16p13.11 deletion/duplication: prenatal diagnosis, postnatal outcome follow-up and phenotypic manifestations: a large cohort study

16p13.11 deletion/duplication: prenatal diagnosis, postnatal outcome follow-up and phenotypic manifestations: a large cohort study | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 6 June 2025 V1 Latest version Share on 16p13.11 deletion/duplication: prenatal diagnosis, postnatal outcome follow-up and phenotypic manifestations: a large cohort study Authors : Xianglian Tang 0000-0002-4101-4391 [email protected] , Jiasun Su , Wei Li , Chaofan Zhou , Yuan Wei , Weiliang Lu , Linlin Wang , … Show All … , Jiao Li , Shujie Zhang , Fei Chen , Yueyun Lan , Sheng He , Zailong Qin , Shengkai Wei , Liang Wang , Peng Huang , and Jingsi Luo Show Fewer Authors Info & Affiliations https://doi.org/10.22541/au.174919691.11919534/v1 495 views 173 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Abstract Objective: To understand phenotyping and prognosis for fetuses with 16p13.11 deletion/duplication in East Asian population. Design: Retrospective prenatal and patient cohort study in southern China. Setting: Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region. Population: All fetuses and patients underwent chromosomal microarray analysis between April 2013 and July 2024. Methods: We conducted a comprehensive ultrasound phenotypic analysis, pedigree analysis and long-term postnatal outcome follow-up on 201 fetuses, as well as phenotypic manifestations on 14 patients with 16p13.11 deletion/duplication. Descriptive statistical analysis was used. Main outcome measures: Prenatal ultrasound characteristics and postnatal clinical phenotypes. Results: The detection rates were 0.08% and 0.18%, the frequencies of de novo occurrence were 26.9% and 14.5%, the rates of abnormal postnatal phenotypes were 25% and 17.5% in our prenatal cohort of deletion and duplication. 28.6% of deletions and 15.9% of duplications exhibited abnormal postnatal phenotypes even if inherited from a phenotypically normal parent. Developmental delay was the most common clinical abnormality. Immune disorders, torticollis, concealed penis and cryptorchidism were closely related phenotypes that had previously gone unnoticed. The deletion was closely associated with isolated choroid plexus cysts. Thickened nuchal translucency and choroid plexus cysts were the Top 2 ultrasound characteristics for duplication. Conclusion: The largest East Asian prenatal cohort is conducive to enhancing genetic counseling for 16p13.11 deletion/duplication syndrome by facilitating a more accurate prediction of fetal prognosis and developmental potential. Keywords 16p13.11 deletion/duplication, Prenatal diagnosis, Postnatal outcome follow-up, Genetic counsel 16p13.11 deletion/duplication: prenatal diagnosis, postnatal outcome follow-up and phenotypic manifestations: a large cohort study Xianglian Tang 1, 2# , Jiasun Su 3# , Wei Li 1 , Chaofan Zhou 1 , Yuan Wei 1 , Weiliang Lu 1 , Linlin Wang 4 , Jiao Li 4 , Shujie Zhang 1 , Fei Chen 1 , Yueyun Lan 1 , Sheng He 1, 2 , Zailong Qin 1, 2 , Shengkai Wei 1 , Liang Wang 1 , Peng Huang 1, 2* , Jingsi Luo 1, 2* 1 Genetic and Metabolic Central Laboratory, Guangxi Birth Defects Research and Prevention Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China. 2 Guangxi Clinical Research Center for Birth Defects, Guangxi Clinical Research Center for Pediatric Diseases, Guangxi Key Laboratory of Reproductive Health and Birth Defects Prevention, Guangxi Key Laboratory of Precision Medicine for Genetic Diseases, Guangxi Key Laboratory of Birth Defects and Stem Cell Biobank, Guangxi Key Laboratory of Birth Defects Research and Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China. 3 Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China. 4 Prenatal Diagnosis Center, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China. # These authors contributed equally to this work. * Correspondence to Peng Huang, Laboratory of Genetics and Metabolism, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People’s Republic of China, E-mail: [email protected] ; Jingsi Luo, Laboratory of Genetics and Metabolism, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People’s Republic of China, E-mail: [email protected] Abstract Objective: To understand phenotyping and prognosis for fetuses with 16p13.11 deletion/duplication in East Asian population. Design: Retrospective prenatal and patient cohort study in southern China. Setting: Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region. Population: All fetuses and patients underwent chromosomal microarray analysis between April 2013 and July 2024. Methods: We conducted a comprehensive ultrasound phenotypic analysis, pedigree analysis and long-term postnatal outcome follow-up on 201 fetuses, as well as phenotypic manifestations on 14 patients with 16p13.11 deletion/duplication. Descriptive statistical analysis was used. Main outcome measures: Prenatal ultrasound characteristics and postnatal clinical phenotypes. Results: The detection rates were 0.08% and 0.18%, the frequencies of de novo occurrence were 26.9% and 14.5%, the rates of abnormal postnatal phenotypes were 25% and 17.5% in our prenatal cohort of deletion and duplication. 28.6% of deletions and 15.9% of duplications exhibited abnormal postnatal phenotypes even if inherited from a phenotypically normal parent. Developmental delay was the most common clinical abnormality. Immune disorders, torticollis, concealed penis and cryptorchidism were closely related phenotypes that had previously gone unnoticed. The deletion was closely associated with isolated choroid plexus cysts. Thickened nuchal translucency and choroid plexus cysts were the Top 2 ultrasound characteristics for duplication. Conclusion: The largest East Asian prenatal cohort is conducive to enhancing genetic counseling for 16p13.11 deletion/duplication syndrome by facilitating a more accurate prediction of fetal prognosis and developmental potential. Keywords 16p13.11 deletion/duplication, Prenatal diagnosis, Postnatal outcome follow-up, Genetic counsel 1 Introduction Deletion (Del)/Duplication (Dup) of the recurrent 16p13.11 region has been associated with a range of neurodevelopmental disorders including developmental delay (DD), intellectual disability (ID), mental retardation (MR), autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), behavioural problem (hyperactive and aggressive behaviour), seizure/epilepsy, schizophrenia, cardiovascular and congenital heart disease (CHD), multiple congenital abnormalities and deformative features (neonatal feeding and respiratory difficulty, small stature, microcephaly/macrocephaly, polydactyly/syndactyly, craniofacial dysmorphism, structural brain abnormality, dysplastic ear, hearing loss/difficulty, hypotonia/hypertonia, pectus excavatum, vertebral anomaly, aortic disease and vision problem). 1-10 The pathogenicity of copy number variations (CNVs) in the 16p13.11 region remains debatable due to variable phenotypes and low penetrance. The evidence supporting haploinsufficiency and triplosensitivity for 16p13.11 recurrent region (BP2-BP3) is considered to be emerging and the score for this region is a 2 in the database of ClinGen (https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37415). Moreover, in the Database of Genomic Variants, the incidences of the 16p13.11 Del and Dup in the general population are approximately 0.03% and 0.14%, respectively. Since clinical features observed in patients are relatively nonspecific, and frequently present in unaffected parents and relatives of affected subjects, the pathological significance of 16p13.11 Del/Dup remains uncertain. Limited and uncertain fetal phenotypes take considerable challenges to prenatal diagnosis and genetic counseling, such as prediction of clinical outcomes and variant interpretation of fetuses with 16p13.11 Del/Dup. Hence, the purpose of this study is to expand knowledge of the increasingly concerning 16p13.11 recurrent region, and provide insights into understanding the fetal phenotype and the wide clinical spectrum of the 16p13.11 Del/Dup syndrome. Herein, we retrospectively reviewed 201 fetuses and 14 patients with 16p13.11 Del/Dup, summarized the clinical details and pregnancy outcomes, including sample types, results of chromosomal microarray analysis (CMA), pedigree analysis, indications for invasive testing, abnormal ultrasound characteristics, postnatal outcome follow-up and abnormal clinical phenotypes, to comprehensively understand fetal phenotyping and the wide clinical spectrum, thereby dissecting genotype-phenotype correlations and facilitating the precise assessment of fetal outcomes and prognosis during genetic counseling. 2 Materials and Methods 2.1 Subjects and ethics approval From April 2013 to July 2024, a total of 79,136 cases of invasive prenatal genetic testing and 4,895 cases of peripheral blood underwent CMA at Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, and we collected data on 16p13.11 Del/Dup. This study was approved by the Medical Ethics committee of Maternal and Child Health, Guangxi Zhuang Autonomous Region, and signed informed consent was obtained from each patient (File NO. 2023-7-18, 17 July 2023). Chorionic villus sampling (CVS), amniocentesis or cordocentesis was performed under ultrasound guidance and peripheral blood was collected following receipt of informed consent and payment from participating families. Our analysis involved various diagnosis techniques, including prenatal examinations, pregnancy outcome follow-up, and detailed assessment of growth and development. Descriptive statistical analysis was used. 2.2 Chromosomal microarray analysis Genomic DNA was extracted from the amniotic fluid, chorionic villi or peripheral blood using a TIANamp Micro DNA Kit (DP316, TIANGEN Biotech, China), the umbilical cord blood using a Lab-Aid DNA kit (824s, Zeesan, China) in accordance with the manufacturer’s protocol. DNA quality was assessed by agarose gel electrophoresis and DNA concentration was measured with a Nanodrop spectrophotometer (Thermo, USA). CMA testing was performed using Illumina HumanCytoSNP-12 v2.1 BeadChip (Illumina, San Diego, CA, USA). The SNP data were collected and analyzed using Illumina Genome Studio and KaryoStudio software, with coordinates being presented according to the human (GRCh37/hg19) assembly. 2.3 Follow-up of outcomes Routine postnatal assessments were performed at birth, by retrieving Gui Women and Children’s Health Service Information Management System or telephone interview through the hospital’s clinical follow-up center. Data collected including sample types, prenatal diagnosis indications, pregnancy complications, pregnancy outcome (termination of pregnancy, eutocia or cesarean), delivery date, gestational age at delivery (preterm or full-term delivery), fetus gender, birth weight/length, head/chest circumference, newborn assessment, physical examination and developmental details as evaluated by a pediatrician. 3 Results We identified 201 fetuses including 60 Del and 141 Dup on 16p13.12-p12.2 region between 14.62 and 22.67 Mb (Human Genome Build 37). The detection rates of 16p13.11 Del and Dup were 0.08% (60/79,136) and 0.18% (141/79,136), respectively. CMA results and clinical information, including sample types, clinical indications and outcome follow-up, were provided in Table S1-S2 and summarized in Table 1. Fetuses with abnormal ultrasound characteristics and postnatal phenotypes were available and collected in Table 2 and Table 3. Furthermore, we detected 91 peripheral blood samples including 22 Del and 69 Dup on 16p13.12-p12.3 region between 14.76 and 19.03 Mb (Human Genome Build 37) (Table S3-S4). 14 patients with clinical abnormalities were collected in Table 4. Unless otherwise noted, no additional genomic abnormalities with clinical relevance were observed in the mentioned cases. 3.1 Prenatal sample Prenatal sample type In our database, the proportions of CVS, amniocentesis and cordocentesis procedures performed in cases of Del were 13.3% (8/60), 68.3% (41/60) and 18.3% (11/60), respectively, and those in cases of Dup were 18.4% (26/141), 66.0% (93/141) and 15.6% (22/141). Interval CMA revealed 71.7% (43/60) Del and 75.2% (106/141) Dup were located inside intervals I and II, 5.0% (3/60) Del and 10.6% (15/141) Dup were located inside interval II only, 23.3% (14/60) Del and 14.2% (20/141) Dup were located inside intervals II and III. Pedigree analysis In addition to the 26 fetuses, the parents of the remaining 34 fetuses refused pedigree verifcation in the cohort of Del. Out of the 26 cases, 7 (26.9%) were de novo , and 19 cases were either paternally (n=7) or maternally (n=12) inherited. In the cohort of Dup, the parents of 79 fetuses refused pedigree analysis, while in the other 62 cases, 9 (14.5%) were de novo , and 53 cases were either paternally (n=26) or maternally (n=27) inherited. Prenatal diagnosis indications Each case is classified according to its most important indication. Indications are listed in order of importance: abnormal ultrasound, abnormal noninvasive prenatal testing (NIPT) results, high risk of serum screening for pregnant women, genetic factors of parents, adverse pregnancy history, pregnancy at advanced maternal age, and pregnancy exposure. Ultrasound abnormalities include structural malformations, abnormal soft markers, fetal growth restriction (FGR) and abnormal amniotic fluid volume. Genetic factors abnormalities include parents with ID, abnormal karyotypes, CNVs and carried the same thalassemia gene. Pregnancy exposure includes poor exposure and medication history during early pregnancy. Prenatal ultrasound phenotype 51.7% (31/60) of Del and 41.8% (59/141) of Dup with abnormal ultrasound phenotypes were observed, and the characteristics of 187 fetuses without additional genomic abnormalities with clinical relevance were analyzed in Table 2. Among 56 fetuses with Del, 10.7% (6/56) of isolated choroid plexus cysts, 7.1% (4/56) of each phenotype (echogenic intracardiac focus, heart defect and dilated renal pelvis), 3.6% (2/56) of each phenotype (renal defect, isolated thickened nuchal translucency, lateral ventricle broadening, single umbilical artery and isolated permanent left superior vena cava). 1.8% (1/56) of each phenotype (subependymal cysts, abdominal mixed mass, short femur length, thickened placent, FGR, cavum septum pellucidum not displayed and colon dilatation). In 131 fetuses with Dup, 5.3% (7/131) of choroid plexus cysts and thickened nuchal translucency, respectively. 3.8% (5/131) of hyperechogenic bowel and oligohydramnios, respectively. 3.1% (4/131) of absent or hypoplastic nasal bone. 2.3% (3/131) of each phenotype (FGR, echogenic intracardiac focus, dilated renal pelvis/hydronephrosis, aberrant right subclavicular artery, abnormal cavum septum pellucidum, heart defect, brain defect, renal defect). 1.5% (2/131) of each phenotype (liver defect, thickened placent, large/small head circumference). 0.8% (1/131) of each phenotype (small magenblase, liquid dark area in the right upper bladder, enlarged cisterna magna, single umbilical artery, widened inferior vena cava, widened inner diameter of rectum, short femur and humerus length, mandible subcutaneous fluid mass, ventriculomegaly, cleft lip and palate, syndactyly and persistent right umbilical vein). Postnatal outcome of follow-up According to the decision of parent, termination of pregnancy was performed in 22 cases in the cohort of Del. Among the newborns, 55.3% (21/38) were male and 44.7% (17/38) were female, with 5.3% (2/38) being delivered preterm. 9 (25%) cases with abnormal postnatal phenotype were collected in Table 3 and depicted in pink in Table S1. In 36 newborns without additional genomic abnormalities with clinical relevance, 16.7% (6/36) were diagnosed as DD. 5.6% (2/36) had immune disorders (urticaria and dermatitis), cardiovascular abnormalities (stenosis of pulmonary artery, patent ductus arteriosus, tricuspid regurgitation, second foramen atrial septal defect (type II), venous sinus defect, coronary sinus defect and patent foramen ovale) and torticollis, respectively. Cases also showed inguinal hernia, cystic teratoma, conjunctivitis, bilateral testicular hydrocele, mild anemia and intestinal adhesions. Additionally, termination of pregnancy was performed in 37 cases in the cohort of Dup. Among the newborns, 60.6% (63/104) were male and 39.4% (41/104) were female, with 12 (11.5%) being delivered preterm. 18 (17.5%) cases with abnormal postnatal phenotype were collected in Table 3 and highlighted in blue in Table S2. In 103 newborns without additional genomic abnormalities with clinical relevance, 5.8% (6/103) were diagnosed as DD. 5.8% (6/103) had immune disorders (dermatitis, angular cheilitis and Kawasaki disease) and cardiovascular abnormalities (atrioventricular block, patent ductus arteriosus, patent foramen ovale, tricuspid regurgitation, pulmonary regurgitation, second foramen atrial septal defect (type II), venous sinus defect, coronary sinus defect, increased anterior blood flow velocity of pulmonary valve, aortic stenosis, sinus rhythm, occasional premature beat), respectively. 4.9% (5/103) showed ophthalmological abnormalities (eye subconjunctival hemorrhage, immature retina, unvascularized retina, myopia and astigmatism). 1.9% (2/103) showed torticollis and urogenital system abnormalities (concealed penis and cryptorchidism), respectively. Cases also showed epilepsy, feeding intolerance, umbilical hernia, cystic teratoma, lymphangioma, pigmentation, depigmented nevus and nevus flammeus, subependymal hemorrhage, conjunctivitis, lacrimal duct stenosis and eye nasolacrimal duct obstruction. 3.2 Peripheral blood sample Clinical phenotypes We detected 22 samples with Del, including 18 cases from pedigree analysis and 2 cases from health checkup. 3 patients with abnormal phenotypes were collected in Table 4 and depicted in pink in Table S3. A female presented tinea versicolor only. 2 children showed DD, epilepsy, nystagmus and myelin developmental delayed, immunodeficiency and autoimmune diseases. 69 samples with Dup were identified, comprising 55 cases from pedigree analysis and 5 cases from health checkup. 11 patients with abnormal phenotypes were collected in Table 4 and highlighted in blue in Table S4. 2 adults presented pityrosporum folliculitis or dermatitis only. 2 adults showed with ID. In the clinical referral series, 7 children were diagnosed as acute respiratory distress syndrome, idiopathic short stature, DD, ID and MR, ADHD, sensory disorder, ASD, epilepsy, feeding intolerance, bronchopulmonary dysplasia, congenital septum pellucidum abnormalities, central atrial septal defect (foramen ovale) and cryptorchidism. 4 Discussion 4.1 Main findings In this study, we investigated 201 fetuses with 16p13.11 Del/Dup in a large prenatal cohort with 79,136 subjects, currently the largest East Asian prenatal cohort of this recurrent region. We analyzed the detection rates (0.08% and 0.18%), the frequencies of de novo occurrence (26.9% and 14.5%) and the rates of abnormal postnatal phenotypes (25% and 17.5%) for 16p13.11 Del/Dup in our prenatal cohort. 28.6% of Del and 15.9% of Dup exhibited abnormal postnatal phenotypes even if inherited from a phenotypically normal parent. We found that developmental delay is the most common anomaly, with immune disorders, cardiovascular and ophthalmological abnormalities, torticollis, concealed penis and cryptorchidism being closely related phenotypes. The phenotypes of CNVs at intervals I+II, II+III are likely more severe than at intervals II alone. The deletion was closely associated with isolated choroid plexus cysts. Thickened nuchal translucency and choroid plexus cysts were the Top 2 specific ultrasonographic soft markers for duplication. 4.2 Strengths and limitations The strengths of this study include the large prenatal cohort and long-term follow-up in southern China. The largest East Asian prenatal cohort enhances genetic counseling for 16p13.11 Del/Dup, which is lacking in the current literature. Limitation of this study is that we have not sequenced genes to identify the presence and significance of other pathological variants. More clinical cases should be included and discussed, conducting long-term follow-up and performing further genetic test, such as next-generation sequencing and third-generation sequencing, to unmask potential genetic factor may be warranted. 4.3 Interpretation Our findings reveal that the detection rates of Del and Dup in southern China were 0.08% (60/79,136) and 0.18% (141/79,136), respectively, which are more representative than those reported in seven small Chinese cohorts. The detection rates of 16p13.11 Del were 0.10% (15/15,263) in Chinese 29 provinces, 11 0.09% (13/15,051) in Chinese Taiwan, 12 0.08% (6/7,617) in Henan, 13 0.06% (5/9,000) in Fujian 14 and 0.06% (4/7,078) in Chengdu. 15 The detection rates of 16p13.11 Dup were 0.06% (9/15,051) in Chinese Taiwan, 12 0.32% (24/7,617) in Henan, 13 0.17% (15/9,000) in Fujian, 14 0.10% (7/7,078) in Chengdu, 15 0.63% (8/1,261) in Chinese Hong Kong 16 and 0.43% (15/3,451) in Shandong. 17 The population prevalence in southern China is of great significance for understanding and genetic counseling this recurrent region in the East Asian population. The majority of studies have focused on the frequency of CNVs in the patient cohort. The 16p13.11 Del was found in 0.5-0.6% of patients with epilepsy, 4,5 0.12% of schizophrenia, 6 0.15% of neurodevelopmental disorders 18 and 0.15% of varied abnormal phenotypes. 19 The 16p13.11 Dup was present in 0.30% of schizophrenia cases, 6 0.27% of neurodevelopmental disorders 18 and 0.19% of Chinese pediatric patients populations with DD. 20 However, in the general population, the prevalence of Del is approximately 0.04-0.05%, 18,19 and Dup is around 0.12%. 18 It follows that estimated population prevalence only considers patient cohorts are higher than the general population. The population prevalence in our prenatal cohort is lower than the patient cohort but higher than the general population reported in above literatures. Estimated the frequency of de novo occurrence and penetrance in different ethnic populations is essential for genetic counseling. In our prenatal cohort, the frequency of de novo occurrence of Del was 26.9% higher than an American cohort (21.7%), 19 and Dup was 14.5% higher than a French and Belgian cohort (8.8%), 21 which represents a distinct of the Chinese population. It is noteworthy that 73.1% of Del and 85.5% of Dup were inherited, most of them have parents with no significant abnormalities. Of whom, 28.6% (4/14) of Del and 15.9% (7/44) of Dup had abnormal phenotypes during postnatal outcome follow-up (Table S1 and S2), indicated incomplete penetrance in 16p13.11 Del/Dup. Besides, the penetrance of 16p13.11 Del has been reported as 13.1% in the United States 19 and 17% in the UK Biobank, 22 whereas Dup at 8.43% in the French and Belgian, 21 7% in the UK Biobank 22 and 10.6% in the Europe and North America. 23 The rates of abnormal postnatal phenotype in our cohort were 25% (9/36) for Del and 17.5% (18/103) for Dup. DD was the most common clinical abnormality, affecting around 16.7% (6/36) of Del and 5.8% (6/103) of Dup. Cardiovascular abnormalities were observed in 5.6% (2/36) of Del and 5.8% (6/103) of Dup, respectively, as same as immune disorders. Moreover, 5.6% (2/36) had dysmorphic feature and 8.3% (3/36) had congenital abnormalities in the Del. In the Dup, 4.9% (5/103) exhibited ophthalmological abnormalities, 1.9% (2/103) had urogenital system abnormalities, 1.9% (2/103) presented with dysmorphic features, 1% (1/103) showed behavioural disturbances and 10.7% (11/103) had congenital abnormalities (Table 3). The majority of individuals with DD, epilepsy, cardiovascular and ophthalmological abnormalities and congenital abnormalities, in supporting the published literature. 10 Asthma and immune disorders in 16p13.11 Dup syndrome have been considered an interesting finding, 24 and our outcome follow-up confirmed a broad impact of the 16p13.11 Del/Dup on the immune system. Notably, torticollis, concealed penis and cryptorchidism are a series of previously unnoticed related phenotypes and are worthy of further investigation. Taken together, it is crucial to refer individuals with 16p13.11 Del/Dup for growth and developmental examination, neurodevelopmental and behavioral diagnosis, as well as cardiovascular, ophthalmological, urogenital and immune system assessment. So far, phenotyping and indications for fetuses with 16p13.11 Del/Dup have been rarely described. In our cohort, 51.7% (31/60) of Del and 41.8% (59/141) of Dup presented with abnormal ultrasound findings, that is to say ultrasound characteristics should be adequately considered during clinical consultations. Studies have reported that 16p13.11 Del was associated with thickened nuchal translucency, whereas 16p13.11 Dup was closely related to echogenic bowel. 11,14 However, only 3.6% (2/56) of Del with thickened nuchal translucency were detected, while 10.7% (6/56) exhibited choroid plexus cysts in our cohort. Meanwhile, only 3.8% (5/131) of Dup with echogenic bowel were found, while 5.3% (7/131) presented with thickened nuchal translucency and choroid plexus cysts, respectively (Table 2). Therfore, we deduced that Del was associated with choroid plexus cysts, and Dup was closely related to thickened nuchal translucency and choroid plexus cysts. Moreover, 7.1% (4/56) had heart defect, 3.6% (2/56) had renal defect and 1.8% (1/56) had brain defect in Del. Heart, renal and brain defect were observed in 2.3% (3/131) of Dup, respectively. These findings suggested that a more comprehensive cardiac, renal and brain evaluation should be conducted on prenatal diagnosis. Besides, oligohydramnios (3.8% (5/131)) and FGR (2.3% (3/131)) raised concerns in Dup, and a more careful assessment of intrauterine fetal growth and development should be performed during genetic counseling. Considering the strong correlation between 16p13.11 Del/Dup and ultrasound soft markers, it is necessary to combine prenatal CMA detection for diagnosis of this recurrent region. The recurrent 16p13.11 region is subdivided into three main intervals (I, II and III), each flanked by sequences rich in low copy repeats (LCRs) (Figure S1). 6 In our prenatal cohort, 71.7% (43/60) of Del I+II and 75.2% (106/141) of Dup I+II were most frequently identified, whereas 5.0% (3/60) of Del II and 10.6% (15/141) of Dup II were rarely observed and presented only with DD, cystic teratoma, torticollis, unvascularized retina and pigmentation in postnatal outcome follow-up. Furthermore, 3 cases with Del II+III, 10 cases with Dup I+II and one case with Dup II+III were found in our patient cohort with a wide range of abnormal phenotypes, and no case within intervals II only. These 14 patients presented with DD, ID/MR, ADHD, ASD, sensory disorder, epilepsy, cryptorchidism, respiratory diseases, immune disorders, cardiovascular, ophthalmological, brain and congenital abnormalities (Table 4). These findings indicated that the phenotypes of intervals I+II, II+III are more severe than intervals II alone, possible interactions and synergistic effect among the involved genes. Interestingly, it has been reported that 16p13.11 Dup is a risk factor for thoracic aortic aneurysm and dissection, 9 predisposing individuals to defective cardiac left-right patterning and laterality disorders. 25 However, none exhibited above cardiovascular abnormalities in our prenatal and patient cohort. Recently, CNVs at 16p13.11 have been reported to increase risk for epilepsy, hypertension and kidney stones. 26 Additionally, 68.3% (28/41) of the individuals in our cohorts of abnormal postnatal phenotypes and patients were male, indicated the possible Male-biased effect of 16p13.11 CNVs, as reported in the UK cohort. 18 5 Conclusion Considering the strong correlation between 16p13.11 Del/Dup and ultrasound soft markers, it is necessary to combine prenatal CMA detection for diagnosis of this recurrent region. Based on the 2024 American College of Medical Genetics and Genomics (ACMG), ClinGen technical standards for the interpretation and reporting of constitutional CNVs, cohort studies and local databases, we recommend that the high-frequency 16p13.11 Del/Dup be classified as a variant of uncertain significance (VUS) in prenatal subjects regardless of the fetal phenotype or pedigree analysis, and fetal outcomes are difficult to predict due to its low-penetrant. Author Contributions XLT: Conceptualization, Formal analysis, Investigation, Resources, Data curation, Visualization, Writing - Original draft, Funding acquisition. JSS: Investigation, Resources, Data curation, Visualization, Writing - Original draft. WL, CFZ, YW, WLL, SJZ, FC, YYL, SH, ZLQ: Investigation, Resources, Data curation. LLW, JL: Investigation, Resources, Genetic diagnosis. SKW, LW: Investigation, Resources. PH, JSL: Conceptualization, Writing - Review & Editing, Supervision, Project administration, Funding acquisition. All authors read and approved the final manuscript. Acknowledgments and Funding information This research was supported by Guangxi Key R&D Program Project (No. 2023AB22090), National Natural Science Foundation of China (82160028), Guangxi Zhuang Autonomous Region Health Department (Z-A20220261), and the Open Project Funding of Guangxi Key Laboratory of Birth Defects and Stem Cell Biobank (Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region) (GXWCH-ZDKF-2022-13). Conflict of Interests The authors declare that they do not have any competing interests. Data Availability Statement The original contributions presented in this study are available within the article and Supplementary Materials. Further inquiries can be directed to the corresponding authors. Ethics Approval This study was approved by the Medical Ethics committee of Maternal and Child Health, Guangxi Zhuang Autonomous Region, and signed informed consent was obtained from each patient (File NO. 2023-7-18, 17 July 2023). References 1. 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The penetrance of copy number variations for schizophrenia and developmental delay. Biol Psychiatry. 2014;75(5):378-385. 24. Li J, Hojlo MA, Chennuri S, Gujral N, Paterson HL, Shefchek KA, et al. Underrepresentation of Phenotypic Variability of 16p13.11 Microduplication Syndrome Assessed With an Online Self-Phenotyping Tool (Phenotypr): Cohort Study. J Med Internet Res. 2021;23(3):e21023. 25. Yu K, Chen W, Chen Y, Shen L, Wu B, Zhang Y, et al. De novo and inherited micro-CNV at 16p13.11 in 21 Chinese patients with defective cardiac left-right patterning. Front Genet. 2024;15:1458953. 26. Auwerx C, Jõeloo M, Sadler MC, Tesio N, Ojavee S, Clark CJ, et al. Rare copy-number variants as modulators of common disease susceptibility. Genome Med. 2024;16(1):5. Table Table 1. Findings of 201 fetuses with 16p13.11 deletion (60 cases) and duplication (141 cases). Table 2. Abnormal ultrasound characteristics of 187 fetuses with 16p13.11 deletion (56 cases) and duplication (131 cases). Table 3. Abnormal postnatal phenotypes of 139 newborns with 16p13.11 deletion (36 cases) and duplication (103 cases). Table 4. Abnormal clinical phenotypes of 14 patients with 16p13.11 deletion (3 cases) and duplication (11 cases). Supplementary data Figure S1. Genomic position of the 16p13.12-p12.3 region. Produced with the University of California, Santa Cruz Genome Browser (http://www.genome.ucsc.edu). Genomic region is subdivided into three intervals (I, II and III) referred to in the article by Ingason et al. are shown as yellow frame. Table S1. CMA, prenatal diagnosis indications and outcome follow-up of 60 fetuses with 16p13.11 deletion. Table S2. CMA, prenatal diagnosis indications and outcome follow-up of 141 fetuses with 16p13.11 duplication. Table S3. CMA and clinical phenotypes of 22 peripheral blood samples with 16p13.11 deletion. Table S4. CMA and clinical phenotypes of 69 peripheral blood samples with 16p13.11 duplication. Supplementary Material File (table.xlsx) Download 21.34 KB Information & Authors Information Version history V1 Version 1 06 June 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords diagnostic studies fetal diagnosis and therapy fetal medicine fetal medicine: perinatal diagnosis—invasive fetal medicine: perinatal diagnosis—ultrasound Authors Affiliations Xianglian Tang 0000-0002-4101-4391 [email protected] Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Jiasun Su Guangzhou Women and Children's Medical Center View all articles by this author Wei Li Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Chaofan Zhou Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Yuan Wei Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Weiliang Lu Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Linlin Wang Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Jiao Li Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Shujie Zhang Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Fei Chen Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Yueyun Lan Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Sheng He Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Zailong Qin Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Shengkai Wei Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Liang Wang Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Peng Huang Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Jingsi Luo Maternity and Child Health Care of Guangxi Zhuang Autonomous Region View all articles by this author Metrics & Citations Metrics Article Usage 495 views 173 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Xianglian Tang, Jiasun Su, Wei Li, et al. 16p13.11 deletion/duplication: prenatal diagnosis, postnatal outcome follow-up and phenotypic manifestations: a large cohort study. 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