the 16p11.2 proximal region. His clinical manifestations mainly include language development delay, poor self-care ability and social interaction skills, and other abnormal behavioral problems. Therefore, individuals with a deletion or duplication of the 16p11.2 region may all exhibit neurological symptoms. We conducted follow-up studies on some cases after birth. Cases 4, which had a proximal deletion, and case 18, which had a distal duplication, both showed underheight or underweight. Therefore, when there is a copy number variation in the 16p11.2 region, height and weight indexes are also indicators that require special attention. Due to the atypical ultrasound phenotype associated with the duplication of the 16p11.2 region, there have been few prenatal cases of 16p11.2 duplication reported. In this study, among the nine detected cases of 16p11.2 duplication, five fetuses and one child did not present any abnormal ultrasound findings. This suggests that, compared to carriers of 16p11.2 microduplication, deletions in this region are more likely to result in aberrant ultrasound findings. Yue et al. [ 17 ] reported that among 20 carriers of 16p11.2 copy number variations (including 15 cases of deletion and 5 cases of duplication), 11 cases with deletion exhibited varying degrees of ultrasound abnormalities, whereas none of the duplication cases showed abnormal ultrasound results. These findings are consistent with the results of our study. In this study, we have documented for the first time the occurrence of pulmonary cystadenoma in individuals with a 16p11.2 duplication (case 10). Currently, there is insufficient evidence to establish a definitive correlation between this specific pulmonary malformation and the 16p11.2 copy number variation. However, it is important to consider that phenotypic variability resulting from inconsistent penetrance and expressivity cannot be entirely ruled out. In cases of 16p11.2 deletion, the most prevalent structural malformations are abnormalities of the skeletal system, such as scoliosis, which may be associated with the deletion of the TBX6 gene [ 18 – 19 ] . In contrast to previous studies (refer to Table 3 ) [ 17 , 20 – 22 ] , the detection rate of skeletal system abnormalities in this study was notably different. Only one case of skeletal system were observed, which may be attributed to two factors: firstly, some cases were diagnosed with 16p11.2 deletion at an early gestational age, leading to the decision to terminate the pregnancy before conducting a four-dimensional color Doppler ultrasound; secondly, the phenotypic manifestations associated with 16p11.2 copy number variations exhibit variability in penetrance and expressivity, resulting in heterogeneous clinical phenotypes among different individuals. Wu et al. [ 23 ] identified an association between the haplotype T-C-A of the single nucleotide polymorphisms rs2289292, rs3809624, and rs3809627 in the TBX6 gene and spinal deformity. The study posited that the manifestation of spinal deformity requires the concurrent presence of deletion and single nucleotide variation alleles at the specified genetic loci. This finding may also elucidate why not all individuals with 16p11.2 deletions, which encompass the TBX6 gene, exhibit spinal abnormalities. Despite the close relationship between the functions of these genes and the clinical phenotype, it remains uncertain whether genetic variation will invariably result in the corresponding phenotype. Further postpartum follow-up studies are necessary to clarify the correlation between genotype and phenotype. Table 3 Comparation of the clinical phenotypes of 16p11.2 deletion cases between this study and previous studies References Abnormalities of the skeletal system Abnormalities of the cardiovascular system Abnormalities of the central nervous system Abnormalities of the urinary system Abnormalities of digestive System Abnormalities of the ultrasound soft markers This study 9.1% (1/11) 9.1% (1/11) 9.1% (1/11) 36.4% (4/11) [17] 13%(2/15) 13%(2/15) 7% (1/15) 53%(8/15) [20] 48% (39/81) 31%(25/81) 11% (9/81) 6% (5/81) [21] 50%(4/8) 38%(3/8) 13% (1/8) [22] 42%(5/12) 58%(7/12) 8%(1/12) 33%(4/12) In this study, five instances of 16p11.2 deletion exhibited abnormalities in ultrasound soft markers. Previous research has indicated that the presence of abnormal ultrasound soft markers, such as increased NT thickness during prenatal screening, is associated with an elevated risk of fetal chromosomal aneuploidy or deletion/duplication. Furthermore, the likelihood of chromosomal abnormalities escalates with greater NT thickness. Notably, when NT measures ≥ 6.5 mm, the risk of chromosomal abnormalities can reach as high as 71.43% [ 24 ] . Among the remaining eight cases, which exhibited no abnormal findings on ultrasound, the indications for prenatal diagnosis were as follows: advanced maternal age, a high risk identified through prenatal serological screening, and abnormal non-invasive prenatal test results. Consequently, it is recommended that prenatal diagnostic procedures be undertaken to assess for chromosomal abnormalities when ultrasound reveals abnormal soft markers or when prenatal diagnostic indications, such as high-risk serological screening and advanced maternal age, are present. In this study, we conducted a comprehensive analysis of the diversity and incomplete penetrance of phenotypes associated with 16p11.2 deletion/duplication syndrome. This investigation contributed additional phenotypic characteristics and expanded the phenotypic spectrum of 16p11.2 copy number variations. A limitation of the study was the decision by some pregnant women to undergo labor induction, which precluded the acquisition of phenotypic data from the postpartum fetus. It is recommended that chromosomal microarray analysis (CMA) be performed when prenatal ultrasound detects malformations in the cardiovascular, nervous, or skeletal systems, or when there are abnormalities in ultrasound soft markers and elevated risks in serological screening, to confirm the presence of 16p11.2 copy number variations. Enhanced follow-up is advised for live births diagnosed with 16p11.2 deletion/duplication to gather additional abnormal phenotypes, further augment the phenotypic spectrum of this syndrome, and aid in genetic counseling. Declarations CONFLICTS OF INTEREST The authors have no conflict of interest to declare. FUNDING STATEMENT This research was funded by the Medical and Health Technology Research Project of Longgang District, Shenzhen City (grant LGWJ2023-56), the Medical and Health Technology Research Project, Special Funds for Science and Technology Innovation in Longgang District, Shenzhen City (grant LGKCYLWS2022013), and the Natural Science Foundation of Shenzhen City (JCYJ20230807141908017). BULLETED STATEMENTS what's already known about this topic? Fetuses with 16p11.2 deletion/duplication exhibit a wide range of clinical characteristics, including varying expressability and incomplete penetrance. The most common structural malformation associated with 16p11.2 deletion is an abnormality of the skeletal system, which is usually associated with scoliosis. what does this study add? The most common structural malformations in 16p11.2 deletion carriers in this study were malformations of the cardiovascular system and brain development. Individuals carrying a 16p11.2 deletion may exhibit underweight and underheight. Compared with 16p11.2 duplication, 16p11.2 deletion is more likely to have abnormal ultrasound phenotype. In addition, we report a pulmonary cystadenoma in a patient with a 16p11.2 duplication for the first time. C ONSENT FOR P UBLICATION STATEMENTS Informed consent for publication was obtained from all the patients in the study. DECLARATIONS a) Ethics approval and consent to participate statement The study was approved by the Medical Ethics Committee of Shenzhen Longgang District Maternal and Child Health Hospital (No. LGFYKYXMLL-2024-39). Written informed consent was obtained from all participants before testing. b) Consent for publication NOT APPLICABLE. c) Availability of data and materials Data are available upon reasonable request from XY Cong. d) Authors' contributions Conceptualization, data analysis, and manuscript writing: XY.Cong, Clinical data collection and experiment: T.Zhang, HY Niu, Ultrasound data collection: GH.Duan. Writing review and editing: XJ.Luo,WQ.Liu. All authors read and approved the manuscript and are accountable for all study aspects. References liva-Teles N, de Stefano MC, Gallagher L et al. Rare Pathogenic Copy Number Variation in the 16p11.2 (BP4-BP5) Region Associated with Neurodevelopmental and Neuropsychiatric Disorders: A Review of the Literature[J]. Int J Environ Res Public Health, 2020,17(24):9253. doi: 10.3390/ijerph17249253. Chung WK, Roberts TP, Sherr EH et al. 16p11.2 deletion syndrome[J]. Curr Opin Genet Dev, 2021 , 68:49-56. doi: 10.1016/j.gde.2021.01.011. Han JY, Cho YG, Jo DS et al. Diversity of Clinical and Molecular Characteristics in Korean Patients with 16p11.2 Microdeletion Syndrome[J]. Int J Mol Sci, 2023,25(1):253. doi: 10.3390/ijms25010253. Weiss LA, Shen Y, Korn JM et al. Association between microdeletion and microduplication at 16p11.2 and autism[J]. N Engl J Med, 358(7):667-75. doi: 10.1056/NEJMoa075974. Taylor CM, Smith R, Lehman C et al. 16p11.2 Recurrent Deletion. 2009 Sep 22 [updated 2021 Oct 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 20301775. Rosenfeld JA, Coppinger J, Bejjani BA et al. Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications[J]. J Neurodev Disord, 2010, 2(1):26-38. doi: 10.1007/s11689-009-9037-4. Cooper GM, Coe BP, Girirajan S et al. A copy number variation morbidity map of developmental delay[J]. Nat Genet, 2011, 43(9):838-846. doi: 10.1038/ng.909. Wang Y, Zhou H, Fu F et al. Prenatal Diagnosis of Chromosome 16p11.2 Microdeletion[J]. Genes (Basel),2022,13(12):2315. doi: 10.3390/genes13122315. Li L, Huang L, Lin S et al. Discordant phenotypes in monozygotic twins with 16p11.2 microdeletions including the SH2B1 gene[J]. Am J Med Genet A, 2017,173(8):2284-2288. doi: 10.1002/ajmg.a.38284. Rein B, Yan Z. 16p11.2 Copy Number Variations and Neurodevelopmental Disorders[J]. Trends Neurosci, 2020,43(11):886-901. doi: 10.1016/j.tins.2020.09.001. Landolfi A, Barone P, Erro R. The Spectrum of PRRT2 -Associated Disorders: Update on Clinical Features and Pathophysiology[J]. Front Neurol, 2021,12:629747. doi: 10.3389/fneur.2021.629747. Sen K, Genser I, DiFazio M et al. Haploinsufficiency of PRRT2 Leading to Familial Hemiplegic Migraine in Chromosome 16p11.2 Deletion Syndrome[J]. Neuropediatrics, 2022,53(4):279-282. doi: 10.1055/a-1863-1798. Scorrano G, Dono F, Corniello C et al. Exploring epileptic phenotypes in PRRT2-related disorders: A report of two cases and literature appraisal[J].Seizure,2024,119:3-11.doi: 10.1016/j.seizure.2024.04.019. Yang L, You C, Qiu S et al. Novel and de novo point and large microdeletion mutation in PRRT2-related epilepsy[J]. Brain Behav, 2020,10(5):e01597. doi: 10.1002/brb3.1597. Abel T, Kim J, Vanrobaeys Y et al. Dissecting 16p11.2 hemi-deletion to study sex-specific striatal phenotypes of neurodevelopmental disorders[J]. Mol Psychiatry,2024,29(5):1310-1321. doi: 10.1038/s41380-024-02411-0. Konyukh M, Delorme R, Chaste P et al. Variations of the candidate SEZ6L2 gene on Chromosome 16p11.2 in patients with autism spectrum disorders and in human populations[J]. PLoS One, 2011, 6(3):e17289. doi: 10.1371/journal.pone.0017289. Yue F, Hao M, Jiang D, Liu R, Zhang H. Prenatal phenotypes and pregnancy outcomes of fetuses with 16p11.2 microdeletion/microduplication. BMC Pregnancy Childbirth. 2024 Jul 22;24(1):494. doi: 10.1186/s12884-024-06702-w. Liu L, Wang J, Liu X et al Prenatal prevalence and postnatal manifestations of 16p11.2 deletions: A new insights into neurodevelopmental disorders based on clinical investigations combined with multi-omics analysis[J]. Clin Chim Acta, 2024, 552:117671. doi: 10.1016/j.cca.2023.117671. Lai W, Feng X, Yue M et al. Identification of Copy Number Variants in a Southern Chinese Cohort of Patients with Congenital Scoliosis[J]. Genes (Basel), 2021,12(8):1213. doi: 10.3390/genes12081213. Wang Y, Zhou H, Fu F et al. Prenatal Diagnosis of Chromosome 16p11.2 Microdeletion. Genes (Basel). 2022 Dec 8;13(12):2315. doi: 10.3390/genes13122315. Cai M, Huang H, Lin N et al. [Prenatal ultrasonographic manifestations and genetic analysis of eight fetuses with 16p11.2 microdeletions]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022 Feb 10;39(2):227-230. Chinese. doi: 10.3760/cma.j.cn511374-20201126-00833. Lin S, Shi S, Zhou Y, Ji Y, Huang P, Wu J, Chen B, Luo Y. Intrauterine phenotypic features associated with 16p11.2 recurrent microdeletions. Prenat Diagn. 2018 May;38(6):381-389. doi: 10.1002/pd.5245. Wu N, Ming X, Xiao J et al. TBX6 null variants and a common hypomorphic allele in congenital scoliosis[J]. N Engl J Med, 2015, 372(4):341-50. doi: 10.1056/NEJMoa1406829. Ji X, Li Q, Qi Y et al. When NIPT meets WES, prenatal diagnosticians face the dilemma: genetic etiological analysis of 2,328 cases of NT thickening and follow-up of pregnancy outcomes[J]. Front Genet, 2023,14:1227724. doi: 10.3389/fgene.2023.1227724. Additional Declarations No competing interests reported. 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16:35:14","extension":"xml","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97886,"visible":true,"origin":"","legend":"","description":"","filename":"84398dfc18ee4b6d80358b5af84629631structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8402789/v1/393803217841dc167386c91c.xml"},{"id":100610467,"identity":"ebc15c42-8314-4b19-9c57-9d8b4ff50232","added_by":"auto","created_at":"2026-01-19 16:33:35","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":109633,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8402789/v1/ed65ab0d4faf3c5c0ab2c07b.html"},{"id":100610553,"identity":"05904ad1-4651-4dcb-a9af-2dcfdb7040d5","added_by":"auto","created_at":"2026-01-19 16:34:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":21341,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCMA results\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCMA reveals deletions in the 16p11.2 region in case 1-11, with case 1-8 of proximal deletions and case 9-11 of a distal deletion (red arrows). Case 12-20 exhibit duplicationsin the 16p11.2 region. Case 12-13, 15-17,20 had proximal duplications; case14 had both proximal and distal duplication; case 18-19 had distal duplications (blue arrows).\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8402789/v1/16fa9bed1780e45ad43535c1.png"},{"id":100610486,"identity":"905ad50c-d833-483c-93e0-928953b9a5cf","added_by":"auto","created_at":"2026-01-19 16:33:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":934092,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eUltrasound findings in the cases with 16p11.2 deletions/duplications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFig.2 (A) Double aortic arch(O-shaped vascular ring); (B) Persistent left superior vena cava(Double superior vena cava); (C) Absence of corpus callosum; (D) Lung cystadenoma.\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8402789/v1/bb936ab552f05f10d2da9a63.png"},{"id":100613478,"identity":"344eac75-618f-43ec-ba78-ee3d51444245","added_by":"auto","created_at":"2026-01-19 17:11:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2253985,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8402789/v1/d5551eb2-c969-440e-a0e1-68c4c7be1a2e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prenatal diagnosis, ultrasound characteristics and pregnancy outcomes of 16p11.2 deletion and duplication syndromes","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWith the widespread application of chromosomal microarray analysis (CMA) in prenatal diagnostics, there has been an increasing identification of fetal diseases and abnormal phenotypes associated with copy number variations (CNVs). The CNV at chromosome 16p11.2 is a prevalent contributor to neurodevelopmental disorders. Approximately 71% of proximal 16p11.2 deletions occur de novo, with an incidence rate of approximately 1 in 2,000 individuals (0.05%). In contrast, the occurrence of 16p11.2 duplication is approximately 3 in 10,000 (0.03%), with approximately 70% of these duplications inherited from parental carriers\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eChromosome 16p11.2 encompasses a cluster of low-copy repeats (LCRs) that facilitate meiotic non-allelic homologous recombination, leading to either deletions or duplications within this region. Copy number variations (CNVs) in the 16p11.2 region predominantly involve two core susceptible areas: one is a CNV in the proximal region encompassing TBX6 (chr16:29.6Mb-30.2Mb), and the other is in the distal region containing SH2B1 (chr16:28.8Mb-29.0Mb). Clinical phenotypes associated with proximal deletions of 16p11.2 include abnormalities of the skeletal and cardiovascular systems, neurodevelopmental disorders, and autism spectrum disorder\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Some fetuses exhibited structural malformations or various soft marker abnormalities on ultrasonography, whereas others displayed no discernible aberrant phenotypes. Previous research has predominantly concentrated on the phenotypes observed in postpartum cases, resulting in a paucity of clinical data concerning prenatal fetuses. Furthermore, there is a lack of systematic descriptions of their clinical features, pregnancy outcomes, and prognosis. Moreover, the diverse phenotypes and incomplete penetrance of these conditions present great challenges to clinical genetic counseling. Therefore, there is an urgent need for additional prenatal case data to further investigate the genotype-phenotype mechanisms influencing the penetrance and expressivity of this syndrome.\u003c/p\u003e \u003cp\u003eThis study retrospectively analyzed the molecular genetic characteristics and abnormal ultrasound findings of 19 fetuses with 16p11.2 deletion or duplication, and enriched the phenotypic spectrum of this syndrome.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects\u003c/h2\u003e \u003cp\u003eBetween November 2018 to August 2025, a cohort of 19 pregnant women who underwent amniocentesis at Longgang Maternal and Child Health Hospital in Shenzhen was selected as participants for this study. These individuals were identified as having a 16p11.2 deletion or duplication through SNP-array analysis. The primary indications for prenatal diagnosis in these cases included congenital structural anomalies, abnormal ultrasound markers, advanced maternal age, and high risk of serological screening. The study was approved by the Medical Ethics Committee (LGFYKYXMLL-2024-39), and written informed consent was obtained from all participants before testing.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAmniotic fluid collection and DNA extraction\u003c/h3\u003e\n\u003cp\u003eAmniocentesis was conducted on cases identified as high-risk, during which 5 mL of amniotic fluid was collected. Subsequently, DNA was extracted from the collected amniotic fluid using the QIAamp DNA Blood Mini Kit (No. 51106, Qiagen, Germany), in accordance with the manufacturer's protocol.\u003c/p\u003e\n\u003ch3\u003eSingle nucleotide polymorphism array analysis (SNP-array)\u003c/h3\u003e\n\u003cp\u003eSNP-array was conducted using the Affymetrix Cytoscan 750K chip (Thermo Fisher, CA, USA). DNA samples were prepared in accordance with the manufacturer's protocol, encompassing steps such as digestion, ligation, PCR amplification, purification, fragmentation, and labeling for hybridization and chip scanning. The short tandem repeat (STR) method was employed to detect any maternal blood contamination, and confirm that there was no contamination. Data analysis was performed using the Chromosome Analysis Suite(ChAS 4.3) software. CNV results were filtered using a threshold of 100 kilobase pairs (Kb) and a minimum of 50 probe markers. Databases, including the UCSC Genome Browser, DECIPHER, DGV, and ClinGen, were consulted for the classification and interpretation of CNVs. Subsequently, the results were categorized into five classifications: pathogenic, likely pathogenic, of undetermined significance, likely benign, and benign.\u003c/p\u003e\n\u003ch3\u003eClassification of 16p11.2 copy number variations\u003c/h3\u003e\n\u003cp\u003eThe 16p11.2 CNVs can be categorized into two primary susceptible regions based on distinct breakpoints: the proximal deletion, also referred to as the typical deletion (BP4-BP5, ISCA-37400), which encompasses the TBX6 gene; and the distal deletion (BP2-BP3, ISCA-37486), which includes the SH2B1 gene.\u003c/p\u003e\n\u003ch3\u003eKaryotype analysis\u003c/h3\u003e\n\u003cp\u003eTwenty milliliters of amniotic fluid were inoculated into two sterile cell culture flasks and incubated at 37\u0026deg;C with 5% CO2 for a duration of 6 to 8 days, contingent upon the growth status of the cultures. Chromosome preparations were conducted using conventional methods, including harvesting, titration, and banding. Partial karyotypes were scanned using Leica automated karyotyping systems, and only well-distributed banded karyotypes were selected for further analysis. The karyotypes were interpreted in accordance with the 2020 International System for Human Cytogenetic Nomenclature (ISCN2020).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePregnancy outcome follow-up\u003c/h2\u003e \u003cp\u003eAll cases with 16p11.2 deletions or duplications detected by SNP array were followed up after birth.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSNP array results\u003c/h2\u003e \u003cp\u003eDuring the study period, a total of 9671 fetuses underwent SNP array testing. Among these, eleven fetuses were identified with 16p11.2 deletions, and eight fetuses exhibited 16p11.2 duplications. The median maternal age was 32\u0026thinsp;\u0026plusmn;\u0026thinsp;6 years, ranging from 22 to 44 years. The median gestational age at the time of prenatal diagnosis was 21\u0026thinsp;\u0026plusmn;\u0026thinsp;5 weeks, with a range spanning from 13 to 31 weeks. Among the eleven cases exhibiting 16p11.2 deletions, cases 1 to case 8 presented with proximal deletions ranging from 500 to 900 kb, encompassing OMIM genes including PRRT2, TBX6, SEZ6L2, KCTD13, ALDOA, KIF22, and TLCD3B. In contrast, case 9 to case11 exhibited a distal deletion, primarily involving OMIM genes such as SH2B1, SPNS1, TUFM, and CD19.\u003c/p\u003e \u003cp\u003eAmong the eight cases identified with 16p11.2 duplications through SNP-array analysis, five cases exhibited proximal duplications ranging from 700 kb to 900 kb, one case presented with both proximal and distal duplications measuring 1863kb, and the other two cases demonstrated distal duplications of 200 kb to 400 kb(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Subsequent familial verification revealed that three of these cases involved de novo mutations, one case inherited from the father. whereas the remaining four cases were not eligible for verification. Karyotype analysis conducted on all 19 fetuses did not reveal any abnormalities.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePathogenicity analysis of CNV\u003c/h2\u003e \u003cp\u003eThe proximal deletions span from 500 to 900 Kb, encompassing the 16p11.2 recurrent region (BP4-BP5, including TBX6). According to the ClinGen database, this region has a Haploinsufficiency Score of 3, indicating it is a well-established region of haploinsufficiency sensitivity. Case 9 and case11 involve the 16p11.2 distal recurrent region (BP2-BP3, including SH2B1), which also has a Haploinsufficiency Score of 3, confirming its status as a recognized haploinsufficiency sensitivity region. Case 10 did not fully encompass the 16p11.2 distal recurrent region. This deletion was classified as a CNV of unclear clinical significance.\u003c/p\u003e \u003cp\u003eMost of the proximal duplications detected via SNP-array analysis fully encompass the recurrent 16p11.2 region (proximal, BP4-BP5), which includes the TBX6 gene. This region has a triplosensitivity score of 3, and according to the ACMG scoring standards, these CNVs were classified as pathogenic. While the duplication observed in case 12 is considered a likely pathogenic CNV. Although it does not entirely cover the recurrent 16p11.2 region, it includes the TBX6 gene, which is a critical gene within this region. Case 14 also fully encompasses the 16p11.2 recurrent region (BP2-BP5) and is similarly classified as a pathogenic CNV. The another two cases encompass the 16p11.2 distal recurrent region (BP2-BP3), which includes the SH2B1 gene and has a triplosensitivity score of 1. Currently, there is insufficient evidence to establish the pathogenicity of this distal region. According to CNV evaluation criteria, these two distal duplications are classified as CNVs of uncertain clinical significance.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eUltrasonic results\u003c/h2\u003e \u003cp\u003eAmong the 19 instances of 16p11.2 deletion or duplication syndrome, ultrasound abnormalities were observed in 7 deletion cases (63.6%, 7/11) and in 3 duplication cases(37.5%, 3/8), as detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Notably, two of these deletion cases demonstrated the cardiovascular system abnormalities: one involving complex congenital heart disease and another characterized by a single umbilical artery. Furthermore, three cases demonstrated craniocerebral abnormalities: one case showed the absence of the corpus callosum accompanied by bilateral lateral ventricle enlargement, one presented with a midsagittal chamber and nuchal translucency (NT) thickening, while another case showed bilateral lateral ventricle dilation combined with posterior cranial fossa cistern dilation. There was also a case that showed clubfeet. An additional case was characterized by isolated NT thickening. Among the eight fetuses with 16p11.2 duplications, one was diagnosed with pulmonary cystadenoma (refer to Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e), and one showed subependymal cyst in the left lateral ventricle combined with tricuspid regurgitation. Another case showed cleft lip and palate. Whereas the remaining five did not display any discernible abnormalities.\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\u003ePrenatal ultrasound features of fetuses with 16p11.2 deletions\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUltrasound findings\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePercent (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbnormal cardiovascular system\u003c/b\u003e\u003c/p\u003e \u003cp\u003eComplex congenital heart disease\u003c/p\u003e \u003cp\u003eSingle umbilical artery\u003c/p\u003e \u003cp\u003e\u003cb\u003eAbnormal craniocerebral\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAbsence of corpus callosum\u003c/p\u003e \u003cp\u003eLateral ventricle widening\u003c/p\u003e \u003cp\u003eMidsail chamber\u003c/p\u003e \u003cp\u003ePosterior cranial fossa cistern widening\u003c/p\u003e \u003cp\u003e\u003cb\u003eAbnormalities of the skeletal system\u003c/b\u003e\u003c/p\u003e \u003cp\u003eclubfoot\u003c/p\u003e \u003cp\u003e\u003cb\u003eNT thicken\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e20\u003c/b\u003e\u003c/p\u003e \u003cp\u003e10\u003c/p\u003e \u003cp\u003e10\u003c/p\u003e \u003cp\u003e\u003cb\u003e50\u003c/b\u003e\u003c/p\u003e \u003cp\u003e10\u003c/p\u003e \u003cp\u003e20\u003c/p\u003e \u003cp\u003e10\u003c/p\u003e \u003cp\u003e10\u003c/p\u003e \u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e \u003cp\u003e10\u003c/p\u003e \u003cp\u003e\u003cb\u003e20\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eNT: thickness of the transparent layer of the neck\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDetailed information of 12 cases with 16p11.2 deletion/duplication\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase \u003c/p\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGA (wk)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIndications for prenatal diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCMA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCNV Size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRegion\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eUltrasound findings\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003csup\u003e+\u0026thinsp;4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUnclear venous catheter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(29351827_30176508)x1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e825Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP4-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSingle umbilical artery; unclear venous catheter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTOP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26\u003csup\u003e+\u0026thinsp;4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHigh risk of prenatal serological screening\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(29580021_30371223)x1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e791Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP4-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDouble aortic arch; the left superior vena cava was persistent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCHD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003csup\u003e+\u0026thinsp;2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAbnormal Ultrasound Findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(29343462_30190029)x1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e846Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP4-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eThe corpus callosum was absent; placenta rotunda; the right lateral ventricle hydrops; the lateral ventricles were widened bilaterally, with the left side 1.3 cm and the right side 2.2 cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTOP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAbnormal Ultrasound Findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(29,580,021_30,190,029)x1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e610Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP4-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNT 3.0mm; the middle velum of the fetus(0.77*0.44cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eLive birth with underheight and underweight\u003c/p\u003e \u003c/td\u003e \u003c/tr\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\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003csup\u003e+\u0026thinsp;5\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAbnormal Ultrasound Findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(29,580,021_30,176,508)x1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e596Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP4-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNT thickening(4.2mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTOP\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\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHigh risk of prenatal serological screening\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(29,580,021_30,177,916)x1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e598Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP4-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTOP\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\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSenior age, History of adverse pregnancy and childbirth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(29,580,021_30,190,029)x1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e610Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP4-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTOP\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAbnormal Ultrasound Findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(29,580,021_30,176,508)x1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e596Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP4-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTOP\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\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003csup\u003e+\u0026thinsp;2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHigh risk of prenatal serological screening, advanced age\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(28,852,776_29,032,280)x1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e180Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP2-BP3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTOP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAbnormal Ultrasound Findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(28,852,776_29,032,280)x1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e180Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP2-BP3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eThe lateral ventricles were widened bilaterally, with the left side of 1.08 cm and the right side of 1.33 cm; Posterior cranial fossa cistern widening\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eLive birth\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAbnormal Ultrasound Findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[hg19] 16p11.2(28,371,467\u0026thinsp;\u0026minus;\u0026thinsp;29,428,532)x1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.06Mb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP2-BP3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eclubfoot\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTOP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003csup\u003e+\u0026thinsp;4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHigh risk of prenatal serological screening\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(29,428,532_30,190,029)x3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e761Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP4-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTOP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHigh risk of sex chromosome screening by NIPT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr(X)\u0026times;2,(Y)\u0026times;1\u003c/p\u003e \u003cp\u003earr[GRCh37] 16p11.2(29,591,327_30,339,365)x3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e748Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP4-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTOP\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\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAbnormal Ultrasound Findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(28,488,011_30,350,748)x3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1863Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP2-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eRight choroid plexus cyst; Pulmonary cystadenoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTOP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAbnormal Ultrasound Findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(29,428,532_30,350,748)x3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e922Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP4-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSubependymal cyst in the left lateral ventricle; tricuspid regurgitation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eLive birth\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAbnormal Ultrasound Findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37]4p16.3p16.1(68,346_7,453,158)x1 arr[GRCh37]11q22.3(104,328,778_105,959,082)x3\u003c/p\u003e \u003cp\u003earr[GRCh37] 16p11.2(29,428,532_30,330,881)x3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e902Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP4-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFetal cleft lip and palate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTOP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNIPT indicates an increase in the number of chromosome 7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[hg19] 16p11.2(29,580,020\u0026ndash;30,190,029)x3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e610Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP4-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eLive birth\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003csup\u003e+\u0026thinsp;4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHigh risk of prenatal serological screening, advanced age\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(28810325_29032280)x3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e222Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP2-BP3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eLive birth with underweight\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\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003csup\u003e+\u0026thinsp;5\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHigh risk of prenatal serological screening\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(28,708,187_29,043,863)x3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e336Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP2-BP3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eLoss to follow-up\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSpeech and language delay, Poor self-care ability in daily life (Clinical manifestations during childhood)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003earr[GRCh37] 16p11.2(29580021_30339365)x3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e759Kb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBP4-BP5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eLanguage development delay and poor social interaction skills\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eGA : gestational age; wk:weeks; TOP: terminate of pregnancy; CHD: congenital heart disease.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePregnancy outcomes and follow-up\u003c/h2\u003e \u003cp\u003eAmong the 19 pregnant women with SNP-array results showing CNVs in the 16p11.2 region, 7 cases with deletions and 4 with duplications opted for termination after genetic counseling. One case (case 5) resulted in spontaneous abortion at 20 weeks due to premature rupture of membranes. Case 2 was delivered via cesarean section at 40 weeks, weighing 3800g, with an Apgar score of 10, but had complex congenital heart disease. The fetus of cases 4 was delivered at 39\u0026thinsp;+\u0026thinsp;6 weeks with normal phenotypes. When he was 30 months old, his height and weight status was classified as underheight (\u0026lt;-2SD) and underweight (\u0026lt;-2SD) with no other abnormal conditions. The 16p11.2 deletion CNV of case 10 was inherited from the mother and the fetus was delivered without any abnormal phenotypes. Case15 and case17 give birth to healthy female infants without any abnormal phenotypes. The fetus of case18 was delivered at 39 weeks, weighing 3130g, with an Apgar score of 10. When he was 32 months old, his weight status was classified as underweight (\u0026lt;-1SD) with no other abnormal conditions. Case 19 was lost to follow-up. In this study, in addition to the prenatal cases, we also included a 2-year-old child who carried a proximal duplication in the 16p11.2 region(case20). His main clinical manifestations include delayed language development, poor self-care ability and interpersonal communication skills(Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eA 99.5% sequence-homologous low-copy repeat, approximately 147 Kb in length, flanks each side of the 16p11.2 core susceptibility region, making it susceptible to nonallelic homologous recombination (NAHR) during cell division. Consequently, daughter cells exhibit a propensity for CNVs within the 16p11.2 region\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. In this study, 11cases of 16p11.2 deletion, identified through SNP-array analysis, displayed variability in size. The differing sizes and locations of these CNVs result in variations in the number and types of genes encompassed, leading to diverse clinical phenotypes.\u003c/p\u003e \u003cp\u003eGeneReviews provided a detailed update on the clinical phenotypes of 16p11.2 deletion in 2021. The conditions observed encompassed a range of developmental delays and mental and behavioral disorders, affecting over 90% of the population studied. Speech disorders were present in 80%\u0026ndash;90% of individuals, while obesity was observed in 75%. Motor coordination difficulties affected 60% of the cohort, and autism spectrum disorders were identified in 20%\u0026ndash;25%. Epilepsy was diagnosed in 25% of cases, and vertebral malformations were present in 21%. Hearing loss was observed in less than 11% of individuals, paroxysmal dyskinesia in up to 9%, and cardiac malformations in 6%\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. The literature on 16p11.2 duplication is limited. Clinical manifestations associated with proximal 16p11.2 duplication, particularly involving the TBX6 gene, encompass developmental delays, intellectual disabilities, seizures, behavioral issues, autism spectrum disorders, microcephaly, and various other congenital anomalies\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Neuropsychiatric symptoms are the most prevalent phenotypes observed in carriers recruited by the 16p11.2, followed by malformations of the skeletal and cardiovascular systems. Due to the challenges in accurately assessing fetal intelligence, language development, and other aspects of nervous system development prenatally, the identification of this syndrome relies heavily on medical imaging techniques such as ultrasound. Given the extensive use of ultrasound in prenatal diagnostics and its efficacy in detecting abnormalities in the cardiovascular and spinal systems, the identification of prenatal phenotypes associated with 16p11.2 is likely to focus primarily on these two systems.\u003c/p\u003e \u003cp\u003eIn this study, among the 11instances of 16p11.2 deletion identified, 3 cases exhibited structural malformations as determined by ultrasound examination. These structural malformations mainly distributed in the skeletal system, the cardiovascular system and the central nervous system. Among the 9 cases with 16p11.2 duplication, two cases with proximal duplications were noted to have abnormalities of the respiratory system and the cardiovascular system. Wang et al.\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e reported that skeleton and cardiovascular system abnormalities were the two most common structural malformations associated with the 16p11.2 deletion. Li et al.\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e documented a case involving monozygotic twins with a 16p11.2 distal deletion. Fetus A exhibited aortic coarctation, left ventricular noncompaction, an atrial septal defect, pericardial effusion, and left hydronephrosis, whereas fetus B presented with a single umbilical artery. Both fetuses experienced intrauterine growth restriction; however, postnatally, fetus A demonstrated moderate delays in speech and psychomotor development, in contrast to fetus B, who exhibited normal cognitive and behavioral development. Recent findings have further corroborated the presence of variability in the penetrance and expressivity of clinical phenotypes among individuals harboring distinct 16p11.2 deletions. The etiological factors contributing to discordant phenotypes in monozygotic twins primarily encompass epigenetic modifications, environmental influences, asymmetric embryonic division, differential cellular differentiation, and aberrant placental blood flow. In instances where ultrasound imaging reveals congenital cardiac structural anomalies in the fetus, it is imperative to conduct a thorough investigation to exclude the presence of copy number variations in the 16p11.2 region.\u003c/p\u003e \u003cp\u003eCarriers of the 16p11.2 copy number variant exhibit a range of neurological symptoms, predominantly including autism spectrum disorder, intellectual disability, epilepsy, and behavioral abnormalities\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. In this study, case 3 exhibited structural abnormalities in the central nervous system as detected by ultrasound. The deleted regions in this instance primarily involve genes such as PRRT2 and SEZ6L2. The precise mechanisms by which these gene deletions result in abnormal phenotypes in patients remain poorly understood. Current research suggests that the PRRT2 gene encodes a transmembrane protein and is recognized a well-defined haploinsufficiency-sensitive gene. Mutations in this gene have been linked to conditions such as episodic kinesigenic dyskinesia 1, benign familial infantile epilepsy type 2, migraine, and complex neurodevelopmental disorders\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. It has been reported that individuals harboring loss-of-function variants in the PRRT2 gene exhibit clinical phenotypes, including epilepsy and paroxysmal kinesigenic dyskinesia\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Similarly, deletions in the SEZ6L2 gene may be linked to phenotypes such as abnormal behavior and autism\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Due to our inability to obtain clinical phenotypic data of the fetal nervous system, and the subsequent decision by the pregnant woman to terminate the pregnancy following the SNP array results, an in-depth investigation into the genotype\u0026ndash;phenotype correlation in these instances were not feasible. Case 20 has a duplication in the 16p11.2 proximal region. His clinical manifestations mainly include language development delay, poor self-care ability and social interaction skills, and other abnormal behavioral problems. Therefore, individuals with a deletion or duplication of the 16p11.2 region may all exhibit neurological symptoms.\u003c/p\u003e \u003cp\u003eWe conducted follow-up studies on some cases after birth. Cases 4, which had a proximal deletion, and case 18, which had a distal duplication, both showed underheight or underweight. Therefore, when there is a copy number variation in the 16p11.2 region, height and weight indexes are also indicators that require special attention.\u003c/p\u003e \u003cp\u003eDue to the atypical ultrasound phenotype associated with the duplication of the 16p11.2 region, there have been few prenatal cases of 16p11.2 duplication reported. In this study, among the nine detected cases of 16p11.2 duplication, five fetuses and one child did not present any abnormal ultrasound findings. This suggests that, compared to carriers of 16p11.2 microduplication, deletions in this region are more likely to result in aberrant ultrasound findings. Yue et al. \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e reported that among 20 carriers of 16p11.2 copy number variations (including 15 cases of deletion and 5 cases of duplication), 11 cases with deletion exhibited varying degrees of ultrasound abnormalities, whereas none of the duplication cases showed abnormal ultrasound results. These findings are consistent with the results of our study.\u003c/p\u003e \u003cp\u003eIn this study, we have documented for the first time the occurrence of pulmonary cystadenoma in individuals with a 16p11.2 duplication (case 10). Currently, there is insufficient evidence to establish a definitive correlation between this specific pulmonary malformation and the 16p11.2 copy number variation. However, it is important to consider that phenotypic variability resulting from inconsistent penetrance and expressivity cannot be entirely ruled out.\u003c/p\u003e \u003cp\u003eIn cases of 16p11.2 deletion, the most prevalent structural malformations are abnormalities of the skeletal system, such as scoliosis, which may be associated with the deletion of the TBX6 gene\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. In contrast to previous studies (refer to Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e, the detection rate of skeletal system abnormalities in this study was notably different. Only one case of skeletal system were observed, which may be attributed to two factors: firstly, some cases were diagnosed with 16p11.2 deletion at an early gestational age, leading to the decision to terminate the pregnancy before conducting a four-dimensional color Doppler ultrasound; secondly, the phenotypic manifestations associated with 16p11.2 copy number variations exhibit variability in penetrance and expressivity, resulting in heterogeneous clinical phenotypes among different individuals. Wu et al. \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e identified an association between the haplotype T-C-A of the single nucleotide polymorphisms rs2289292, rs3809624, and rs3809627 in the TBX6 gene and spinal deformity. The study posited that the manifestation of spinal deformity requires the concurrent presence of deletion and single nucleotide variation alleles at the specified genetic loci. This finding may also elucidate why not all individuals with 16p11.2 deletions, which encompass the TBX6 gene, exhibit spinal abnormalities. Despite the close relationship between the functions of these genes and the clinical phenotype, it remains uncertain whether genetic variation will invariably result in the corresponding phenotype. Further postpartum follow-up studies are necessary to clarify the correlation between genotype and phenotype.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparation of the clinical phenotypes of 16p11.2 deletion cases between this study and previous studies\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReferences\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbnormalities of the skeletal system\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAbnormalities of the cardiovascular system\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAbnormalities of the central nervous system\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAbnormalities of the urinary system\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAbnormalities of digestive System\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAbnormalities of the ultrasound soft markers\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThis study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.1% (1/11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.1% (1/11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.1% (1/11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e36.4% (4/11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e[17]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13%(2/15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13%(2/15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7% (1/15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e53%(8/15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e[20]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48% (39/81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31%(25/81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11% (9/81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6% (5/81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e[21]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50%(4/8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38%(3/8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13% (1/8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e[22]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42%(5/12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58%(7/12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8%(1/12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e33%(4/12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn this study, five instances of 16p11.2 deletion exhibited abnormalities in ultrasound soft markers. Previous research has indicated that the presence of abnormal ultrasound soft markers, such as increased NT thickness during prenatal screening, is associated with an elevated risk of fetal chromosomal aneuploidy or deletion/duplication. Furthermore, the likelihood of chromosomal abnormalities escalates with greater NT thickness. Notably, when NT measures\u0026thinsp;\u0026ge;\u0026thinsp;6.5 mm, the risk of chromosomal abnormalities can reach as high as 71.43% \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Among the remaining eight cases, which exhibited no abnormal findings on ultrasound, the indications for prenatal diagnosis were as follows: advanced maternal age, a high risk identified through prenatal serological screening, and abnormal non-invasive prenatal test results. Consequently, it is recommended that prenatal diagnostic procedures be undertaken to assess for chromosomal abnormalities when ultrasound reveals abnormal soft markers or when prenatal diagnostic indications, such as high-risk serological screening and advanced maternal age, are present.\u003c/p\u003e \u003cp\u003eIn this study, we conducted a comprehensive analysis of the diversity and incomplete penetrance of phenotypes associated with 16p11.2 deletion/duplication syndrome. This investigation contributed additional phenotypic characteristics and expanded the phenotypic spectrum of 16p11.2 copy number variations. A limitation of the study was the decision by some pregnant women to undergo labor induction, which precluded the acquisition of phenotypic data from the postpartum fetus. It is recommended that chromosomal microarray analysis (CMA) be performed when prenatal ultrasound detects malformations in the cardiovascular, nervous, or skeletal systems, or when there are abnormalities in ultrasound soft markers and elevated risks in serological screening, to confirm the presence of 16p11.2 copy number variations. Enhanced follow-up is advised for live births diagnosed with 16p11.2 deletion/duplication to gather additional abnormal phenotypes, further augment the phenotypic spectrum of this syndrome, and aid in genetic counseling.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCONFLICTS OF INTEREST \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflict of interest to declare. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by the Medical and Health Technology Research Project of Longgang District, Shenzhen City (grant LGWJ2023-56), the Medical and Health Technology Research Project, Special Funds for Science and Technology Innovation in Longgang District, Shenzhen City (grant LGKCYLWS2022013), and the Natural Science Foundation of Shenzhen City (JCYJ20230807141908017).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBULLETED STATEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003ewhat's already known about this topic?\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eFetuses with 16p11.2 deletion/duplication exhibit a wide range of clinical characteristics, including varying expressability and incomplete penetrance. The most common structural malformation associated with 16p11.2 deletion is an abnormality of the skeletal system, which is usually associated with scoliosis.\u003c/p\u003e\n\u003col start=\"2\"\u003e\n\u003cli\u003ewhat does this study add?\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe most common structural malformations in 16p11.2 deletion carriers in this study were malformations of the cardiovascular system and brain development. Individuals carrying a 16p11.2 deletion may exhibit underweight and underheight. Compared with 16p11.2 duplication, 16p11.2 deletion is more likely to have abnormal ultrasound phenotype. In addition, we report a pulmonary cystadenoma in a patient with a 16p11.2 duplication for the first time.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003cstrong\u003eONSENT\u003c/strong\u003e\u003cstrong\u003eFOR\u003c/strong\u003e\u003cstrong\u003e P\u003c/strong\u003e\u003cstrong\u003eUBLICATION STATEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent for publication was obtained from all the patients in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDECLARATIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea) \u003c/strong\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cstrong\u003e statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Medical Ethics Committee of Shenzhen Longgang District Maternal and Child Health Hospital (No. LGFYKYXMLL-2024-39). Written informed consent was obtained from all participants before testing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb) \u003c/strong\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNOT APPLICABLE.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ec) \u003c/strong\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are available upon reasonable request from XY Cong.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ed) \u003c/strong\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, data analysis, and manuscript writing: XY.Cong, Clinical data collection and experiment: T.Zhang, HY Niu, Ultrasound data collection: GH.Duan. Writing review and editing: XJ.Luo,WQ.Liu. All authors read and approved the manuscript and are accountable for all study aspects.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eliva-Teles N, de Stefano MC, Gallagher L et al. Rare Pathogenic Copy Number Variation in the 16p11.2 (BP4-BP5) Region Associated with Neurodevelopmental and Neuropsychiatric Disorders: A Review of the Literature[J]. Int J Environ Res Public Health, 2020,17(24):9253. doi: 10.3390/ijerph17249253. \u003c/li\u003e\n\u003cli\u003eChung WK, Roberts TP, Sherr EH et al. 16p11.2 deletion syndrome[J]. Curr Opin Genet Dev, 2021 , 68:49-56. doi: 10.1016/j.gde.2021.01.011. \u003c/li\u003e\n\u003cli\u003eHan JY, Cho YG, Jo DS et al. Diversity of Clinical and Molecular Characteristics in Korean Patients with 16p11.2 Microdeletion Syndrome[J]. Int J Mol Sci, 2023,25(1):253. doi: 10.3390/ijms25010253. \u003c/li\u003e\n\u003cli\u003eWeiss LA, Shen Y, Korn JM et al. Association between microdeletion and microduplication at 16p11.2 and autism[J]. N Engl J Med, 358(7):667-75. doi: 10.1056/NEJMoa075974. \u003c/li\u003e\n\u003cli\u003eTaylor CM, Smith R, Lehman C et al. 16p11.2 Recurrent Deletion. 2009 Sep 22 [updated 2021 Oct 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews\u0026reg; [Internet]. Seattle (WA): University of Washington, Seattle; 1993\u0026ndash;2024. PMID: 20301775.\u003c/li\u003e\n\u003cli\u003eRosenfeld JA, Coppinger J, Bejjani BA et al. Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications[J]. J Neurodev Disord, 2010, 2(1):26-38. doi: 10.1007/s11689-009-9037-4.\u003c/li\u003e\n\u003cli\u003eCooper GM, Coe BP, Girirajan S et al. A copy number variation morbidity map of developmental delay[J]. Nat Genet, 2011, 43(9):838-846. doi: 10.1038/ng.909. \u003c/li\u003e\n\u003cli\u003eWang Y, Zhou H, Fu F et al. Prenatal Diagnosis of Chromosome 16p11.2 Microdeletion[J]. Genes (Basel),2022,13(12):2315. doi: 10.3390/genes13122315. \u003c/li\u003e\n\u003cli\u003eLi L, Huang L, Lin S et al. Discordant phenotypes in monozygotic twins with 16p11.2 microdeletions including the SH2B1 gene[J]. Am J Med Genet A, 2017,173(8):2284-2288. doi: 10.1002/ajmg.a.38284. \u003c/li\u003e\n\u003cli\u003eRein B, Yan Z. 16p11.2 Copy Number Variations and Neurodevelopmental Disorders[J]. Trends Neurosci, 2020,43(11):886-901. doi: 10.1016/j.tins.2020.09.001.\u003c/li\u003e\n\u003cli\u003eLandolfi A, Barone P, Erro R. The Spectrum of \u003cem\u003ePRRT2\u003c/em\u003e-Associated Disorders: Update on Clinical Features and Pathophysiology[J]. Front Neurol, 2021,12:629747. doi: 10.3389/fneur.2021.629747. \u003c/li\u003e\n\u003cli\u003eSen K, Genser I, DiFazio M et al. Haploinsufficiency of PRRT2 Leading to Familial Hemiplegic Migraine in Chromosome 16p11.2 Deletion Syndrome[J]. Neuropediatrics, 2022,53(4):279-282. doi: 10.1055/a-1863-1798. \u003c/li\u003e\n\u003cli\u003eScorrano G, Dono F, Corniello C et al. Exploring epileptic phenotypes in PRRT2-related disorders: A report of two cases and literature appraisal[J].Seizure,2024,119:3-11.doi: 10.1016/j.seizure.2024.04.019. \u003c/li\u003e\n\u003cli\u003eYang L, You C, Qiu S et al. Novel and de novo point and large microdeletion mutation in PRRT2-related epilepsy[J]. Brain Behav, 2020,10(5):e01597. doi: 10.1002/brb3.1597.\u003c/li\u003e\n\u003cli\u003eAbel T, Kim J, Vanrobaeys Y et al. Dissecting 16p11.2 hemi-deletion to study sex-specific striatal phenotypes of neurodevelopmental disorders[J]. Mol Psychiatry,2024,29(5):1310-1321. doi: 10.1038/s41380-024-02411-0.\u003c/li\u003e\n\u003cli\u003eKonyukh M, Delorme R, Chaste P et al. Variations of the candidate SEZ6L2 gene on Chromosome 16p11.2 in patients with autism spectrum disorders and in human populations[J]. PLoS One, 2011, 6(3):e17289. doi: 10.1371/journal.pone.0017289.\u003c/li\u003e\n\u003cli\u003eYue F, Hao M, Jiang D, Liu R, Zhang H. Prenatal phenotypes and pregnancy outcomes of fetuses with 16p11.2 microdeletion/microduplication. BMC Pregnancy Childbirth. 2024 Jul 22;24(1):494. doi: 10.1186/s12884-024-06702-w.\u003c/li\u003e\n\u003cli\u003eLiu L, Wang J, Liu X et al Prenatal prevalence and postnatal manifestations of 16p11.2 deletions: A new insights into neurodevelopmental disorders based on clinical investigations combined with multi-omics analysis[J]. Clin Chim Acta, 2024, 552:117671. doi: 10.1016/j.cca.2023.117671. \u003c/li\u003e\n\u003cli\u003eLai W, Feng X, Yue M et al. Identification of Copy Number Variants in a Southern Chinese Cohort of Patients with Congenital Scoliosis[J]. Genes (Basel), 2021,12(8):1213. doi: 10.3390/genes12081213.\u003c/li\u003e\n\u003cli\u003eWang Y, Zhou H, Fu F et al. Prenatal Diagnosis of Chromosome 16p11.2 Microdeletion. Genes (Basel). 2022 Dec 8;13(12):2315. doi: 10.3390/genes13122315. \u003c/li\u003e\n\u003cli\u003eCai M, Huang H, Lin N et al. [Prenatal ultrasonographic manifestations and genetic analysis of eight fetuses with 16p11.2 microdeletions]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022 Feb 10;39(2):227-230. Chinese. doi: 10.3760/cma.j.cn511374-20201126-00833.\u003c/li\u003e\n\u003cli\u003eLin S, Shi S, Zhou Y, Ji Y, Huang P, Wu J, Chen B, Luo Y. Intrauterine phenotypic features associated with 16p11.2 recurrent microdeletions. Prenat Diagn. 2018 May;38(6):381-389. doi: 10.1002/pd.5245. \u003c/li\u003e\n\u003cli\u003eWu N, Ming X, Xiao J et al. TBX6 null variants and a common hypomorphic allele in congenital scoliosis[J]. N Engl J Med, 2015, 372(4):341-50. doi: 10.1056/NEJMoa1406829. \u003c/li\u003e\n\u003cli\u003eJi X, Li Q, Qi Y et al. When NIPT meets WES, prenatal diagnosticians face the dilemma: genetic etiological analysis of 2,328 cases of NT thickening and follow-up of pregnancy outcomes[J]. Front Genet, 2023,14:1227724. doi: 10.3389/fgene.2023.1227724.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"16p11.2 deletion/duplication, single nucleotide polymorphism microarray technology(SNP-array), prenatal phenotypes, copy number variation(CNV), abnormal ultrasound findings","lastPublishedDoi":"10.21203/rs.3.rs-8402789/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8402789/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRecurrent copy number variations (CNVs) in the 16p11.2 region are a prevalent cause of neurodevelopmental disorders. This study aims to investigate the prenatal phenotypic characteristics of 19 fetuses with 16p11.2 deletion/duplication syndromes and the results of single nucleotide polymorphism array (SNP-array) analysis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively analyzed 9671 pregnant women who underwent amniocentesis in Longgang Maternal and Child Health Hospital in Shenzhen from November 2018 to August 2025. SNP-array and G-banding karyotyping were performed on amniotic fluid samples from those pregnant women. The fetuses with 16p11.2 deletion/duplication detected by SNP-array were followed up.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOut of the 9671 cases, 19 were diagnosed with 16p11.2 deletion/duplication, yielding a detection rate of 0.2%(19/9671). Among these cases, eleven fetuses exhibited a 16p11.2 deletion, while eight fetuses demonstrated a 16p11.2 duplication. Of these, eight deletions encompassed the proximal 16p11.2 region (BP4-BP5), while three deletions involved the distal 16p11.2 region (BP2-BP3). Among the eightidentified duplications, five encompassed the BP4-BP5 region, and two involved the BP2-BP3 region. Another case exhibited both proximal and distal duplications (BP2-BP5). Among the 19 cases diagnosed with 16p11.2 deletion or duplication, six cases exhibited structural abnormalities in different systems, includingtwo caseswith cardiovascular abnormalities, one case with cerebral abnormalities. Additionally, one fetus demonstrated pulmonary abnormalities, one presented clubfeet and another one presented with cleft lip and palate. Various ultrasound soft marker abnormalities were observed in five cases, including nuchal translucency thickening, lateral ventricular enlargement, single umbilical artery, and choroid plexus cyst. Eight cases showed no significant ultrasound abnormalities.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eFetuses possessing a 16p11.2 deletion or duplication demonstrate a broad spectrum of clinical features, characterized by incomplete penetrance and variable expressivity. In comparison to 16p11.2 duplication, individuals with a\u003c/p\u003e","manuscriptTitle":"Prenatal diagnosis, ultrasound characteristics and pregnancy outcomes of 16p11.2 deletion and duplication syndromes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-19 15:37:43","doi":"10.21203/rs.3.rs-8402789/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"26502866908845835167840196379466060183","date":"2026-01-19T13:39:05+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-14T13:19:34+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-22T05:23:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-19T23:39:58+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-19T23:39:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pregnancy and Childbirth","date":"2025-12-19T08:55:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ba9b1c57-d3b5-447e-863c-d859e7b2393c","owner":[],"postedDate":"January 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T15:37:44+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-19 15:37:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8402789","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8402789","identity":"rs-8402789","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}