Comprehensive Analysis of Clinical Phenotype and Genetic Characteristics in Chinese Children with Retinoblastoma Caused by RB1 Gene Variant

Comprehensive Analysis of Clinical Phenotype and Genetic Characteristics in Chinese Children with Retinoblastoma Caused by RB1 Gene Variant | 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 Comprehensive Analysis of Clinical Phenotype and Genetic Characteristics in Chinese Children with Retinoblastoma Caused by RB1 Gene Variant zheng fu, hui yang, weiwei xiong, xue yin, weifang fang, xiuting li, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4697501/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective: To summarize the clinical phenotype and genetic characteristics of 15 children with RB1 gene variant in Chinese population. Methods: Case series study, Retrospective analysis. From January 1, 2022 to March 31, 2024, clinical data and genetic testing results of 15 children with retinoblastoma caused by RB1 gene mutation admitted to Xiamen Hospital of Fudan University Affiliated Pediatrics Hospital.Retrieve the PubMed database using keywords such as "China", "Retinoplastoma", and " RB1 genetic mutations", and collect English literature from the establishment of the database until March 2024.To describe and summarize the main clinical manifestations and genotype characteristics of children with retinoblastoma caused by RB1 gene variant. Results: In this study, 15 children with 25 eyes, 8 males and 7 females, were diagnosed at 7 to 36 months, mean 16.00 ± 8.61 months; 10 patients affected both eyes and 5 single eyes. In the main complaint, 2 cases found no vision on physical examination, and 13 cases had white pupil. None of the 15 cases had a family genetic history.Whole-exon sequencing analysis found that 14 of 15 children were heterozygous for RB1 variant, 1 was chimeric variant, and 5 cases were not reported in the literature(c.608-1G>A, c.1818T>A, c.962dupA, c.2086A>T, c.574A>T. All 15 children were treated with eye preservation, including superselected arterial interventional chemotherapy, freezing, photocoagulation, systemic chemotherapy, eye picking, etc. The follow-up time was about 12-132 months, with an average of 39.20 ± 24.07 months, all with normal living conditions. Conclusions: Genetic testing is still an effective method to confirm RB1 gene variation. The supplementary RB1 gene variation spectrum of Chinese people can provide a basis for the early diagnosis and treatment and genetic counseling of children. Retinoblastoma China RB1 gene mutation Figures Figure 1 Figure 2 Figure 3 Background Retinoblastoma (retinoblastoma, RB) is the most common primary intraocular malignancy in children, with an incidence rate of approximately 1 / 20000 to 1 / 15000 [1] . China has about 1100 new patients every year, and 84% of them are late high-risk patients [2-3] . Retinoblastoma can involve either one or both eyes, and sometimes intracranial tumors, namely ateral retinoblastoma. Without timely and effective treatment, retinoblastoma may spread to the brain through the optic nerve or through the blood to the bone marrow and lead to death. RB usually develops before the age of 6 years, but most patients with family history or both eyes develop before 1 year of age [1,4 – 5] . The case review of children with RB1 gene mutation in our study, combined with the literature review, summarized the clinical and genetic characteristics of RB caused by RB1 gene mutation in Chinese people in recent years, aiming to improve the understanding of child ophthalmologists on this disease. Methods 1. subject investigate 1.1 The object The clinical characterization and genetic data of 15 children with retinoblastoma admitted to Xiamen Hospital and Shanghai Xinhua Hospital of Xiamen Hospital from January 1,2022 to March 31,2024 were collected for retrospective analysis. This study was approved by the Medical Ethics Committee of the Pediatric Hospital affiliated to Fudan University (EC-023-063). The guardians of all the children signed the informed consent form. 1.2 Whole-exome sequencing, data analysis, and pedigree validation DNA extraction and whole exome sequencing: After obtaining informed consent from the parents of the child, 2 mL of peripheral venous blood from the child and his parents was collected with anticoagulation vessels and sent to the University Institute of Medical Laboratory for testing. The variant pathogenicity classification was based on the American Society of Medical Genetics and Genomics (ACMG) and the American Society of Molecular Pathology (AMP) guidelines (appendix), with the reference of the ClinGen Sequence Variation Interpretation Working Group and the British Society for Clinical Genome Sciences (ACGS). 1.3 Diagnosis guidelines All of the 15 children were confirmed by a chief physician. Reference guidelines [6] Diagnostic criteria for retinoblastoma (1) clinical symptoms and signs and symptoms: anterior chamber, iris, lens, vitreous, retina, and other systemic manifestations; (2) radiographic optic nerve and muscle changes; (3) histopathological diagnosis of single ocular detachment in some binocular cases. 1.4 Follow-up: On average, every 3 to 6 months, including general anesthesia fundus examination, the optos panoramic 200 scanning laser ophthalmoscope, local anesthesia fundus examination, etc. According to the condition (stable, recurrence), cranial and orbital enhanced magnetic resonance imaging (magnetic resonance imaging, MRI) was reviewed. 1.5 Literature search and screening In PubMed, " RB1 ", "Retinoblastoma" and the author from "China", and in the database, " RB1 " and "retinoblastoma" were the keywords. Read the abstract or full text screening for Chinese children with RB1 gene variant reported from the database to March 2024. 2 Statistical analysis Statistical analysis was conducted using SPSS 22.0 software. Normal metric data were expressed as ± s, non normal metric data were expressed as M (Q1, Q3), and count data were expressed as examples (n) and percentages (%) Results In this study, 15 children with 25 eyes, 8 male 13 eyes, 7 females 12 eyes, diagnosed 6 to 36 months, mean of 16.00 ± 8.61 months; 10 patients affected both eyes and 5 single eyes. In the main complaint, 2 cases found no vision on physical examination, and 13 cases had white pupil. None of the 15 cases had a family genetic history. 1. Clinical characterization analysis of 15 children with RB1 gene variation In this study, 15 children were diagnosed in 1 eye in stage B, 7 eyes in stage C, 10 eyes in stage D and 7 eyes in stage E. Two cases required monocular enucleation due to their condition and another eye preservation. In the remaining 13 cases, combined eye preservation therapy was used for more than two kinds, including superselected arterial interventional chemotherapy, cryotherapy, photocoagulation, systemic chemotherapy, eye pick, etc. The follow-up period was about 12 to 132 months, with a mean of 39.20 ± 24.07 months. By the time of the study, all 15 children had normal self-care life.(Tab 1). 2. Genotypes of children with a RB1 gene variant After validation by Sanger sequencing and pedigree origin analysis, among 15 children in this study, 14 were heterozygous (93.33%) of RB1 gene, one was chimeric (6.67%), distributed in 8 exons (6,8,10,14,16,18,19,20) and 4 introns (6,14,23, and 24). Base-level analysis, as point mutations are common. In the amino acid level analysis, the variant type with nonsense mutation (9) was the most common, followed by shear mutation (3), frame-shift mutation (2) and missense mutation (1). All 15 cases were assessed as pathogenic variants according to the ACMG related guidelines.10 were known variants and 5 were unreported variants (c.608-1G>A、c.1818T>A、c.962dupA、c.2086A>T,c.574A>T).(Tab 2). 3. Literature Review Review of the literature. Chinese, retinoblastoma and RB1 gene mutation were used as keywords to search literature in PubMed database. Other genetic variants or chromosomal variants or other syndromes were excluded [5] . Discussion The RB1 gene (retinoblastoma prone gene) is located in band 4 of region 1 of the long arm of human chromosome 13, with 27 exons in a range of 180 kb and 4.7kbmRNA. Its protein product is a 115 kb nuclear phosphoprotein. Inactivation of the RB1 gene by various causes is the direct cause of retinoblastoma. The type of RB 1 gene mutations: with the base change as the standard, mutations can be divided into four types of [ 7 ] : point mutations (replacement and substitution), small deletion, small insertion and complex mutation. With amino acid level as standard, mainly frameshift or nonsense mutations [8-10] . In recent years, domestic researchers have made great efforts in the diagnosis and treatment of retinoblastoma, and made timely diagnosis of diseases. The improvement in diagnostics is greatly attributed to the well-established application of molecular genetic methods, detecting RB 1 gene mutations, combined with genetic analysis, enabling early diagnosis of RB1 and genetic counseling at the molecular level. There are many new cases of RB every year, and the types of RB1 gene mutations are diverse. It is still necessary to improve the RB1 gene data set in Chinese people. As of March 31,2024, more than 1,000 pathogenic or likely pathogenic variants were included in the ClinVar database, and about 255 gene mutations have been reported in China [9,11-14] . In this study, 15 cases of RB1 mutations in 10 children were reported in domestic literature, and 15 cases were germ cell mutations. Previous literature reports indicate that 10% to 12% of sporadic patients with unilateral RB carry germ cell gene mutation [15] , and germ cell mutations are 50% likely to be transmitted to the offspring of patients, which can increase the risk of the offspring. The base mutation mode is dominated by point mutations, which often change the normal genetic information. After Sanger sequencing, validation and pedigree origin analysis (Tab 2), 14 cases were heterozygous variant and 1 case was chimeric variant. In five cases of unreported RB1 gene, base A repeat at position 962, which changed the tyrosine sequence at position 321 to the termination code; A to T exon 20 at position 2086 in A case 4, which caused the arginine sequence at position 696 to the termination code; and T to A mutation at exon 1818, causing the tyrosine sequence at position 606 to become the termination code. The A to T mutation occurred at position 574 in case 5, which changed the lysine sequence at position 192 to the stop code. At the amino acid level, all four children were nonsense mutations, affecting the quality of the protein encoded by the RB1 gene. There is limited research on the direct role of intron mutations in the development of retinoblastoma [16] . Our study identified four intronic mutations, one case has not been reported in the literature. The previous cases within 1 year were mostly both eyes and mostly heterozygous variant [17] . Only 2% of the cases were confirmed in one eye, and the clinical histological tumor characteristics were clearly advanced stage, and the median age of onset was within 1 year. The RB1 level is often more difficult to detect in such cases. Reasons include abnormal amplification of the gene coding another transcription factor, MYCN causing [11] . Or new germ line chimeric mutations, with a low proportion of chimerism causing [18] . Case 1 had the G to A mutation at position 608-1, which was a chimeric variant and affected the transmission of normal genetic information. Clinically, the diagnosis was 7 months old, and the monocular stage E was diagnosed. After six systemic chemotherapy and one interventional treatment, the huge tumor in the vitreous cavity still covered the optic nipple and the whole retinal detachment, and finally the enucleation was chosen(Fig1). Normal for 3 years of postoperative follow-up. Case 6 is obviously different from previous studies: small onset age, high tumor grade, single eye, abnormal RB1 level can be detected, but chimeric type, and this case deserves attention. In addition, the risk of a second cancer in previous studies suggesting that patients with low-level germline chimeric RB1 mutations later in life is currently unknown, so close follow-up of case 6 is still required clinically.(Fig2-3) Chai P et al [19] analyzed 44 RB1 gene mutation cases and confirmed that the mutations were evenly distributed in exon 1 to exon 27 genes of RB1 , and the mutation pattern of Chinese people was not different compared with that of foreign countries. Medline Found the presence of mutant in the 25 exons of the RB1 gene as well as in the promoter. Confirmed the presence of mutant in 20 exons of the RB1 gene as well as in the promoter [ 20 ] . More known mutations in the RB1 gene were also identified in our study, including mutations in exons 8 and 18. Again, it is verified that there is no substantial difference between RB1 gene mutation in terms of mutation location. In five cases of mutations not reported in the literature, the proportion of RB1 complex mutations was higher in Chinese people based on base changes. Conclusions In conclusion, this study analyzed the correlation of genotype and phenotype in 15 children with RB1 gene variation, and found the complexity and diversity of RB1 gene variation in children with retinoblastoma. At the same time, the Chinese RB1 gene variation spectrum is added again, which can provide a basis for the early diagnosis and treatment and genetic consultation of children. Future studies are needed to further explore the association between RB1 gene variation and clinical manifestations, and the impact of different variant types on treatment and prognosis in pediatric children. Abbreviations RetcamIII Digital wide area fundus imaging system for newborns Declarations Acknowledgements Not applicable. Author contributions ZF:Data collection and analysis, paper writing and paper revision;HY: Financial support, research guidance; WX,XY,WF,XL,XW:data organization and analysis; All authors read and approved the final version of the manuscript. Funding This work was sponsored by Fujian provincial health technology project(Xiamen Natural Science Foundation no. 3502Z20227410) and Key Laboratory Project of Pediatric Surgery, Xiamen Pediatric Hospital affiliated with Fudan University (grant no. CHP-2023-XKL-018). Data availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate The present study was approved by the Medical Ethics Committee of the Pediatric Hospital affiliated to Fudan University (EC-023-063) and was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants before the study. Consent for publication Not applicable Competing interests The authors declare no competing interests. Author details 1、Ophthalmology, Pediatric Hospital of Fudan University (Xiamen Hospital) 2、Key Laboratory of Surgery, Pediatric Hospital of Fudan University (Xiamen Hospital) Ophthalmology, Pediatric Hospital of Fudan University (Xiamen Hospital); 361000,92 Yibin Road, Huli District, Xiamen References Fabian ID, Onadim Z, Karaa E, Duncan C, Chowd- hury T, Scheimberg I, Ohnuma SI, Reddy MA, Sagoo MS (2018) The management of retinoblastoma. Onco- gene 37(12):1551–1560. https://doi.org/10.1038/ s41388-017-0050-x. Zhao J, Li S, Shi J, et al. 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Cancer, 2000; 19(9):846-849 Tables Table 1: Clinical profiles of 15 children diagnosed with retinoblastoma Characteristics Total(n=15) Unilateral (n=4) Bilateral (n=11) Gender Male 8(53.3%) 3(75.0%) 5(45.4%) Female 7(46.7%) 1(25.0%) 6(54.5%) Age at Diagnosis (months) Median age 16±8.61 21±2.66 17±8.05 12 6 (20.2%) 2(35.6%) 4(3.4%) Treatment methods Enucleation 3(20.0%) 1(25.0%) 2(18.2%) No enucleation 12(80.0%) 3(75.0%) 9(81.8%) Table 2 : Asummary of RB1 mutations in the 15 Rb patients Patient ID Location Mutational type Mutation Change in protein Laterality Status 1 Intron6 Splicing C.608-1G>A / Unilateral Novel 2 Exon19 Nonsense C.1818T>A p.Tyr606* Bilateral Novel 3 Exon10 Nonsense C.962dupA P.Tyr321* Bilateral Novel 4 Exon20 Nonsense C.2086A>T P.Arg696* Bilateral Novel 5 Exon6 Nonsense C.574A>T P.Lys192* Unilateral Novel 6 Intron14 Splicing C.1390-1G>A / Bilateral Novel 7 Exon10 Nonsense C.958C>T P.Arg320* Bilateral Reported 8 Exon14 Nonsense C1363C>T P.Arg455* Bilateral Reported 9 Exon16 Frameshit C.1450-1451delAT P.Met484Valfs*8 Unilateral Reported 10 Intron24 Frameshit C.2520+3_2520+6del / Bilateral Reported 11 Intron23 Splicing C.2489+1G>T / Bilateral Reported 12 Exon8 Nonsense C.751C>T P.Arg251* Unilateral Reported 13 Exon18 Nonsense C.1735C>T P.Arg579* Bilatera Reported 14 Exon18 Nonsense C.1735C>T P.Arg579* Bilatera Reported 15 Exon20 Missense C.1981C>T P.Arg661Trp Unilateral Reported Additional Declarations No competing interests reported. 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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-4697501","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":327584086,"identity":"6da55e05-4dbc-40f1-821a-fbba4d17b20d","order_by":0,"name":"zheng fu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABB0lEQVRIiWNgGAWjYFACxgZmBgOGBAb2xsYHHyqAAhJEa+E5fNhwxhmYlgT8mpjBSiTS0qR524jQotve3Py5oKAuz+BAjoEE77zDcvyzG9gefPyBW4vZmYMNxjMMDhcbHDhjYCC57bCxxJ0D7IYz8NhidiOxIZnH4EDihoM9BgmG2w4nNtxIYJPmwafl/sOGwzwGdYkbDoM0zjlcPx+k5Q9eWxgbm3kMmBM3HGNLbDjYcDjBAKQFn/fNziQ2M/MYHE6ceYb5MGPDsXTDjTcS2yR70vBoOX788WeeP3WJffcftv/+U2MtL3cj+ZjEDxvcWtBBMwMocolXDwR1JKkeBaNgFIyCkQEAXFxdll+OTTMAAAAASUVORK5CYII=","orcid":"","institution":"Children’s Hospital of Fudan University Xiamen Branch","correspondingAuthor":true,"prefix":"","firstName":"zheng","middleName":"","lastName":"fu","suffix":""},{"id":327584087,"identity":"a29042be-29bd-4ae1-acb8-695e10a0055e","order_by":1,"name":"hui yang","email":"","orcid":"","institution":"Children’s Hospital of Fudan University Xiamen Branch","correspondingAuthor":false,"prefix":"","firstName":"hui","middleName":"","lastName":"yang","suffix":""},{"id":327584088,"identity":"5153d50e-4b74-4bcc-b31c-1eba2dc02495","order_by":2,"name":"weiwei xiong","email":"","orcid":"","institution":"Children’s Hospital of Fudan University Xiamen Branch","correspondingAuthor":false,"prefix":"","firstName":"weiwei","middleName":"","lastName":"xiong","suffix":""},{"id":327584089,"identity":"b8e5622a-c7bb-4c0b-b971-eaa5d4cf569b","order_by":3,"name":"xue yin","email":"","orcid":"","institution":"Children’s Hospital of Fudan University Xiamen Branch","correspondingAuthor":false,"prefix":"","firstName":"xue","middleName":"","lastName":"yin","suffix":""},{"id":327584090,"identity":"4f2ed7a7-a83a-4f61-971c-5fcd490984ab","order_by":4,"name":"weifang fang","email":"","orcid":"","institution":"Children’s Hospital of Fudan University Xiamen Branch","correspondingAuthor":false,"prefix":"","firstName":"weifang","middleName":"","lastName":"fang","suffix":""},{"id":327584091,"identity":"21adfa32-cbce-4e03-96fa-ac3989a768cc","order_by":5,"name":"xiuting li","email":"","orcid":"","institution":"Children’s Hospital of Fudan University Xiamen Branch","correspondingAuthor":false,"prefix":"","firstName":"xiuting","middleName":"","lastName":"li","suffix":""},{"id":327584092,"identity":"3cb830c7-daa3-4140-8828-aae5743f958a","order_by":6,"name":"xixiang wei","email":"","orcid":"","institution":"Children’s Hospital of Fudan University Xiamen Branch","correspondingAuthor":false,"prefix":"","firstName":"xixiang","middleName":"","lastName":"wei","suffix":""}],"badges":[],"createdAt":"2024-07-06 15:53:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4697501/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4697501/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62324112,"identity":"0c6d24e5-b947-4a73-ab9c-b6f7d339a6d4","added_by":"auto","created_at":"2024-08-13 02:25:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":619663,"visible":true,"origin":"","legend":"\u003cp\u003eRetcam shows a huge tumor in the vitreous cavity, with no visible optic papilla. Partial calcification can be seen in the tumor body, but neovascularization can still be seen crawling\u003c/p\u003e","description":"","filename":"fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4697501/v1/60306dd7f80e670c32ef4585.png"},{"id":62324108,"identity":"932a3d17-7c8c-46ce-9fb9-05b279978193","added_by":"auto","created_at":"2024-08-13 02:25:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":11053,"visible":true,"origin":"","legend":"\u003cp\u003eRetinoblastoma pedigree of Case 6. The black arrow indicates a proband with unilateral illness.\u003c/p\u003e","description":"","filename":"fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-4697501/v1/77cd32c7caed581a3fbcd532.png"},{"id":62324110,"identity":"0e3a70e7-8cfe-41cc-b75d-03ec46fa6c3e","added_by":"auto","created_at":"2024-08-13 02:25:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":247602,"visible":true,"origin":"","legend":"\u003cp\u003eGenetic analysis of the \u003cem\u003eRB1\u003c/em\u003e gene in Case 6 shows that the family (father, mother, proband) has one trace chimeric mutation. Arrows indicate the location of the mutation.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRB1\u003c/em\u003e:NM_000321.2:c.608-1G\u0026gt;A\u003c/p\u003e","description":"","filename":"fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-4697501/v1/8b816a1743bb93d63025cd5b.png"},{"id":65518140,"identity":"a1cab209-bf6e-416b-9ab3-e7d7d028e653","added_by":"auto","created_at":"2024-09-29 03:16:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1946298,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4697501/v1/42168f4c-655c-4b41-9653-44b8353023c2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comprehensive Analysis of Clinical Phenotype and Genetic Characteristics in Chinese Children with Retinoblastoma Caused by RB1 Gene Variant","fulltext":[{"header":"Background","content":"\u003cp\u003eRetinoblastoma (retinoblastoma, RB) is the most common primary intraocular malignancy in children, with an incidence rate of approximately 1 / 20000 to 1 / 15000\u003csup\u003e\u0026nbsp;[1]\u003c/sup\u003e. China has about 1100 new patients every year, and 84% of them are late high-risk patients \u003csup\u003e[2-3]\u003c/sup\u003e. Retinoblastoma can involve either one or both eyes, and sometimes intracranial tumors, namely ateral retinoblastoma. Without timely and effective treatment, retinoblastoma may spread to the brain through the optic nerve or through the blood to the bone marrow and lead to death. RB usually develops before the age of 6 years, but most patients with family history or both eyes develop before 1 year of age\u003csup\u003e\u0026nbsp;[1,4 \u0026ndash; 5]\u003c/sup\u003e.\u0026nbsp;The case review of children with\u0026nbsp;\u003cem\u003eRB1\u003c/em\u003e gene mutation in our study, combined with the literature review, summarized the clinical and genetic characteristics of RB caused by\u0026nbsp;\u003cem\u003eRB1\u003c/em\u003e gene mutation in Chinese people in recent years, aiming to improve the understanding of child ophthalmologists on this disease.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e1. subject investigate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.1 The object\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe clinical characterization and genetic data of 15 children with retinoblastoma admitted to Xiamen Hospital and Shanghai Xinhua Hospital of Xiamen Hospital from January 1,2022 to March 31,2024 were collected for retrospective analysis. This study was approved by the Medical Ethics Committee of the Pediatric Hospital affiliated to Fudan University (EC-023-063). The guardians of all the children signed the informed consent form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.2 Whole-exome sequencing, data analysis, and pedigree validation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDNA extraction and whole exome sequencing: After obtaining informed consent from the parents of the child, 2 mL of peripheral venous blood from the child and his parents was collected with anticoagulation vessels and sent to the University Institute of Medical Laboratory for testing. The variant pathogenicity classification was based on the American Society of Medical Genetics and Genomics (ACMG) and the American Society of Molecular Pathology (AMP) guidelines (appendix), with the reference of the ClinGen Sequence Variation Interpretation Working Group and the British Society for Clinical Genome Sciences (ACGS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.3 Diagnosis guidelines\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll of the 15 children were confirmed by a chief physician. Reference guidelines\u003csup\u003e\u0026nbsp;[6]\u003c/sup\u003e Diagnostic criteria for retinoblastoma (1) clinical symptoms and signs and symptoms: anterior chamber, iris, lens, vitreous, retina, and other systemic manifestations; (2) radiographic optic nerve and muscle changes; \u0026nbsp;(3) histopathological diagnosis of single ocular detachment in some binocular cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.4 Follow-up:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOn average, every 3 to 6 months, including general anesthesia fundus examination, the optos panoramic 200 scanning laser ophthalmoscope, local anesthesia fundus examination, etc. According to the condition (stable, recurrence), cranial and orbital enhanced magnetic resonance imaging (magnetic resonance imaging, MRI) was reviewed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.5 Literature search and screening\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn PubMed, \u0026quot;\u003cem\u003eRB1\u003c/em\u003e\u0026quot;, \u0026quot;Retinoblastoma\u0026quot; and the author from \u0026quot;China\u0026quot;, and in the database, \u0026quot;\u003cem\u003eRB1\u003c/em\u003e\u0026quot; and \u0026quot;retinoblastoma\u0026quot; were the keywords. Read the abstract or full text screening for Chinese children with \u003cem\u003eRB1\u003c/em\u003e gene variant reported from the database to March 2024.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2 \u0026nbsp;Statistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis was conducted using SPSS 22.0 software. Normal metric data were expressed as \u0026plusmn; s, non normal metric data were expressed as M (Q1, Q3), and count data were expressed as examples (n) and percentages (%)\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn this study, 15 children with 25 eyes, 8 male 13 eyes, 7 females 12 eyes, diagnosed 6 to 36 months, mean of 16.00 \u0026plusmn; 8.61 months; 10 patients affected both eyes and 5 single eyes. In the main complaint, 2 cases found no vision on physical examination, and 13 cases had white pupil. None of the 15 cases had a family genetic history.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1. Clinical characterization analysis of 15 children with \u003cem\u003eRB1\u003c/em\u003e gene variation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, 15 children were diagnosed in 1 eye in stage B, 7 eyes in stage C, 10 eyes in stage D and 7 eyes in stage E.\u0026nbsp;Two cases required monocular enucleation due to their condition and another eye preservation. In the remaining 13 cases, combined eye preservation therapy was used for more than two kinds, including superselected arterial interventional chemotherapy, cryotherapy, photocoagulation, systemic chemotherapy, eye pick, etc.\u0026nbsp;The follow-up period was about 12 to 132 months, with a mean of 39.20 \u0026plusmn; 24.07 months.\u0026nbsp;By the time of the study, all 15 children had normal self-care life.(Tab 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Genotypes of \u0026nbsp;children with a \u003cem\u003eRB1\u003c/em\u003e gene variant\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter validation by Sanger sequencing and pedigree origin analysis, among 15 children in this study, 14 were heterozygous (93.33%) of \u003cem\u003eRB1\u003c/em\u003e gene, one was chimeric (6.67%), distributed in 8 exons (6,8,10,14,16,18,19,20) and 4 introns (6,14,23, and 24). Base-level analysis, as point mutations are common. In the amino acid level analysis, the variant type with nonsense mutation (9) was the most common, followed by shear mutation (3), frame-shift mutation (2) and missense mutation (1).\u0026nbsp;All 15 cases were assessed as pathogenic variants according to the ACMG related guidelines.10 were known variants and 5 were unreported variants (c.608-1G\u0026gt;A、c.1818T\u0026gt;A、c.962dupA、c.2086A\u0026gt;T,c.574A\u0026gt;T).(Tab 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Literature Review\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eReview of the literature. Chinese, retinoblastoma and RB1 gene mutation were used as keywords to search literature in PubMed database. Other genetic variants or chromosomal variants or other syndromes were excluded\u003csup\u003e\u0026nbsp;[5]\u0026nbsp;\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe\u0026nbsp;\u003cem\u003eRB1\u003c/em\u003e gene (retinoblastoma prone gene) is located in band 4 of region 1 of the long arm of human chromosome 13, with 27 exons in a range of 180 kb and 4.7kbmRNA. Its protein product is a 115 kb nuclear phosphoprotein. Inactivation of the\u0026nbsp;\u003cem\u003eRB1\u003c/em\u003e gene by various causes is the direct cause of retinoblastoma. The type of RB 1 gene mutations: with the base change as the standard, mutations can be divided into four types of\u003csup\u003e\u0026nbsp;[\u003c/sup\u003e\u003csup\u003e7\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e: point mutations (replacement and substitution), small deletion, small insertion and complex mutation.\u0026nbsp;With amino acid level as standard, mainly frameshift or nonsense mutations\u003csup\u003e\u0026nbsp;[8-10]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;In recent years, domestic researchers have made great efforts in the diagnosis and treatment of retinoblastoma, and made timely diagnosis of diseases. The improvement in diagnostics is greatly attributed to the well-established application of molecular genetic methods, detecting RB 1 gene mutations, combined with genetic analysis, enabling early diagnosis of \u003cem\u003eRB1\u003c/em\u003e and genetic counseling at the molecular level. There are many new cases of RB every year, and the types of \u003cem\u003eRB1\u003c/em\u003e gene mutations are diverse. It is still necessary to improve the \u003cem\u003eRB1\u003c/em\u003e gene data set in Chinese people.\u0026nbsp;As of March 31,2024, more than 1,000 pathogenic or likely pathogenic variants were included in the ClinVar database, and about 255 gene mutations have been reported in China\u003csup\u003e\u0026nbsp;[9,11-14]\u003c/sup\u003e.\u0026nbsp;In this study, 15 cases of \u003cem\u003eRB1\u003c/em\u003e mutations in 10 children were reported in domestic literature, and 15 cases were germ cell mutations. Previous literature reports indicate that 10% to 12% of sporadic patients with unilateral RB carry germ cell gene mutation\u003csup\u003e\u0026nbsp;[15]\u003c/sup\u003e, and germ cell mutations are 50% likely to be transmitted to the offspring of patients, which can increase the risk of the offspring.\u0026nbsp;The base mutation mode is dominated by point mutations, which often change the normal genetic information. After Sanger sequencing, validation and pedigree origin analysis (Tab 2), 14 cases were heterozygous variant and 1 case was chimeric variant.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;In five cases of unreported \u003cem\u003eRB1\u003c/em\u003e gene, base A repeat at position 962, which changed the tyrosine sequence at position 321 to the termination code; A to T exon 20 at position 2086 in A case 4, which caused the arginine sequence at position 696 to the termination code; and T to A mutation at exon 1818, causing the tyrosine sequence at position 606 to become the termination code. The A to T mutation occurred at position 574 in case 5, which changed the lysine sequence at position 192 to the stop code. At the amino acid level, all four children were nonsense mutations, affecting the quality of the protein encoded by the \u003cem\u003eRB1\u003c/em\u003e gene.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;There is limited research on the direct role of intron mutations in the development of retinoblastoma\u003csup\u003e[16]\u003c/sup\u003e. Our study identified four intronic mutations, one case has not been reported in the literature. The previous cases within 1 year were mostly both eyes and mostly heterozygous variant\u003csup\u003e\u0026nbsp;[17]\u003c/sup\u003e. Only 2% of the cases were confirmed in one eye, and the clinical histological tumor characteristics were clearly advanced stage, and the median age of onset was within 1 year. The \u003cem\u003eRB1\u003c/em\u003e level is often more difficult to detect in such cases. Reasons include abnormal amplification of the gene coding another transcription factor, \u003cem\u003eMYCN\u003c/em\u003e\u0026nbsp; causing\u003csup\u003e\u0026nbsp;[11]\u003c/sup\u003e. Or new germ line chimeric mutations, with a low proportion of chimerism causing\u003csup\u003e\u0026nbsp;[18]\u003c/sup\u003e. Case 1 had the G to A mutation at position 608-1, which was a chimeric variant and affected the transmission of normal genetic information. Clinically, the diagnosis was 7 months old, and the monocular stage E was diagnosed. After six systemic chemotherapy and one interventional treatment, the huge tumor in the vitreous cavity still covered the optic nipple and the whole retinal detachment, and finally the enucleation was chosen(Fig1). Normal for 3 years of postoperative follow-up. Case 6 is obviously different from previous studies: small onset age, high tumor grade, single eye, abnormal \u003cem\u003eRB1\u003c/em\u003e level can be detected, but chimeric type, and this case deserves attention. In addition, the risk of a second cancer in previous studies suggesting that patients with low-level germline chimeric \u003cem\u003eRB1\u003c/em\u003e mutations later in life is currently unknown, so close follow-up of case 6 is still required clinically.(Fig2-3)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Chai P et al\u003csup\u003e\u0026nbsp;[19]\u003c/sup\u003e analyzed 44 \u003cem\u003eRB1\u003c/em\u003e gene mutation cases and confirmed that the mutations were evenly distributed in exon 1 to exon 27 genes of \u003cem\u003eRB1\u003c/em\u003e, and the mutation pattern of Chinese people was not different compared with that of foreign countries.\u0026nbsp;Medline Found the presence of mutant \u003csup\u003e\u0026nbsp;\u003c/sup\u003ein the 25 exons of the \u003cem\u003eRB1\u003c/em\u003e gene as well as in the promoter. Confirmed the presence of mutant\u003csup\u003e\u0026nbsp;\u003c/sup\u003ein 20 exons of the \u003cem\u003eRB1\u003c/em\u003e gene as well as in the promoter\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e20\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e .\u0026nbsp;More known mutations in the \u003cem\u003eRB1\u003c/em\u003e gene were also identified in our study, including mutations in exons 8 and 18. Again, it is verified that there is no substantial difference between \u003cem\u003eRB1\u003c/em\u003e gene mutation in terms of mutation location. In five cases of mutations not reported in the literature, the proportion of \u003cem\u003eRB1\u003c/em\u003e complex mutations was higher in Chinese people based on base changes.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, this study analyzed the correlation of genotype and phenotype in 15 children with\u0026nbsp;\u003cem\u003eRB1\u003c/em\u003e gene variation, and found the complexity and diversity of\u0026nbsp;\u003cem\u003eRB1\u003c/em\u003e gene variation in children with retinoblastoma. At the same time, the Chinese\u0026nbsp;\u003cem\u003eRB1\u003c/em\u003e gene variation spectrum is added again, which can provide a basis for the early diagnosis and treatment and genetic consultation of children. Future studies are needed to further explore the association between\u0026nbsp;\u003cem\u003eRB1\u003c/em\u003e gene variation and clinical manifestations, and the impact of different variant types on treatment and prognosis in pediatric children.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eRetcamIII \u0026nbsp; \u0026nbsp; Digital wide area fundus imaging system for newborns\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZF:Data collection and analysis, paper writing and paper revision;HY: Financial support, research guidance; WX,XY,WF,XL,XW:data organization and analysis; All authors read and approved the final version of the manuscript. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was sponsored by Fujian provincial health technology project(Xiamen Natural Science Foundation \u0026nbsp;no. 3502Z20227410) \u0026nbsp;and \u0026nbsp; Key \u0026nbsp;Laboratory Project \u0026nbsp;of Pediatric \u0026nbsp; Surgery, \u0026nbsp;Xiamen \u0026nbsp;Pediatric \u0026nbsp; Hospital \u0026nbsp;affiliated with Fudan University (grant no. CHP-2023-XKL-018).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe present study was approved by the Medical Ethics Committee of the Pediatric Hospital affiliated to Fudan University (EC-023-063) and was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants before the study. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1、Ophthalmology, Pediatric Hospital of Fudan University (Xiamen Hospital)\u003c/p\u003e\n\u003cp\u003e2、Key Laboratory of Surgery, Pediatric Hospital of Fudan University (Xiamen Hospital)\u003c/p\u003e\n\u003cp\u003eOphthalmology, Pediatric Hospital of Fudan University (Xiamen Hospital); 361000,92 Yibin Road, Huli District, Xiamen\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFabian ID, Onadim Z, Karaa E, Duncan C, Chowd- hury T, Scheimberg I, Ohnuma SI, Reddy MA, Sagoo MS (2018) The management of retinoblastoma. Onco- gene 37(12):1551\u0026ndash;1560. https://doi.org/10.1038/ s41388-017-0050-x.\u003c/li\u003e\n\u003cli\u003eZhao J, Li S, Shi J, et al. Clinical presentation and group classification of newly diagnosed intraocular retinoblastoma in China[J]. Br J Ophthalmol, 2011, 95(10): 1372‑1375. DOI: 10.1136/bjo. 2010. 191130.\u003c/li\u003e\n\u003cli\u003eDimaras H, Kimani K, Dimba EA, et al. Retinoblastoma[J].Lancet, 2012, 379(9824): 1436‑1446. DOI: 10. 1016 /S0140‑6736(11)61137-9.\u003c/li\u003e\n\u003cli\u003eBroaddus E,Topham A,Singh AD. Incidence of retinoblastomain the USA: 1975‑2004[J]. Br J Ophthalmol, 2009, 93(1):21‑23. DOI: 10. 1136/bjo. 2008. 138750.\u003c/li\u003e\n\u003cli\u003eOrtiz MV,Dunkel IJ. Retinoblastoma[J]. J Child Neurol,2016,31(2): 227-236. DOI: 10. 1177/0883073815587943.\u003c/li\u003e\n\u003cli\u003eChinese Guidelines for Diagnosis and Treatment of Retinoblastoma (2019).Chin J Ophthalmol，October 2019, Vol. 55.\u003c/li\u003e\n\u003cli\u003eLan X, Xu W, Tang X,et al.Spectrum of \u003cem\u003eRB1\u003c/em\u003e Germline Mutations and Clinical Features in Unrelated Chinese Patients With Retinoblastoma.Front Genet. 2020 Mar 11;11:142. doi: 10.3389/fgene.2020.00142. genomic, gene expression, and clinical studies. Lancet Oncol 14(4):327\u0026ndash;334. https://doi.org/10.1016/s1470- 2045(13)70045-7.\u003c/li\u003e\n\u003cli\u003eLan X, Xu W, Tang X, Ye H, Song X, Lin L, Ren X, Yu G, Zhang H, Wu S (2020) Spectrum of \u003cem\u003eRB1\u003c/em\u003e germline mutations and clinical features in unrelated Chinese patients with retinoblastoma. 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Mol Vis 25:215\u0026ndash;221.\u003c/li\u003e\n\u003cli\u003eRushlow D, Mol B, Kennett J, Char- acterisation of retinoblastomas without \u003cem\u003eRB1\u003c/em\u003e mutations: genomic,gene expression,and clinical studies.Lancet Oncol 14(4):327-334. https://doi.org/10.1016/s1470- 2045(13)70045-7.\u003c/li\u003e\n\u003cli\u003eYuan L, Gao Y, Lo S, et al.Prediction of retinoblastoma: linkage analysis of families with hereditary retinoblastoma by using polymorphic sites within the Rb gene.Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1995 Oct;17(5):338-42.\u003c/li\u003e\n\u003cli\u003eWu S, Zou X, Sun Z,et al.Unilateral retinocytoma associated with a variant in the \u003cem\u003eRB1\u003c/em\u003e gene.Mol Genet Genomic Med. 2020 Apr;8(4):e1156. doi: 10.1002.\u003c/li\u003e\n\u003cli\u003eYi XQ, Qian J, Guo J,et al.Clinical features of patients with retinocytoma.Chin J Ophthalmol. 2021 Jul 11;57(7):526-530. doi: 10.3760/cma.j.cn112142-20200831-00564.\u003c/li\u003e\n\u003cli\u003eMehyar M, Mosallam M, Tbakhi A, Saab A, Sultan I,Deebajah R, Jaradat I, AlJabari R, Mohammad M,AlNawaiseh I, Al-Hussaini M, Yousef YA. 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Hum Mutat 35(3):384\u0026ndash;391. https://doi.org/10.1002/humu.22488.\u003c/li\u003e\n\u003cli\u003eLuo Y, Yu J, Li Y, et.Clinical characteristics and germline mutation spectrum of \u003cem\u003eRB1\u003c/em\u003e in Chinese patients with retinoblastoma: A dual-center study of 145 patients.Exp Eye Res. 2021 Apr;205:108456. doi: 10.1016/j.exer.2021.108456.\u003c/li\u003e\n\u003cli\u003eShen HX, Zhang QD, Xiao XS, et al. Analysis of \u003cem\u003eRB1\u003c/em\u003e gene mutation characteristics in patients with retinal cell carcinoma in China and Japan. Cancer, 2000; 19(9):846-849\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"538\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\" style=\"width: 99.8141%;\"\u003e\n \u003cp\u003eTable 1: Clinical profiles of 15 children diagnosed with retinoblastoma\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.86245353159851%\" valign=\"bottom\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.029739776951672%\"\u003e\n \u003cp\u003eTotal(n=15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.79182156133829%\"\u003e\n \u003cp\u003eUnilateral (n=4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.31598513011152%\"\u003e\n \u003cp\u003eBilateral (n=11)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.86245353159851%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.029739776951672%\"\u003e\n \u003cp\u003e8(53.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.79182156133829%\"\u003e\n \u003cp\u003e3(75.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.31598513011152%\"\u003e\n \u003cp\u003e5(45.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.89219330855018%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eFemale \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 7(46.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.79182156133829%\"\u003e\n \u003cp\u003e1(25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.31598513011152%\"\u003e\n \u003cp\u003e6(54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\"\u003e\n \u003cp\u003eAge at Diagnosis (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.86245353159851%\"\u003e\n \u003cp\u003eMedian age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.029739776951672%\"\u003e\n \u003cp\u003e16\u0026plusmn;8.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.79182156133829%\"\u003e\n \u003cp\u003e21\u0026plusmn;2.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.31598513011152%\"\u003e\n \u003cp\u003e17\u0026plusmn;8.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.89219330855018%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026lt;=12 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 9(79.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.79182156133829%\"\u003e\n \u003cp\u003e3(64.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.31598513011152%\"\u003e\n \u003cp\u003e6(96.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.89219330855018%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026gt;12 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;6 \u0026nbsp;(20.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.79182156133829%\"\u003e\n \u003cp\u003e2(35.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.31598513011152%\"\u003e\n \u003cp\u003e4(3.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003cbr\u003e\u0026nbsp;Treatment methods\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.86245353159851%\"\u003e\n \u003cp\u003eEnucleation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.029739776951672%\"\u003e\n \u003cp\u003e3(20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.79182156133829%\"\u003e\n \u003cp\u003e1(25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.31598513011152%\"\u003e\n \u003cp\u003e2(18.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.89219330855018%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eNo enucleation \u0026nbsp; \u0026nbsp; \u0026nbsp;12(80.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.79182156133829%\"\u003e\n \u003cp\u003e3(75.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.31598513011152%\"\u003e\n \u003cp\u003e9(81.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"648\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"7\" style=\"width: 99.8457%;\"\u003e\n \u003cp\u003eTable 2 : Asummary of \u003cem\u003eRB1\u003c/em\u003e mutations in the 15 Rb patients\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\" valign=\"top\"\u003e\n \u003cp\u003ePatient\u0026nbsp;ID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\" valign=\"top\"\u003e\n \u003cp\u003eLocation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\" valign=\"top\"\u003e\n \u003cp\u003eMutational\u003cbr\u003e\u0026nbsp;type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\" valign=\"top\"\u003e\n \u003cp\u003eMutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\" valign=\"top\"\u003e\n \u003cp\u003eChange\u0026nbsp;in\u003cbr\u003e\u0026nbsp;protein\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\" valign=\"top\"\u003e\n \u003cp\u003eLaterality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\" valign=\"top\"\u003e\n \u003cp\u003eStatus\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eIntron6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eSplicing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC.608-1G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eUnilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eExon19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC.1818T\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003ep.Tyr606*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eBilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eExon10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC.962dupA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003eP.Tyr321*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eBilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eExon20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC.2086A\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003eP.Arg696*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eBilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eExon6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC.574A\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003eP.Lys192*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eUnilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eIntron14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eSplicing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC.1390-1G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eBilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eExon10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC.958C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003eP.Arg320*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eBilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eExon14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC1363C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003eP.Arg455*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eBilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eExon16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eFrameshit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC.1450-1451delAT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003eP.Met484Valfs*8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eUnilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eIntron24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eFrameshit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC.2520+3_2520+6del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eBilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eIntron23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eSplicing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC.2489+1G\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eBilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eExon8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC.751C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003eP.Arg251*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eUnilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eExon18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC.1735C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003eP.Arg579*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eBilatera\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eExon18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC.1735C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003eP.Arg579*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eBilatera\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.574074074074074%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.493827160493828%\"\u003e\n \u003cp\u003eExon20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.654320987654321%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.993827160493826%\"\u003e\n \u003cp\u003eC.1981C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.444444444444443%\"\u003e\n \u003cp\u003eP.Arg661Trp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.962962962962964%\"\u003e\n \u003cp\u003eUnilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.876543209876543%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Retinoblastoma, China, RB1 gene mutation","lastPublishedDoi":"10.21203/rs.3.rs-4697501/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4697501/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e To summarize the clinical phenotype and genetic characteristics of 15 children with \u003cem\u003eRB1\u003c/em\u003e gene variant in Chinese population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eCase series study, Retrospective analysis. From January 1, 2022 to March 31, 2024, clinical data and genetic testing results of 15 children with retinoblastoma caused by\u003cem\u003e RB1\u003c/em\u003e gene mutation admitted to Xiamen Hospital of Fudan University Affiliated Pediatrics Hospital.Retrieve the PubMed database using keywords such as \"China\", \"Retinoplastoma\", and \"\u003cem\u003eRB1\u003c/em\u003e genetic mutations\", and collect English literature from the establishment of the database until March 2024.To describe and summarize the main clinical manifestations and genotype characteristics of children with retinoblastoma caused by\u003cem\u003e RB1\u003c/em\u003e gene variant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e In this study, 15 children with 25 eyes, 8 males and 7 females, were diagnosed at 7 to 36 months, mean 16.00 ± 8.61 months; 10 patients affected both eyes and 5 single eyes. In the main complaint, 2 cases found no vision on physical examination, and 13 cases had white pupil. None of the 15 cases had a family genetic history.Whole-exon sequencing analysis found that 14 of 15 children were heterozygous for \u003cem\u003eRB1\u003c/em\u003e variant, 1 was chimeric variant, and 5 cases were not reported in the literature(c.608-1G\u0026gt;A, c.1818T\u0026gt;A, c.962dupA, c.2086A\u0026gt;T, c.574A\u0026gt;T. All 15 children were treated with eye preservation, including superselected arterial interventional chemotherapy, freezing, photocoagulation, systemic chemotherapy, eye picking, etc. The follow-up time was about 12-132 months, with an average of 39.20 ± 24.07 months, all with normal living conditions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eGenetic testing is still an effective method to confirm \u003cem\u003eRB1\u003c/em\u003e gene variation. The supplementary \u003cem\u003eRB1\u003c/em\u003e gene variation spectrum of Chinese people can provide a basis for the early diagnosis and treatment and genetic counseling of children.\u003c/p\u003e","manuscriptTitle":"Comprehensive Analysis of Clinical Phenotype and Genetic Characteristics in Chinese Children with Retinoblastoma Caused by RB1 Gene Variant","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-13 02:25:46","doi":"10.21203/rs.3.rs-4697501/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"13d2164a-4ce8-488c-aedb-8c60d15db59c","owner":[],"postedDate":"August 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-29T03:08:33+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-13 02:25:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4697501","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4697501","identity":"rs-4697501","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}