Prenatal Diagnosis of Complete Paternal Uniparental Isodisomy for Chromosome 3: A Case Report

Prenatal Diagnosis of Complete Paternal Uniparental Isodisomy for Chromosome 3: A Case Report | 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 Case Report Prenatal Diagnosis of Complete Paternal Uniparental Isodisomy for Chromosome 3: A Case Report xiufen bu, Xu Li, Shihao Zhou, Liangcheng Shi, Xuanyu Jiang, Can Peng, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-778220/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background Paternal uniparental disomy (UPD) of chromosome 3 is a very rare condition. At present, only 5 cases of paternal UPD(3) has been reported. This was the second ascertained paternal UPD(3) with no apparent disease phenotype. Case presentation We hereby reported a case of a fetus with normal karyotype and normal ultrasound features at the whole gestation. A copy neutral regions of homozygosity on chromosome 3 was indentified by Single Nucleotide Polymophism array (SNP array). Subsequent SNP array data of parent–child trios showed the fetus has carried complete paternal uniparental isodisomy (isoUPD) of chromosome 3. The parents decided to continue the pregnancy after genetic counseling. The neonate had normal physical findings at birth and develops normally after 1.5 years. Conclusions The findings could provide further evidence to confirm that there was no important imprinted genes causing serious diseases on paternal chromosome 3 and provided a reference for the prenatal diagnosis and genetic counseling of UPD(3) in the future. Molecular Biology General Biochemistry Uniparental isodisomy 3 Imprinted genes Prenatal diagnosis SNP array Figures Figure 1 Figure 2 Figure 3 Background Uniparental disomy (UPD) is a rare condition and defined as an inheritance of two chromosomes only from one of parents with no representative copy from another. The condition that the pair of chromosomes inherited from pairing homologous chromosomes of a parent is termed uniparental heterodisomy (hetUPD). If they came from identical copies of one chromosome, the condition is termed uniparental isodisomy (isoUPD). According to the original parent, UPD can be classified into maternal UPD (matUPD) and paternal UPD (patUPD). Presence of UPD is associated with advanced parental age. According to the latest scientific literature, the estimated incidence of UPD is 1/2000 in live births [ 1 ] . IsoUPD cases are encountered less frequently than hetUPD, and patUPD occurs less frequently than matUPD (the ratio is approximately 1:3) [ 2 ] . Thus, Paternal isoUPD was found to be extremely rare. At present, patUPD(3) has rarely been reported (only 5 cases) and poses a great challenge for prenatal genetic counseling. UPD does not involve an aneuploidy and can not be detected by common clinical chromosome detection techniques. In this study, a prenatal UPD case with negative results of non-invasive prenatal screening (NIPT) and karyotype analysis was diagnosed by Single Nucleotide Polymophism array(SNP array) and followed up. Case Presentation A healthy woman (Gravida 4,Induced abortion 2,Missed abortion 1,Para 0) was referred to the the Department of Medical Genetics at Changsha hospital for maternal and child health care for opinion counseling due to advanced parental age(maternal age:46;paternal age:59),high-risk of Down's Screening in mid-pregnancy(T21 1:140) and adverse pregnancy history at 18 weeks and 3 days of gestation.Subsequent amniocentesis was arranged, and G-banding karyotype analysis (320 bands) of the cultured amniocytes revealed a normal karyotype of 46, XX(Fig. 1 ). Affymetrix CytoScan 750K SNP array on uncultured amniocytes did not detect pathogenic copy number variants and revealed a regions of homozygosity (ROH) on chromosome 3 (Fig. 2 ). SNP microarray data of parent–child trios showed the fetus has carried complete paternal isoUPD(3) (Fig. 3). The fetus was no structural deformity during the whole pregnancy. And the biparietal diameter(BPD), head circumference(HC), femur length(FL),humerus length(HL) and abdominal circumference(AC) measured by ultrasound consistent with gestational age(Table 1 ). In addition, we mainly focus on Placental Mature Grading. Besides that, the parents with an unremarkable family history refused the further examination of whole exome sequencing (WES) on uncultured amniocytes and decided to continue the pregnancy after genetic counseling. At 36 weeks and 6 days of gestation, the pregnant woman had to have a Caesarean due to preeclampsia. A 2550g female infant was delivered and had normal physical findings with Apgar score = 10 at 1 minute after birth. Now aged 1.5, the baby can walk independently and speak a few simple duplicated words. Physical examination shows that she has achieved her appropriate developmental milestones and no physical abnormalities. Table 1 The corresponding ultrasonic values of different gestational ages Gestational age BPD(mm) HC(mm) FL(mm) HL(mm) AC(mm) 24 + 59 222 44 37 197 28 + 70 262 54 47 240 32 + 79 297 63 56 280 36 + 93 338 67 58 320 Discussion And Conclusions UPD usually arises through initial meiotic segregation error.IsoUPD is caused by nondisjunction of sister chromatid in meiosis II,while hetUPD is caused by nondisjunction of homologous chromosomes in meiosis I.Trisomy rescue is one of the reasons for UPD and results from fertilization of a disomic spermatocyte and a normal oocyte in pat UPD.Subsequently, one of the supernumerary chromosomes is eliminated to restore the normal chromosomal number [ 3 ] .The rescue events could occur after the division of the zygote and result in disomy/trisomy mosaicism.when a fetus has a normal karyotype and diagnosed with UPD, mosaicism usually may be found in multiple parts of the placenta biopsy.Trisomy mosaicism can lead to dysfunction of placental and bring about fetal growth restriction,heart malformation,skin edema,and so on [ 4 , 5 ] .So it is very important to keep an eye on the growth of the fetus and assess the maturity of the placenta when UPD is found. IsoUPD inherited two identical copies of one homolog and harbors the risk of resulting in homozygosity for a chromosomal recessive disorders in the offspring of a heterozygous carrier. To date, there have been only 3 reported cases of recessive diseases resulting from pat UPD(3) with normal karyotype. One was a case of Pierson syndrome with distinct renal and ocular abnormalities caused by paternally-inherited homozygous mutation in the LAMB2 gene. The proband died from sepsis at 17 months [ 6 ] . Another was a 10-year-old girl with epilepsy, severe intellectual disability and progressive neurological decline caused by a homozygous pathogenic splice-site mutation in the GLB1 gene resulting mosaic pat UPD(3) [ 7 ] . In addition, microcytic anemia in a infant with sideroblastic anemia type 2 caused by rare nonsense homozygous variant of SLC25A38 gene resulting pat UPD(3) [ 8 ] . The three reported cases are definitely caused by single-gene disorders.Therefore, it is necessary to carry out further examination to exclude recessive gene pathogenic mutation when UPD is found in prenatal diagnosis.In our case,the fetus without abnormal ultrasound features at the whole gestation and the parents refused the further examination.So,we had to monitor and follow up the growth and development of the newborn. As a rare abnormality,UPD leads to abnormal phenotype not only through homozygous recessive disorders,but also through gene imprinting.At present, identified chromosomes bearing imprinted genes include 6,7,11,14,15,and 20 [ 9 ] .However,only three imprinted genes predicted by bioinformatics on chromosome 3: two maternally expressed genes ( ALDH1L and Z1C1 ) and one paternally expressed gene ( HES1 ). No clear imprinted region and gene report were found.Currently,only one case of paternal UPD for entire chromosome 3 has been described with no apparent disease phenotype.The individual identified serendipitously in the study of a whole genome linkage scan and did not display any obvious adverse phenotypic disorders at age 42 [ 10 ] .Physical examination over the 1.5 years of our case has not shown any significant growth or developmental abnormalities, observations that suggest there is no important imprinted gene on paternal chromosome 3 that causes serious diseases. Nevertheless we will continue to follow this case to confirm this suggestion. To sum up,the influence of UPD on a phenotype might be difficult to establish or predict in prenatal diagnosis, due to mosaicism for a trisomic cell line,to homozygosity for recessive pathogenic mutations,or to disorder of imprinted genes.The case we reported was the second case of complete paternal isoUPD(3) with no abnormality.Our study further evidenced that there were no important paternal imprinted genes causing rare genetic disorders on chromosome 3 and provides reference for the diagnosis and consultation of UPD(3) in prenatal diagnosis in the future. Abbreviations UPD Uniparental disomy hetUPD Uniparental heterodisomy isoUPD Uniparental isodisomy matUPD Maternal uniparental disomy patUPD Paternal uniparental disomy NIPT Non-invasive prenatal screening ROH Regions of homozygosity SNP array Single nucleotide polymophism array WES Whole exome sequencing Declarations Authors' contributions All authors contributed, read and approved the final manuscript. Funding There was no funding for this study. Availability of data and materials Not applicable to this article as no datasets were generated or analysed during the current study. Consent for publication Parental consent was obtained for the publication of this case report. Competing interests The authors declare that they have no competing interests. Acknowledgements We thank the patient and their parents for their participation in this research. References Nakka P, Pattillo Smith S, O'Donnell-Luria AH, et al. Characterization of Prevalence and Health Consequences of Uniparental Disomy in Four Million Individuals from the General Population. Am J Hum Genet. 2019;105(5):921–32. Benn P. Uniparental disomy: Origin, frequency, and clinical significance. Prenat Diagn. 2021;41(5):564–72. Matsubara K, Kagami M, Fukami M. Uniparental disomy as a cause of pediatric endocrine disorders. Clin Pediatr Endocrinol. 2018;27(3):113–21. Eggermann T, Soellner L, Buiting K, Kotzot D. Mosaicism and uniparental disomy in prenatal diagnosis. Trends Mol Med. 2015;21(2):77–87. Pan M, Li FT, Li Y, et al. Discordant results between fetal karyotyping and non-invasive prenatal testing by maternal plasma sequencing in a case of uniparental disomy 21 due to trisomic rescue. Prenat Diagn. 2013;33(6):598–601. Matejas V, Muscheites J, Wigger M, Kreutzer HJ, Nizze H, Zenker M. Paternal isodisomy of chromosome 3 unmasked by autosomal recessive microcoria-congenital nephrosis syndrome (Pierson syndrome) in a child with no other phenotypic abnormalities. Am J Med Genet A. 2011;155A(10):2601–4. Myers KA, Bennett MF, Chow CW, et al. Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay. Am J Med Genet A. 2018;176(1):230–4. Andolfo I, Martone S, Ribersani M, et al. Apparent recessive inheritance of sideroblastic anemia type 2 due to uniparental isodisomy at the SLC25A38 locus. Haematologica. 2020;105(12):2883–6. Del Gaudio D, Shinawi M, Astbury C, et al. Diagnostic testing for uniparental disomy: a points to consider statement from the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2020;22(7):1133–41. Xiao P, Liu P, Weber JL, Papasian CJ, Recker RR, Deng HW. Paternal uniparental isodisomy of the entire chromosome 3 revealed in a person with no apparent phenotypic disorders. Hum Mutat. 2006;27(2):133–7. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major Revision 22 Aug, 2021 Review # 2 received at journal 21 Aug, 2021 Reviewer # 2 agreed at journal 20 Aug, 2021 Reviews received at journal 17 Aug, 2021 Reviewers invited by journal 17 Aug, 2021 Reviewer # 1 agreed at journal 16 Aug, 2021 Review # 1 received at journal 16 Aug, 2021 Editor assigned by journal 16 Aug, 2021 Editor invited by journal 15 Aug, 2021 Submission checks completed at journal 10 Aug, 2021 First submitted to journal 01 Aug, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-778220","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":44961647,"identity":"67b0c3d7-c739-48b2-b56b-5c99ea4995e0","order_by":0,"name":"xiufen bu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYBACfvkHiQ8S/0jwyLM3EKlFsiHhscHDBgsZw54DRGoxOJD4TPJhQ4UNw40EorUcTpNI3CHBwzjz8cYbDDU20YQddrAt2SLxjAQPu3RasQXDsbTcBkJa+A7zJN5IYAPaMjvHTIKx4TBhLQzH+D9IgLQw3DxDpBaBMwxJEoltQC03eIjUIjmDIdkgAegXwx6gXxKI8Qu/BEPiwx8Vdfby7Ic33vhQY0OEX5CAgUQCKcohWkjVMQpGwSgYBSMDAAAlnEBPjl0wZQAAAABJRU5ErkJggg==","orcid":"","institution":"Changsha hospital for maternal and child health care","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"xiufen","middleName":"","lastName":"bu","suffix":""},{"id":44961648,"identity":"ac684e60-bc59-4675-bdbd-742a225c1bac","order_by":1,"name":"Xu Li","email":"","orcid":"","institution":"Yiyang medical college","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xu","middleName":"","lastName":"Li","suffix":""},{"id":44961649,"identity":"18606b6a-fcdc-4169-afc8-240eb5647fe9","order_by":2,"name":"Shihao Zhou","email":"","orcid":"","institution":"changsha hospital for maternal and child health care","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shihao","middleName":"","lastName":"Zhou","suffix":""},{"id":44961650,"identity":"19180754-2daf-4e47-8bab-58dfd1f9fb01","order_by":3,"name":"Liangcheng Shi","email":"","orcid":"","institution":"changsha hospital for maternal and child health care","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Liangcheng","middleName":"","lastName":"Shi","suffix":""},{"id":44961651,"identity":"e3658eb8-05a7-4aaf-9eae-dbb8977349aa","order_by":4,"name":"Xuanyu Jiang","email":"","orcid":"","institution":"changsha hospital for maternal and child health care","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xuanyu","middleName":"","lastName":"Jiang","suffix":""},{"id":44961652,"identity":"d6960805-890f-4ca9-b578-87fe04c4060b","order_by":5,"name":"Can Peng","email":"","orcid":"","institution":"changsha hospital for maternal and child health care","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Can","middleName":"","lastName":"Peng","suffix":""},{"id":44961653,"identity":"bc17e0e0-4f6c-4729-852e-30910d20dbaa","order_by":6,"name":"Hongyu Li","email":"","orcid":"","institution":"changsha hospital for maternal and child health care","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hongyu","middleName":"","lastName":"Li","suffix":""},{"id":44961654,"identity":"7618514a-d102-4de7-8417-38eae68afc99","order_by":7,"name":"Jun He","email":"","orcid":"","institution":"changsha hospital for maternal and child health care","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"He","suffix":""}],"badges":[],"createdAt":"2021-08-03 10:14:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-778220/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-778220/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":12370522,"identity":"859f2306-d53b-41d1-aa00-4976d8d1bdff","added_by":"auto","created_at":"2021-08-12 14:34:25","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":85284,"visible":true,"origin":"","legend":"Normal karyotype of the fetus. The fetal amniotic fluid sample showed a normal 46, XX karyotype.","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-778220/v1/085096980a19f379acb6b4df.jpg"},{"id":12370520,"identity":"87db4b04-5c0a-4e76-983b-7d9a89cdc6e6","added_by":"auto","created_at":"2021-08-12 14:34:24","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2695362,"visible":true,"origin":"","legend":"Regions of homozygosity (ROH) in entire chromosome 3 found by SNP array analysis of the fetus.\nA ChAS revealed a complete ROH across the entire chromosome (purple rectangle, blue arrow).\nB A whole chromosome view clearly shows the copy neutral ROH on chromosome 3 in the fetus (red arrow).\n","description":"","filename":"Fig.2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-778220/v1/4444dd8f020c147e4bfeda4e.jpg"},{"id":12370889,"identity":"f55f50c2-a11a-4f83-88aa-757368bb5280","added_by":"auto","created_at":"2021-08-12 14:37:24","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3226666,"visible":true,"origin":"","legend":"Complete paternal uniparental isodisomy (isoUPD) of chromosome 3.\nA ChAS software directly indicates the UPD originates from her father after comparing the genotyping results between the fetus and her parents (red arrows).\nB Classification of UPD using the UPDtool showed the fetus was complete paternal isoUPD. FracHom (Blue line) is fraction of homocygous SNPs, FracME (Red line) is fraction of mendelian error SNPs, FracldentFather (Green line) is fraction of SNPs where the genotype is identical to the father, Fracldent Mother (Black line) is fraction of SNPs where the genotype is identical to the mother,FracError(Yellow line) is fraction of errors.UPDtool available at the following link: (http://www.unituebingen.de/uni/thk/de/f-genomik-software.html.)\n","description":"","filename":"Fig.3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-778220/v1/79b541ee4419bd204a62c0c8.jpg"},{"id":13709113,"identity":"ae5b1848-cd7f-4138-b364-d7012b9018de","added_by":"auto","created_at":"2021-09-17 14:11:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":473792,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-778220/v1/1e8a1198-8a88-4cc7-bfc9-ff01094c16ad.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003ePrenatal Diagnosis of Complete Paternal Uniparental Isodisomy for Chromosome 3: A Case Report\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eUniparental disomy (UPD) is a rare condition and defined as an inheritance of two chromosomes only from one of parents with no representative copy from another. The condition that the pair of chromosomes inherited from pairing homologous chromosomes of a parent is termed uniparental heterodisomy (hetUPD). If they came from identical copies of one chromosome, the condition is termed uniparental isodisomy (isoUPD). According to the original parent, UPD can be classified into maternal UPD (matUPD) and paternal UPD (patUPD). Presence of UPD is associated with advanced parental age. According to the latest scientific literature, the estimated incidence of UPD is 1/2000 in live births\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. IsoUPD cases are encountered less frequently than hetUPD, and patUPD occurs less frequently than matUPD (the ratio is approximately 1:3)\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Thus, Paternal isoUPD was found to be extremely rare. At present, patUPD(3) has rarely been reported (only 5 cases) and poses a great challenge for prenatal genetic counseling.\u003c/p\u003e \u003cp\u003eUPD does not involve an aneuploidy and can not be detected by common clinical chromosome detection techniques. In this study, a prenatal UPD case with negative results of non-invasive prenatal screening (NIPT) and karyotype analysis was diagnosed by Single Nucleotide Polymophism array(SNP array) and followed up.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA healthy woman (Gravida 4,Induced abortion 2,Missed abortion 1,Para 0) was referred to the the Department of Medical Genetics at \u003cem\u003eChangsha hospital for maternal and child health care\u003c/em\u003e for opinion counseling due to advanced parental age(maternal age:46;paternal age:59),high-risk of Down\u0026apos;s Screening in mid-pregnancy(T21 1:140) and adverse pregnancy history at 18 weeks and 3 days of gestation.Subsequent amniocentesis was arranged, and G-banding karyotype analysis (320 bands) of the cultured amniocytes revealed a normal karyotype of 46, XX(Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Affymetrix CytoScan 750K SNP array on uncultured amniocytes did not detect pathogenic copy number variants and revealed a regions of homozygosity (ROH) on chromosome 3 (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). SNP microarray data of parent\u0026ndash;child trios showed the fetus has carried complete paternal isoUPD(3) (Fig. 3). The fetus was no structural deformity during the whole pregnancy. And the biparietal diameter(BPD), head circumference(HC), femur length(FL),humerus length(HL) and abdominal circumference(AC) measured by ultrasound consistent with gestational age(Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). In addition, we mainly focus on Placental Mature Grading. Besides that, the parents with an unremarkable family history refused the further examination of whole exome sequencing (WES) on uncultured amniocytes and decided to continue the pregnancy after genetic counseling. At 36 weeks and 6 days of gestation, the pregnant woman had to have a Caesarean due to preeclampsia. A 2550g female infant was delivered and had normal physical findings with Apgar score\u0026thinsp;=\u0026thinsp;10 at 1 minute after birth. Now aged 1.5, the baby can walk independently and speak a few simple duplicated words. Physical examination shows that she has achieved her appropriate developmental milestones and no physical abnormalities.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThe corresponding ultrasonic values of different gestational ages\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGestational\u0026nbsp;age\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBPD(mm)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHC(mm)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFL(mm)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHL(mm)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAC(mm)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24\u003csup\u003e+\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e222\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e197\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28\u003csup\u003e+\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e240\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003csup\u003e+\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e297\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e280\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36\u003csup\u003e+\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e338\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e320\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion And Conclusions","content":"\u003cp\u003eUPD usually arises through initial meiotic segregation error.IsoUPD is caused by nondisjunction of sister chromatid in meiosis II,while hetUPD is caused by nondisjunction of homologous chromosomes in meiosis I.Trisomy rescue is one of the reasons for UPD and results from fertilization of a disomic spermatocyte and a normal oocyte in pat UPD.Subsequently, one of the supernumerary chromosomes is eliminated to restore the normal chromosomal number\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e.The rescue events could occur after the division of the zygote and result in disomy/trisomy mosaicism.when a fetus has a normal karyotype and diagnosed with UPD, mosaicism usually may be found in multiple parts of the placenta biopsy.Trisomy mosaicism can lead to dysfunction of placental and bring about fetal growth restriction,heart malformation,skin edema,and so on\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.So it is very important to keep an eye on the growth of the fetus and assess the maturity of the placenta when UPD is found.\u003c/p\u003e \u003cp\u003eIsoUPD inherited two identical copies of one homolog and harbors the risk of resulting in homozygosity for a chromosomal recessive disorders in the offspring of a heterozygous carrier. To date, there have been only 3 reported cases of recessive diseases resulting from pat UPD(3) with normal karyotype. One was a case of Pierson syndrome with distinct renal and ocular abnormalities caused by paternally-inherited homozygous mutation in the \u003cem\u003eLAMB2\u003c/em\u003e gene. The proband died from sepsis at 17 months\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Another was a 10-year-old girl with epilepsy, severe intellectual disability and progressive neurological decline caused by a homozygous pathogenic splice-site mutation in the \u003cem\u003eGLB1\u003c/em\u003e gene resulting mosaic pat UPD(3)\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. In addition, microcytic anemia in a infant with sideroblastic anemia type 2 caused by rare nonsense homozygous variant of \u003cem\u003eSLC25A38\u003c/em\u003e gene resulting pat UPD(3)\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. The three reported cases are definitely caused by single-gene disorders.Therefore, it is necessary to carry out further examination to exclude recessive gene pathogenic mutation when UPD is found in prenatal diagnosis.In our case,the fetus without abnormal ultrasound features at the whole gestation and the parents refused the further examination.So,we had to monitor and follow up the growth and development of the newborn.\u003c/p\u003e \u003cp\u003eAs a rare abnormality,UPD leads to abnormal phenotype not only through homozygous recessive disorders,but also through gene imprinting.At present, identified chromosomes bearing imprinted genes include 6,7,11,14,15,and 20\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e.However,only three imprinted genes predicted by bioinformatics on chromosome 3: two maternally expressed genes (\u003cem\u003eALDH1L\u003c/em\u003e and \u003cem\u003eZ1C1\u003c/em\u003e) and one paternally expressed gene (\u003cem\u003eHES1\u003c/em\u003e). No clear imprinted region and gene report were found.Currently,only one case of paternal UPD for entire chromosome 3 has been described with no apparent disease phenotype.The individual identified serendipitously in the study of a whole genome linkage scan and did not display any obvious adverse phenotypic disorders at age 42\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.Physical examination over the 1.5 years of our case has not shown any significant growth or developmental abnormalities, observations that suggest there is no important imprinted gene on paternal chromosome 3 that causes serious diseases. Nevertheless we will continue to follow this case to confirm this suggestion.\u003c/p\u003e \u003cp\u003eTo sum up,the influence of UPD on a phenotype might be difficult to establish or predict in prenatal diagnosis, due to mosaicism for a trisomic cell line,to homozygosity for recessive pathogenic mutations,or to disorder of imprinted genes.The case we reported was the second case of complete paternal isoUPD(3) with no abnormality.Our study further evidenced that there were no important paternal imprinted genes causing rare genetic disorders on chromosome 3 and provides reference for the diagnosis and consultation of UPD(3) in prenatal diagnosis in the future.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eUPD Uniparental disomy\u003c/p\u003e \u003cp\u003ehetUPD Uniparental heterodisomy\u003c/p\u003e \u003cp\u003eisoUPD Uniparental isodisomy\u003c/p\u003e \u003cp\u003ematUPD Maternal uniparental disomy\u003c/p\u003e \u003cp\u003epatUPD Paternal uniparental disomy\u003c/p\u003e \u003cp\u003eNIPT Non-invasive prenatal screening\u003c/p\u003e \u003cp\u003eROH Regions of homozygosity\u003c/p\u003e \u003cp\u003eSNP array Single nucleotide polymophism array\u003c/p\u003e \u003cp\u003eWES Whole exome sequencing\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed, read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere was no funding for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable to this article as no datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eParental consent was obtained for the publication of this case report.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the patient and their parents for their participation in this research.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNakka P, Pattillo Smith S, O'Donnell-Luria AH, et al. Characterization of Prevalence and Health Consequences of Uniparental Disomy in Four Million Individuals from the General Population. Am J Hum Genet. 2019;105(5):921\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBenn P. Uniparental disomy: Origin, frequency, and clinical significance. Prenat Diagn. 2021;41(5):564\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsubara K, Kagami M, Fukami M. Uniparental disomy as a cause of pediatric endocrine disorders. Clin Pediatr Endocrinol. 2018;27(3):113\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEggermann T, Soellner L, Buiting K, Kotzot D. Mosaicism and uniparental disomy in prenatal diagnosis. Trends Mol Med. 2015;21(2):77\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan M, Li FT, Li Y, et al. Discordant results between fetal karyotyping and non-invasive prenatal testing by maternal plasma sequencing in a case of uniparental disomy 21 due to trisomic rescue. Prenat Diagn. 2013;33(6):598\u0026ndash;601.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatejas V, Muscheites J, Wigger M, Kreutzer HJ, Nizze H, Zenker M. Paternal isodisomy of chromosome 3 unmasked by autosomal recessive microcoria-congenital nephrosis syndrome (Pierson syndrome) in a child with no other phenotypic abnormalities. Am J Med Genet A. 2011;155A(10):2601\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMyers KA, Bennett MF, Chow CW, et al. Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay. Am J Med Genet A. 2018;176(1):230\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndolfo I, Martone S, Ribersani M, et al. Apparent recessive inheritance of sideroblastic anemia type 2 due to uniparental isodisomy at the SLC25A38 locus. Haematologica. 2020;105(12):2883\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDel Gaudio D, Shinawi M, Astbury C, et al. Diagnostic testing for uniparental disomy: a points to consider statement from the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2020;22(7):1133\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiao P, Liu P, Weber JL, Papasian CJ, Recker RR, Deng HW. Paternal uniparental isodisomy of the entire chromosome 3 revealed in a person with no apparent phenotypic disorders. Hum Mutat. 2006;27(2):133\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"molecular-cytogenetics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mocy","sideBox":"Learn more about [Molecular Cytogenetics](http://molecularcytogenetics.biomedcentral.com/)","snPcode":"13039","submissionUrl":"https://submission.nature.com/new-submission/13039/3","title":"Molecular Cytogenetics","twitterHandle":"@OAgenetics","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Uniparental isodisomy 3, Imprinted genes, Prenatal diagnosis, SNP array","lastPublishedDoi":"10.21203/rs.3.rs-778220/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-778220/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003ePaternal uniparental disomy (UPD) of chromosome 3 is a very rare condition. At present, only 5 cases of paternal UPD(3) has been reported. This was the second ascertained paternal UPD(3) with no apparent disease phenotype.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCase presentation \u003c/strong\u003eWe hereby reported a case of a fetus with normal karyotype and normal ultrasound features at the whole gestation. A copy neutral regions of homozygosity on chromosome 3 was indentified by Single Nucleotide Polymophism array (SNP array). Subsequent SNP array data of parent–child trios showed the fetus has carried complete paternal uniparental isodisomy (isoUPD) of chromosome 3. The parents decided to continue the pregnancy after genetic\u0026nbsp;counseling. The neonate had normal physical findings at birth and develops\u0026nbsp;normally\u0026nbsp;after\u0026nbsp;1.5\u0026nbsp;years. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e The findings could provide further evidence to confirm that there was no important imprinted genes causing serious diseases on paternal chromosome 3 and provided a reference for the prenatal diagnosis and genetic counseling of UPD(3) in the future.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Prenatal Diagnosis of Complete Paternal Uniparental Isodisomy for Chromosome 3: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-08-12 14:34:22","doi":"10.21203/rs.3.rs-778220/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revision","date":"2021-08-22T10:29:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-08-22T00:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2021-08-21T00:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-08-17T06:15:53+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-08-17T06:15:21+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-08-17T00:00:00+00:00","index":1,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-08-17T00:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorAssigned","content":"","date":"2021-08-16T17:24:08+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-08-15T23:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-08-10T21:05:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2021-08-02T00:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-cytogenetics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mocy","sideBox":"Learn more about [Molecular Cytogenetics](http://molecularcytogenetics.biomedcentral.com/)","snPcode":"13039","submissionUrl":"https://submission.nature.com/new-submission/13039/3","title":"Molecular Cytogenetics","twitterHandle":"@OAgenetics","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7ed36a8c-15b4-42c0-885a-4a8552a245e8","owner":[],"postedDate":"August 12th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":6396289,"name":"Molecular Biology"},{"id":6396290,"name":"General Biochemistry"}],"tags":[],"updatedAt":"2021-10-09T18:15:49+00:00","versionOfRecord":[],"versionCreatedAt":"2021-08-12 14:34:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-778220","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-778220","identity":"rs-778220","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}