Familial exudative vitreoretinopathy caused by CTNNB1 gene mutation in a Chinese family: A case report

Familial exudative vitreoretinopathy caused by CTNNB1 gene mutation in a Chinese family: 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 Familial exudative vitreoretinopathy caused by CTNNB1 gene mutation in a Chinese family: A case report Yanan Wang, Yujie Chang, Yuqiong Chai, Hongtao Lei, Weiyan Yan, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3893221/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 Background Familial exudative vitreoretinopathy (FEVR) is an inherited disorder of retinal vascularization insufficiency caused primarily by genetic mutations. So far, FEVR has been less reported in the Chinese population. This study will provide a case of FEVR due to CTNNB1 splice mutation in a Chinese family, which will be helpful for genetic counseling and clinical diagnosis. Case presentation: We analyzed a case of familial exudative vitreoretinopathy of Chinese Han origin using whole-exome sequencing. The results showed that the patient presents with neurodevelopmental disorders accompanied by spastic diplegia and visual impairment, as well as FEVR. Whole exome sequencing revealed a splicing mutation of c.1060 + 1G > A in the CTNNB1 gene of the patient. This may be the reason for the pathogenicity of FEVR observed in this patient. Our analysis indicates that this variant produces a truncated protein that contributes to the development of the disease. Genetic testing confirmed the FEVR diagnosis of patients from the study pedigree. Conclusions The c.1060 + 1G > A heterozygous mutation in the CTNNB1 gene can lead to FEVR disease, which expands the spectrum of CTNNB1 gene functional loss mutations in the Chinese population. Familial exudative vitreoretinopathy CTNNB1 gene Heterozygous mutation Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Familial exudative vitreoretinopathy (FEVR) is a lifelong, blinding genetic disease of vitreoretinal vascular dysplasia. This disease mostly occurs in infants; its incidence rate can reach 0.63% ~ 1.19%. In the early stage of the disease, it may be limited to peripheral retinal vascular dysplasia. The onset of the disease is hidden, and the onset is usually without warning [1, 2] . With the progression of the disease, retinal ischemia can be accompanied by vascular-free areas and proliferative lesions in the temporal peripheral retina, accompanied by lipid exudate in the retina or under the retina, as well as retinal folds and macular displacement, which will eventually lead to retinal detachment due to organization and traction, resulting in severe visual loss and even blindness [3, 4] . FEVR has diverse genetic modes and high genetic heterogeneity, mainly including autosomal dominant inheritance, autosomal recessive inheritance, X-linked recessive inheritance, and some other scattered genetic modes [5, 6] . Different genetic patterns are related to their associated gene mutation sites. As of now, the discovered FEVR pathogenic genes include Norrie disease protein ( NDP ), frizzled class receptor ( FZD4 ), Low-density lipoprotein receptor-related protein 5 ( LRP5 ), tetraspanin 12 ( TSPAN12 ), catenin beta-1 ( CTNNB1 ), zinc finger protein 408 ( ZNF408 ), catenin alpha-1 ( CTNNA1 ), atonal bHLH transcription factor 7 ( ATOH7 ), exudative vitreoretinopathy 3 ( EVR3 ), kinesin family member 11 ( KIF11 ), RCC1 and BTB domain-containing protein 1 ( RCBTB1 ) and jagged protein 1 ( JAG1 ) [7-10] . These genes play important roles in signaling pathways such as Wnt, Notch, and Wnt/β-catenin. In this study, CTNNB1 gene variation was analyzed in 1 child with strabismus, hand-eye coordination disorder, inability to sit alone, movement lag, and mental retardation, to clarify the pathogenic causes and provide evidence for clinical diagnosis. Methods 1.1 Family description The patient was a 1-year-old boy who delivered at full-term and was of normal weight. With strabismus, hand-eye coordination disorder, eyes cannot chase objects, developmental delay/intellectual delay (DD/ID), and so on, the patient had a clinical diagnosis of FEVR type 7, and his parents did not exhibit similar symptoms. The patient underwent a complete physical examination, ocular examination (including fundus examination, ocular ultrasound, fundus fluorescein angiography, etc.), laboratory examination, medical history, and family history inquiry. This study was approved by the Ethics Committee of Medical Genetics and Prenatal Diagnosis of Luoyang Maternal and Child Health Hospital, and the patients' families signed informed consent. 1.2 Extraction of Genomic DNA and Whole exome sequencing DNA extraction was performed on peripheral blood samples using the Qiagen Genome DNA Extraction Kit, and the concentration of DNA (0.2 ~ 0.4 ng/μL) was detected using a Nano-Drop measuring instrument, and the purity (A260/A280 ratio within the range of 1.8 ~ 2.0), the qualified DNA samples are stored at -20 ℃ for future use. To begin with, we used Enzymatics' fragmented enzymes to break the genomic DNA of family members into fragments of 250 - 300 bp in length and amplified the genome library using the KAPA HiFi Ready Mix enzyme from KAPABiosystems. Then, IDT xGen Exome Research Panel v1.0 capture kit was used for full exon capture (covering 19396 gene coding region DNA sequences, target region range 39M, to detect point mutation and small fragment deletion insertion mutation within 20bp). Next, genomic library concentration (concentration ≥ 10 ng/uL) was detected using Qubit 4.0 equipment and Qubit dsDNA HS Assay Kit, and genomic library fragment length (300bp~550bp) was measured using the QSeq400 fragment analyzer. After passing the library inspection, the enriched target fragments were sequenced using the NovaSeq 6000 equipment from Illumina, USA, and the PE150 (read length 150bp) mode was selected. The data output was about 10G, and the average sequencing depth of the entire exon sequencing target region was greater than 100X. More than 95% of the target sequence had a sequencing depth of 20X. 1.3 Sanger sequencing validation Last, we compared the sequencing data obtained with the reference sequence of the human genome GRCh37/hg19. If a suspicious mutation is detected, we use Sanger sequencing to verify the site of genomic DNA of family members, and designed primers targeting the CTNNB1 : chr3:41268844-F: 5´-TGGCTCTTCTCAGACATGTG-3´, chr3:41268844-R: 5´-GCTACAATCCAGATGACAGG-3´, and amplified them. The PCR products were purified by agarose gel electrophoresis and sequenced by ABI3730xl genetic analyzer. The sequencing results were analyzed by Chromas software. The NGS quality control data of this study shows a target area coverage of 99.8%, an average depth of 125.92, and a proportion of 98.1% with an average depth of > 20X in the target area. 1.4 Pathogenicity analysis of CTNNB1 (Mut. c.1060+1G>A) The Mutation pathogenicity was determined according to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the Clinvar database, and the Mutation Taster software. Minigene technology, also known as in vitro validation of mRNA splicing abnormalities. By cloning the target genome fragment with a mutation site (c.1060+1G>A) (PrimerSTAR MAX DNA Polymerase, TaKaRa), constructing a recombinant expression vector (Rapid Plasmid Mini Kit, SIMGEN), transfecting Hela and 293T cell lines, RNA extraction and cDNA inversion (DNA Gel Exctration Kit, SIMGEN; Trizol（RNAiso PLUS）, TaKaRa; HifairTM 1st Strand cDNA Synthesis SuperMix for qPCR(gDNA digester plus), YEASEN), and then verifying the effect of the mutation on mRNA splicing using electrophoresis and Sanger sequencing. The primers used in the experiment are shown in Supplementary Materials. Results 2.1 Clinical symptoms The patient was a 1-year-old boy born spontaneously at full term with normal weight. He was the first child of a non-consanguineous couple and presented clinically with poor hand-eye coordination, poor lower limb support, inability to sit alone, motor retardation, mental retardation, intermittent strabismus, and nystagmus (Fig. 1a). The facial features of the patient are sparse hair, strabismus, wide nose tip, thin upper lip, large ears, and long, flat philtrum. The patient had no history of hypoxia, and neonates at birth, normal heart and lung function, and no history of maternal medication or radiation exposure. The patient's pedigree is shown in Fig. 1b. Fundus examination showed that the patient's fundus was in a leopard-like pattern, and degeneration areas were visible in the temporal peripheral retina of both eyes, with suspected holes in the degeneration areas (Fig. 1c). Eye ultrasound shows a flocculent moderate echo in the vitreous body of both eyes of the patient. In addition, a short strip of moderate echo can be seen, connected to the temporal bulbar wall, and the temporal bulbar wall is locally less smooth. Point out indications of bilateral vitreous opacity and suspected local detachment of the retina in both eyes (Fig. 1d). FFA examination showed that the patient's fundus showed the presence of avascular areas around the retina accompanied by an increase in vascular branches, and the distal branches could be claw shaped and rigid in shape (Fig. 1e). The mother had two pregnancies and one full-term delivery. In the 20th week when she was pregnant with her second child, the prenatal testing of the fetus showed no abnormalities. 2.2 Analysis of CTNNB1 gene variation Both the patient and his parents underwent WES analysis. The results showed that the patient carried a heterozygous mutation c.1060+1G>A in CTNNB1 , located at the+1 position of intron8. The c.1060+1 base mutated from guanine to adenine, which belongs to the "Class I mutation region" that affects splicing (Fig.2a). The Clinvar database shows that the disease and pathogenicity rating corresponding to c.1060+1G>A is: inborn_genetic_diseases (pathogenic). The Mutation Taster software predicts a range of 0 ~ 1 points for mutation sites, with higher scores being more harmful. The c.1060+1G>A heterozygous mutation is scored as 1.0 (with a prediction level of D), indicating that the mutation site is highly pathogenic. Referring to the interpretation guide of ACMG gene mutation, the mutation at this site is determined as PVS1+PM6+PM2_Supporting, graded as Pathogenic. We validated the CTNNB1 mutation using Sanger sequencing. The results showed that the patient (proband) had a c.1060+1G>A heterozygous mutation at the chr3: 41268844, and his father and mother were both wild-type at this locus (Fig.2b). 2.3 Minigene for pathogenicity detection of mutations We used Minigene technology to detect the pathogenicity of c.1060+1G>A splicing mutation. Insert a portion of Intron7 (474bp) - Exon8 (145bp) - and a portion of Intron8 (566bp) into the pcMINI vector containing the universal ExonA-IntrnA-MCS-IntronB-ExonB (Fig. 3a). Then we performed Sanger sequencing verification on the constructed vector. The results showed that both wild-type and mutant minigenes were successfully inserted into the corresponding vectors (Fig. 3b). The RT-PCR detection results showed that the wild-type was a single band in HeLa and 293T cells, which was consistent with the expected size (534bp) and named band a; The mutant type is also a single band, named band b (Fig. 3c). Perform Sanger sequencing on the wild-type band a and mutant band b produced in two cell lines. The results show that wild-type band a is a normal shear band, with ExonA (192bp) - Exon8 (145bp) - ExonB (57bp) as the shear mode; Mutant band b is an abnormal shear band with Exon8 jumping, and the shear mode is ExonA (192bp) - ExonB (57bp) (Fig. 3d). Exon8 jumps in the cDNA representation: c.916_1060del p.Leu306Valfs*6, and the mutation creates a premature termination codon (PTC) in Exon9, generating a truncated protein of length 310aa (Fig. 3e). Discussion The CTNNB1 gene is located on chromosome 3p22.1 and encodes a protein with adhesive connectivity function β-catenin, which supports the integrity between epithelium layers and mediates intercellular signal transduction. As a multitasking protein, β-catenin is not only a core component of the cadherin complex, but also a key factor in typical Wnt signaling, playing an important role in stem cell renewal and cell proliferation and differentiation during embryonic development. Many studies have found that abnormal activation of β-catenin may promote the development of a variety of tumors, such as colorectal cancer and hepatocellular carcinoma [11, 12] . The ablation of β-catenin can affect the development of the nervous system [13] . Normally, the extracellular ligand protein Wnt binds to the specific receptor Frizzled protein on the cell membrane, activating the intracellular Dvl protein, causing GSK3 to lose activity, thereby avoiding β-catenin is phosphorylated and stably accumulates in the cytoplasm. When the concentration of β-catenin in the cytoplasm reaches a certain level, it can migrate to the nucleus, where β-catenin combines with the transcription factor family T cell factor/lymphoid enhancer factor (TCF/LEF), activates a series of downstream target genes, thereby promoting cell proliferation, differentiation and maturation, and causing changes in related functions of the body (As shown in Fig.4). The mouse model with knockout mutations in FEVR-related genes (FZD4, LRP5, TSPAN12, and CTNNB1) showed defects in the retinal vascular system, indicating that decreased Wnt signaling pathway activity can lead to FEVR [14] . In recent years, various heterozygous variants of CTNNB1 have been associated with human diseases, including NEDSDV (MIM 615075), and FEVR (MIM 617572). Among patients with previously reported CTNNB1 -related neurodevelopmental disorders, many suffer from ocular abnormalities, including strabismus, hyperopia, and astigmatism, which are associated with vitreoretinopathy [15] . Among patients with visual defects due to NEDSDV, the prevalence was 78.4% among Chinese and 69.4% among non-Chinese. NEDSDV is an autosome dominant genetic disease, characterized by developmental delay/intellectual delay (DD/ID), language disorder, microcephaly, motor retardation, autism spectrum disorder (ASD), muscle hypotonia, progressive peripheral spasm, craniofacial malformation and visual abnormalities of different degrees [16, 17] . It has been found that endothelial β-catenin signaling supports postnatal brain and retinal angiogenesis by promoting sprouting, tip cell formation, VEGFR (Vascular Endothelial Growth Factor Receptor) 2 expression, and Sox17 (and Sox7) [18] . In vivo experiments on β-catenin knockout mice have also shown that haploinsufficiency of this gene leads to dyssynaptic plasticity, neuronal network connectivity, and synaptic adhesion, providing a potential pathogenic mechanism for neurodevelopmental disorders [19, 20] . Thus, if the Wnt/β-catenin signaling pathway is inactivated, the signaling of VEGF and SOX17 is blocked, which may be the reason why patients have both abnormal retinal vascular development and abnormal neurodevelopment. As of now, there are few reports of NEDSDV patients in China. In this study, we reported a case of c.1060+1G>A heterozygous mutation of the CTNNB1 gene in Han Chinese, who was diagnosed with FEVR and presented with strabismus, hand-eye coordination disorder, larger ears, poor elbow support, lower limb hypertonia and spasm, DD/ID and other global developmental delays, and some facial abnormalities consistent with previous reports. We found a foreign report related to this mutation reported by Kuechler et al. [21] in the Clinvar database, but there was no clinical description of FEVR in their case. So far, there are less than 100 reported functional deletion mutations in the CTNNB1 gene in the literature, mainly from non-Chinese populations. Dixon et al. [22] first reported the relationship between CTNNB1 haploid dysfunction and FEVR in 2016, a few cases have been reported, and the majority of patients are of Asian ethnicity [23, 24] . In the study of Yan et al. [25] , the clinical characteristics and genetic results of 24 patients with CTNNB1 pathogenic variation in the Chinese Mainland were reported. This is currently the largest case series of NEDSDV caused by CTNNB1 mutation in China. Among them, 19 patients had mild visual impairment, and 1 patient had familial exudative vitreoretinopathy. The larger ears of the patients in our study are consistent with those reported by Yan et al. and Ho's cohort. This phenotype has only been reported in the Chinese population, whether there is a racial difference in the clinical presentation of these larger ears is unknown. In addition, we also found that in addition to the c.1060+1G>A heterozygous mutation, the patient also had three novel gene mutation sites: the NIPBL gene c.3130G>A (p.Asp1044Asn), the CNGA1 gene c.568G>T (p.Glu190X), and the FBN2 gene c.5370A>G (p.Ile1790Met). CNGA1 gene is located on chromosome 4p12 and contains 13 Exon. The protein encoded by CNGA1 is involved in K + transport, light transduction, visual perception, and response stimulation. This gene is a susceptibility gene for Retinitis pigmentosa (RP), especially for Retinitis pigmentosa Autosome recessive inheritance (ARRP). Its symptoms are mainly chronic progressive visual field loss, night blindness, abnormal electroretinogram, and decreased vision. In the later stages of the disease, central vision loss may occur [26] . The ACMG guidelines classify this mutation site as Likely Pathogenic (Table 1). Therefore, it is currently unknown whether the FEVR and other ocular manifestations of this patient have the effect of CNGA1 , and further research is needed to elucidate its specific mechanism. In this study, we reported a case of FEVR caused by CTNNB1 mutation in Chinese Han nationality, which further elucidates that FEVR disease caused by CTNNB1 heterozygous mutation may be related to the loss of Wnt/ β-catenin signaling pathway activity. At the same time, this case also enriched the spectrum of CTNNB1 gene function loss variation in the Chinese population. Conclusions The c.1060 + 1G > A heterozygous mutation in the CTNNB1 gene can lead to FEVR disease, which expands the spectrum of CTNNB1 gene functional loss mutations in the Chinese population. Abbreviations FEVR Familial exudative vitreoretinopathy CTNNB1 Catenin beta 1 NEDSDV Neurodevelopmental disorders with spastic diplegia and visual impairment DD/ID Developmental delay/Intellectual delay FFA Fundus fluorescein angiography WES Whole exon sequencing Declarations Acknowledgements We would like to thank all the participants and the staff for their valuable contribution to this research. Ethics approval and consent to participate I confirm that the relevant guidelines and regulations performed all methods. The parents of the proband signed an informed consent form. The study was approved by the Ethics Committee of Medical Genetics and Prenatal Diagnosis of Luoyang Maternal and Child Health Hospital. The ethics number is LYFY-YCCZ-2023008. Consent for publication Obtain the informed consent of the patient and her family, and publish information and images in an online open-access publication. Availability of data and materials The datasets generated and analysed during the current study are available in the Genome Sequence Archive for Human repository, and accession number to datasets is HRA005666. It can be accessed from the following link: https://bigd.big.ac.cn/gsa-human/browse/HRA005666. Competing interests The authors declare no competing interests. Funding This work was supported by the Department of Genetics and Prenatal Diagnosis of the Luoyang Maternal and Child Health Hospital. The funding agency did not participate in the design or implementation of this study. Authors' contributions W.Y. brewed and designed experiments, critically reviewed the knowledge content of the article, and obtained research funding. C.Y. and C.Y. performed sequencing and analysis, L.H. and Y.W. prepared figures, Z.W. provides administrative, technical, or material support, and W.Y. and C.Y. wrote the main manuscript. Acknowledgements We want to thank all the participants and the staff for contributing to this research. Authors' information Yanan Wang ( Corresponding author; First author ): Luoyang City; CHINA; Luoyang Maternal and Child Health Hospital; Genetics and Prenatal Diagnosis Department; Chief physician; E-mail: [email protected] Yujie Chang: Luoyang City; CHINA; Luoyang Maternal and Child Health Hospital; Genetics and Prenatal Diagnosis Department; E-mail: [email protected] Yuqiong Chai: Luoyang City; CHINA; Luoyang Maternal and Child Health Hospital; Genetics and Prenatal Diagnosis Department; E-mail: [email protected] Hongtao Lei: Luoyang City; CHINA; Luoyang Maternal and Child Health Hospital; Pediatric Ophthalmology Department; E-mail: [email protected] Weiyan Yan: Luoyang City; CHINA; Luoyang Maternal and Child Health Hospital; Pediatric Ophthalmology Department; E-mail: [email protected] Weiwei Zang: Luoyang City; CHINA; Luoyang Maternal and Child Health Hospital; Genetics and Prenatal Diagnosis Department; E-mail: [email protected] There is no conflict of interest between the authors. References Tang H, Li N, Li Z, et al. Fundus examination of 199 851 newborns by digital imaging in China: a multicentre cross-sectional study [J]. Br J Ophthalmol. 2018;102(12):1742–6. Sun W, Xiao X, Li S et al. Pathogenic variants and associated phenotypic spectrum of TSPAN12 based on data from a large cohort [J]. Graefe's Archive for Clinical and Experimental Ophthalmology, 2021, 259(10): 2929–39. Shukla D, Singh J, Sudheer G, et al. Familial exudative vitreoretinopathy (FEVR). Clinical profile and management [J]. Indian J Ophthalmol. 2003;51(4):323–8. Wang Z, Chen C, Sun L et al. Symmetry of folds in FEVR: a genotype-phenotype correlation study [J]. Experimental Eye Research, 2019, 186(107720. Dixon MW, Stem MS, Schuette JL, et al. CTNNB1 mutation associated with familial exudative vitreoretinopathy (FEVR) phenotype [J]. Ophthalmic Genet. 2016;37(4):468–70. Joussen A, Gordes R, Heußen F, et al. Retinal exudative disease in childhood: Coats' disease and familial exudative vitreoretinopathy (FEVR) [J]. Klin Monbl Augenheilkd. 2013;230(9):902–13. Coussa RG, Zhao Y, Debenedictis MJ, et al. Novel mutation in CTNNB1 causes familial exudative vitreoretinopathy (FEVR) and microcephaly: case report and review of the literature [J]. Ophthalmic Genet. 2020;41(1):63–8. Gilmour D. Familial exudative vitreoretinopathy and related retinopathies [J]. Eye. 2015;29(1):1–14. Wang Y, Zhang Z, Huang L, et al. Update on the phenotypic and genotypic spectrum of KIF11-Related retinopathy [J]. Genes. 2022;13(4):713. Xu H, Zhang S, Huang L, et al. Identification of novel variants in the FZD4 gene associated with familial exudative vitreoretinopathy in Chinese families [J]. Volume 48. Clinical & Experimental Ophthalmology; 2020. pp. 356–65. 3. Heuberger J, Birchmeier W. Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling [J]. Cold Spring Harb Perspect Biol. 2010;2(2):a002915. Clevers H, Nusse R. Wnt/β-catenin signaling and disease [J]. Cell. 2012;149(6):1192–205. Zechner D, Fujita Y, Hülsken J, et al. β-Catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system [J]. Dev Biol. 2003;258(2):406–18. Zhou Y, Wang Y, Tischfield M, et al. Canonical WNT signaling components in vascular development and barrier formation [J]. J Clin Investig. 2014;124(9):3825–46. Rossetti LZ, Bekheirnia MR, Lewis AM, et al. Missense variants in CTNNB1 can be associated with vitreoretinopathy—Seven new cases of CTNNB1-associated neurodevelopmental disorder including a previously unreported retinal phenotype [J]. Volume 9. Molecular Genetics & Genomic Medicine; 2021. p. e1542. 1. De Ligt J, Willemsen MH, Van Bon BWM, et al. Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability [J]. N Engl J Med. 2012;367(20):1921–9. Ho S, Tsang M, H-Y, Fung JL-F, et al. CTNNB1-related neurodevelopmental disorder in a Chinese population: A case series [J]. Am J Med Genet Part A. 2022;188(1):130–7. Martowicz A, Trusohamn M, Jensen N et al. Endothelial β-catenin signaling supports postnatal brain and retinal angiogenesis by promoting sprouting, tip cell formation, and VEGFR (vascular endothelial growth factor receptor) 2 expression [J]. Arteriosclerosis, thrombosis, and vascular biology, 2019, 39(11): 2273–88. Tucci V, Kleefstra T, Hardy A, et al. Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features [J]. J Clin Investig. 2014;124(4):1468–82. Wickham RJ, Alexander JM, Eden LW, et al. Learning impairments and molecular changes in the brain caused by β-catenin loss [J]. Hum Mol Genet. 2019;28(17):2965–75. Kuechler A, Willemsen MH, Albrecht B, et al. De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum [J]. Hum Genet. 2015;134(1):97–109. Dixon MW, Stem MS, Schuette JL, et al. CTNNB1 mutation associated with familial exudative vitreoretinopathy (FEVR) phenotype [J]. Ophthalmic Genet. 2016;37(4):468–70. Wang H, Zhao Y, Yang L, et al. Identification of a novel splice mutation in CTNNB1 gene in a Chinese family with both severe intellectual disability and serious visual defects [J]. Neurol Sci. 2019;40(8):1701–4. Li N, Xu Y, Li G, et al. Exome sequencing identifies a de novo mutation of CTNNB1 gene in a patient mainly presented with retinal detachment, lens and vitreous opacities, microcephaly, and developmental delay: Case report and literature review [J]. Med (Baltim). 2017;96(20):e6914. Yan D, Sun Y, Xu N et al. Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants [J]. Molecular Genetics & Genomic Medicine, 2022, 10(11): e2067. Saito K, Gotoh N, Kang I, et al. A case of retinitis pigmentosa homozygous for a rare CNGA1 causal variant [J]. Sci Rep. 2021;11(1):4681. Table Table 1. Detection Results of Gene Mutations. Gene Transcript The location of the genome Zygotic type Pathogenicity rating of ACMG Genetic mode Diseases related to gene mutations CTNNB1 NM_001330729 Exon 8 chr3:41268844 c.1060+1G>A Heterozygote Pathogenic AD Exudative vitreoretinopathy type 7 (MIM: 617572) NIPBL NM_015384 Exon 11 chr5:36995732 c.3130G>A p.D1044N Heterozygote; Verified; By his father Uncertain significance AD Cornelia de Lange syndrome 1 (MIM: 122470) CNGA1 NM_001142564 Exon 7 chr4:47945286 c.568G>T p.E190X Heterozygote Likely pathogenic unknown Retinitis pigmentosa 49 (MIM: 613756) FBN2 NM_001999 Exon 42 chr5:127642879 c.5370A>G p.I1790M Heterozygote Uncertain significance AD Contractural arachnodactyly, congenital (MIM: 121050); Early-onset macular degeneration (MIM: 616118 ) Note: AD: Autosomal dominant inheritance; AR: Autosomal recessive inheritance. Additional Declarations No competing interests reported. Supplementary Files supplementarymaterial1.pdf supplementarymaterial2.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3893221","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":269155938,"identity":"4dfdcb9e-6358-45dd-978f-35bd579d872b","order_by":0,"name":"Yanan Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYPACCTk29uYDBz78IF6LjTE/z7HEgzN7iNeSljhzRo7xYQ42ItQa3Eh+9uDnjsOMGw7kfDjMwMMgzy92gJCWNHPD3jOHmQ0OnN1wuMCCwXDm7AT8WsxuJJhJ8LYdZjM42Lvh8AwehgSD2wS1pH+T/Nt2mMfgMM+DwzxsRGnJMZPmbUuTkGzjYSBOi/2ZN2XSsm02Bvw8QLfN7JEg7BfJ9vRtkm/bJOrb5B8//vDhh408vzQBLQwCqAokCCgHAf4DRCgaBaNgFIyCkQ0AO2tKA8okf0IAAAAASUVORK5CYII=","orcid":"","institution":"Luoyang maternal and Child Health Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yanan","middleName":"","lastName":"Wang","suffix":""},{"id":269155939,"identity":"a3b88e61-9c56-4721-887c-634f735b4739","order_by":1,"name":"Yujie Chang","email":"","orcid":"","institution":"Luoyang maternal and Child Health Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yujie","middleName":"","lastName":"Chang","suffix":""},{"id":269155940,"identity":"84d78ff6-baea-48bf-8f03-f317ca9322f8","order_by":2,"name":"Yuqiong Chai","email":"","orcid":"","institution":"Luoyang maternal and Child Health Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuqiong","middleName":"","lastName":"Chai","suffix":""},{"id":269155941,"identity":"3c26aa39-6298-4e10-a0fb-c677e7d925db","order_by":3,"name":"Hongtao Lei","email":"","orcid":"","institution":"Luoyang maternal and Child Health Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hongtao","middleName":"","lastName":"Lei","suffix":""},{"id":269155942,"identity":"44412b76-332f-4ee3-8cfd-66ab120f8aa6","order_by":4,"name":"Weiyan Yan","email":"","orcid":"","institution":"Luoyang maternal and Child Health Hospital","correspondingAuthor":false,"prefix":"","firstName":"Weiyan","middleName":"","lastName":"Yan","suffix":""},{"id":269155943,"identity":"fcbf1629-1d69-4858-92ba-10081da16844","order_by":5,"name":"Weiwei Zang","email":"","orcid":"","institution":"Luoyang maternal and Child Health Hospital","correspondingAuthor":false,"prefix":"","firstName":"Weiwei","middleName":"","lastName":"Zang","suffix":""}],"badges":[],"createdAt":"2024-01-24 06:59:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3893221/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3893221/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50327510,"identity":"8024dfcc-3f59-441a-9c45-90b972ea9d50","added_by":"auto","created_at":"2024-01-29 20:41:13","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":7290659,"visible":true,"origin":"","legend":"\u003cp\u003eClinical features and genetic family maps of patients. (a) Ocular characteristics of the patient. (b) Genetic family tree. The pedigree showed that Ⅱ-1 in the family had a heterozygous variant (\u003cem\u003eCTNNB1\u003c/em\u003e:c.1060+1G\u0026gt;A), marked in black, and the arrow indicated the proband. The variant was not found in other members of this family. (c) Fundus examination. R: right eye, L: left eye. (d) Ocular ultrasonography. OD: right eye, OS: left eye. (e) Fundus fluorescein angiography (FFA) examination.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3893221/v1/65e0d95f46e87ab0cafcde6d.jpg"},{"id":50327514,"identity":"4f4fa3ec-1487-4e0a-a62b-9b54e444e2b3","added_by":"auto","created_at":"2024-01-29 20:41:13","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":5766976,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eCTNNB1\u003c/em\u003egene sequencing analysis results. (a) Location of c.1060+1G\u0026gt;A mutation in the corresponding exon or intron. (b) Verification results of Sanger sequencing.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3893221/v1/c266921e9fc99ae466e4d52d.jpg"},{"id":50327513,"identity":"654ef209-a947-4f70-9564-2168460e70c1","added_by":"auto","created_at":"2024-01-29 20:41:13","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":6130692,"visible":true,"origin":"","legend":"\u003cp\u003eResults of pcMINI carrier detection. (a) Schematic diagram of pcMINI carrier construction; (b) Sanger sequencing validation for vector construction; (c\u0026amp;d) RT-PCR transcriptional analysis agarose gel electrophoresis map and the corresponding Sanger sequencing result map of the shear band. The wild-type and mutant-type bands in Hela and 293T cells were labeled a and b respectively. (e) Effects of the c.1060+1G\u0026gt;A mutation on protein structure.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3893221/v1/af7c9e62b636af804e7e68e1.jpg"},{"id":50327511,"identity":"222b09ae-a7c1-4b7a-9fe1-9b621a7645dd","added_by":"auto","created_at":"2024-01-29 20:41:13","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3473006,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic diagram of the effects of CTNNB1-related Wnt/β-catenin signaling pathway on the human body.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3893221/v1/36f8fc1afd7c3e29e25f4ddb.jpg"},{"id":55692921,"identity":"9132d584-88a0-40a8-be3b-65b3ed1ab1ef","added_by":"auto","created_at":"2024-05-02 00:11:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":831403,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3893221/v1/412ad7d5-fe05-40f2-9a4e-78946754419f.pdf"},{"id":50327508,"identity":"ad76f6bd-a3a0-4ce6-b5e5-24227acc1fb2","added_by":"auto","created_at":"2024-01-29 20:41:12","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":38998,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarymaterial1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3893221/v1/0ff8c1efbe4d74d73bd031aa.pdf"},{"id":50327509,"identity":"8098606f-a9c9-413d-8e97-2e1f0c2b4a32","added_by":"auto","created_at":"2024-01-29 20:41:12","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":88802,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarymaterial2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3893221/v1/2dc18094a9ff17c936175514.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Familial exudative vitreoretinopathy caused by CTNNB1 gene mutation in a Chinese family: A case report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFamilial exudative vitreoretinopathy (FEVR) is a lifelong, blinding genetic disease of vitreoretinal vascular dysplasia. This disease mostly occurs in infants; its incidence rate can reach 0.63% ~ 1.19%. In the early stage of the disease, it may be limited to peripheral retinal vascular dysplasia. The onset of the disease is hidden, and the onset is usually without warning\u003csup\u003e[1, 2]\u003c/sup\u003e. With the progression of the disease, retinal ischemia can be accompanied by vascular-free areas and proliferative lesions in the temporal peripheral retina, accompanied by lipid exudate in the retina or under the retina, as well as retinal folds and macular displacement, which will eventually lead to retinal detachment due to organization and traction, resulting in severe visual loss and even blindness\u003csup\u003e[3, 4]\u003c/sup\u003e. FEVR has diverse genetic modes and high genetic heterogeneity, mainly including autosomal dominant inheritance, autosomal recessive inheritance, X-linked recessive inheritance, and some other scattered genetic modes\u003csup\u003e[5, 6]\u003c/sup\u003e. Different genetic patterns are related to their associated gene mutation sites.\u003c/p\u003e\n\u003cp\u003eAs of now, the discovered FEVR pathogenic genes include Norrie disease protein (\u003cem\u003eNDP\u003c/em\u003e), frizzled class receptor (\u003cem\u003eFZD4\u003c/em\u003e), Low-density lipoprotein receptor-related protein 5 (\u003cem\u003eLRP5\u003c/em\u003e), tetraspanin 12 (\u003cem\u003eTSPAN12\u003c/em\u003e), catenin beta-1 (\u003cem\u003eCTNNB1\u003c/em\u003e), zinc finger protein 408 (\u003cem\u003eZNF408\u003c/em\u003e), catenin alpha-1 (\u003cem\u003eCTNNA1\u003c/em\u003e), atonal bHLH transcription factor 7 (\u003cem\u003eATOH7\u003c/em\u003e), exudative vitreoretinopathy 3 (\u003cem\u003eEVR3\u003c/em\u003e), kinesin family member 11 (\u003cem\u003eKIF11\u003c/em\u003e), RCC1 and BTB domain-containing protein 1 (\u003cem\u003eRCBTB1\u003c/em\u003e) and jagged protein 1 (\u003cem\u003eJAG1\u003c/em\u003e)\u003csup\u003e[7-10]\u003c/sup\u003e. These genes play important roles in signaling pathways such as Wnt, Notch, and Wnt/β-catenin. In this study, \u003cem\u003eCTNNB1\u003c/em\u003e gene variation was analyzed in 1 child with strabismus, hand-eye coordination disorder, inability to sit alone, movement lag, and mental retardation, to clarify the pathogenic causes and provide evidence for clinical diagnosis.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e1.1 Family description\u003c/p\u003e\n\u003cp\u003eThe patient was a 1-year-old boy who delivered at full-term and was of normal weight. With strabismus, hand-eye coordination disorder, eyes cannot chase objects, developmental delay/intellectual delay (DD/ID), and so on, the patient had a clinical diagnosis of FEVR type 7, and his parents did not exhibit similar symptoms. The patient underwent a complete physical examination, ocular examination (including fundus examination, ocular ultrasound, fundus fluorescein angiography, etc.), laboratory examination, medical history, and family history inquiry. This study was approved by the Ethics Committee of Medical Genetics and Prenatal Diagnosis of Luoyang Maternal and Child Health Hospital, and the patients' families signed informed consent.\u003c/p\u003e\n\u003cp\u003e1.2\u0026nbsp; Extraction of Genomic DNA and Whole exome sequencing\u003c/p\u003e\n\u003cp\u003eDNA extraction was performed on peripheral blood samples using the Qiagen Genome DNA Extraction Kit, and the concentration of DNA (0.2 ~ 0.4 ng/μL) was detected using a Nano-Drop measuring instrument, and the purity (A260/A280 ratio within the range of 1.8 ~ 2.0), the qualified DNA samples are stored at -20 ℃ for future use.\u003c/p\u003e\n\u003cp\u003eTo begin with, we used Enzymatics' fragmented enzymes to break the genomic DNA of family members into fragments of 250 - 300 bp in length and amplified the genome library using the KAPA HiFi Ready Mix enzyme from KAPABiosystems. Then, IDT xGen Exome Research Panel v1.0 capture kit was used for full exon capture (covering 19396 gene coding region DNA sequences, target region range 39M, to detect point mutation and small fragment deletion insertion mutation within 20bp). Next, genomic library concentration (concentration ≥ 10 ng/uL) was detected using Qubit 4.0 equipment and Qubit dsDNA HS Assay Kit, and genomic library fragment length (300bp~550bp) was measured using the QSeq400 fragment analyzer. After passing the library inspection, the enriched target fragments were sequenced using the NovaSeq 6000 equipment from Illumina, USA, and the PE150 (read length 150bp) mode was selected. The data output was about 10G, and the average sequencing depth of the entire exon sequencing target region was greater than 100X. More than 95% of the target sequence had a sequencing depth of 20X.\u003c/p\u003e\n\u003cp\u003e1.3\u0026nbsp; Sanger sequencing validation\u003c/p\u003e\n\u003cp\u003eLast, we compared the sequencing data obtained with the reference sequence of the human genome GRCh37/hg19. If a suspicious mutation is detected, we use Sanger sequencing to verify the site of genomic DNA of family members, and designed primers targeting the \u003cem\u003eCTNNB1\u003c/em\u003e: chr3:41268844-F: 5´-TGGCTCTTCTCAGACATGTG-3´,\u0026nbsp;chr3:41268844-R: 5´-GCTACAATCCAGATGACAGG-3´, and amplified them. The PCR products were purified by agarose gel electrophoresis and sequenced by ABI3730xl genetic analyzer. The sequencing results were analyzed by Chromas software. The NGS quality control data of this study shows a target area coverage of 99.8%, an average depth of 125.92, and a proportion of 98.1% with an average depth of \u0026gt; 20X in the target area.\u003c/p\u003e\n\u003cp\u003e1.4\u0026nbsp; Pathogenicity analysis of \u003cem\u003eCTNNB1\u003c/em\u003e (Mut. c.1060+1G\u0026gt;A)\u003c/p\u003e\n\u003cp\u003eThe Mutation pathogenicity was determined according to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the Clinvar database, and the Mutation Taster software.\u003c/p\u003e\n\u003cp\u003eMinigene technology, also known as in vitro validation of mRNA splicing abnormalities. By cloning the target genome fragment with a mutation site (c.1060+1G\u0026gt;A) (PrimerSTAR MAX DNA Polymerase, TaKaRa), constructing a recombinant expression vector (Rapid Plasmid Mini Kit, SIMGEN), transfecting Hela and 293T cell lines, RNA extraction and cDNA inversion (DNA Gel Exctration Kit, SIMGEN; Trizol（RNAiso PLUS）, TaKaRa; HifairTM 1st Strand cDNA Synthesis SuperMix for qPCR(gDNA digester plus), YEASEN), and then verifying the effect of the mutation on mRNA splicing using electrophoresis and Sanger sequencing. The primers used in the experiment are shown in Supplementary Materials.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e2.1\u0026nbsp; Clinical symptoms\u003c/p\u003e\n\u003cp\u003eThe patient was a 1-year-old boy born spontaneously at full term with normal weight. He was the first child of a non-consanguineous couple and presented clinically with poor hand-eye coordination, poor lower limb support, inability to sit alone, motor retardation, mental retardation, intermittent strabismus, and nystagmus (Fig. 1a). The facial features of the patient are sparse hair, strabismus, wide nose tip, thin upper lip, large ears, and long, flat philtrum. The patient had no history of hypoxia, and neonates at birth, normal heart and lung function, and no history of maternal medication or radiation exposure. The patient\u0026apos;s pedigree is shown in Fig. 1b. Fundus examination showed that the patient\u0026apos;s fundus was in a leopard-like pattern, and degeneration areas were visible in the temporal peripheral retina of both eyes, with suspected holes in the degeneration areas (Fig. 1c). Eye ultrasound shows a flocculent moderate echo in the vitreous body of both eyes of the patient. In addition, a short strip of moderate echo can be seen, connected to the temporal bulbar wall, and the temporal bulbar wall is locally less smooth. Point out indications of bilateral vitreous opacity and suspected local detachment of the retina in both eyes (Fig. 1d). FFA examination showed that the patient\u0026apos;s fundus showed the presence of avascular areas around the retina accompanied by an increase in vascular branches, and the distal branches could be claw shaped and rigid in shape (Fig. 1e). The mother had two pregnancies and one full-term delivery. In the 20th week when she was pregnant with her second child, the prenatal testing of the fetus showed no abnormalities.\u003c/p\u003e\n\u003cp\u003e2.2\u0026nbsp; Analysis of \u003cem\u003eCTNNB1\u003c/em\u003e gene variation\u003c/p\u003e\n\u003cp\u003eBoth the patient and his parents underwent WES analysis. The results showed that the patient carried a heterozygous mutation c.1060+1G\u0026gt;A in \u003cem\u003eCTNNB1\u003c/em\u003e, located at the+1 position of intron8. The c.1060+1 base mutated from guanine to adenine, which belongs to the \u0026quot;Class I mutation region\u0026quot; that affects splicing (Fig.2a). The Clinvar database shows that the disease and pathogenicity rating corresponding to c.1060+1G\u0026gt;A is: inborn_genetic_diseases (pathogenic). The Mutation Taster software predicts a range of 0 ~ 1 points for mutation sites, with higher scores being more harmful. The c.1060+1G\u0026gt;A heterozygous mutation is scored as 1.0 (with a prediction level of D), indicating that the mutation site is highly pathogenic. Referring to the interpretation guide of ACMG gene mutation, the mutation at this site is determined as PVS1+PM6+PM2_Supporting, graded as Pathogenic.\u003c/p\u003e\n\u003cp\u003eWe validated the \u003cem\u003eCTNNB1\u003c/em\u003e mutation using Sanger sequencing. The results showed that the patient (proband) had a c.1060+1G\u0026gt;A heterozygous mutation at the chr3: 41268844, and his father and mother were both wild-type at this locus (Fig.2b).\u003c/p\u003e\n\u003cp\u003e2.3\u0026nbsp; Minigene for pathogenicity detection of mutations\u003c/p\u003e\n\u003cp\u003eWe used Minigene technology to detect the pathogenicity of c.1060+1G\u0026gt;A splicing mutation. Insert a portion of Intron7 (474bp) - Exon8 (145bp) - and a portion of Intron8 (566bp) into the pcMINI vector containing the universal ExonA-IntrnA-MCS-IntronB-ExonB (Fig. 3a). Then we performed Sanger sequencing verification on the constructed vector. The results showed that both wild-type and mutant minigenes were successfully inserted into the corresponding vectors (Fig. 3b). The RT-PCR detection results showed that the wild-type was a single band in HeLa and 293T cells, which was consistent with the expected size (534bp) and named band a; The mutant type is also a single band, named band b (Fig. 3c). Perform Sanger sequencing on the wild-type band a and mutant band b produced in two cell lines. The results show that wild-type band a is a normal shear band, with ExonA (192bp) - Exon8 (145bp) - ExonB (57bp) as the shear mode; Mutant band b is an abnormal shear band with Exon8 jumping, and the shear mode is ExonA (192bp) - ExonB (57bp) (Fig. 3d). Exon8 jumps in the cDNA representation: c.916_1060del p.Leu306Valfs*6, and the mutation creates a premature termination codon (PTC) in Exon9, generating a truncated protein of length 310aa (Fig. 3e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe \u003cem\u003eCTNNB1\u003c/em\u003e gene is located on chromosome 3p22.1 and encodes a protein with adhesive connectivity function \u0026beta;-catenin, which supports the integrity between epithelium layers and mediates intercellular signal transduction. As a multitasking protein, \u0026beta;-catenin is not only a core component of the cadherin complex, but also a key factor in typical Wnt signaling, playing an important role in stem cell renewal and cell proliferation and differentiation during embryonic development. Many studies have found that abnormal activation of \u0026beta;-catenin may promote the development of a variety of tumors, such as colorectal cancer and hepatocellular carcinoma\u003csup\u003e[11, 12]\u003c/sup\u003e. The ablation of \u0026beta;-catenin can affect the development of the nervous system\u003csup\u003e[13]\u003c/sup\u003e. Normally, the extracellular ligand protein Wnt binds to the specific receptor Frizzled protein on the cell membrane, activating the intracellular Dvl protein, causing GSK3 to lose activity, thereby avoiding \u0026beta;-catenin is phosphorylated and stably accumulates in the cytoplasm. When the concentration of \u0026beta;-catenin in the cytoplasm reaches a certain level, it can migrate to the nucleus, where \u0026beta;-catenin combines with the transcription factor family T cell factor/lymphoid enhancer factor (TCF/LEF), activates a series of downstream target genes, thereby promoting cell proliferation, differentiation and maturation, and causing changes in related functions of the body (As shown in Fig.4). The mouse model with knockout mutations in FEVR-related genes (FZD4, LRP5, TSPAN12, and CTNNB1) showed defects in the retinal vascular system, indicating that decreased Wnt signaling pathway activity can lead to FEVR\u003csup\u003e[14]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn recent years, various heterozygous variants of \u003cem\u003eCTNNB1\u003c/em\u003e have been associated with human diseases, including NEDSDV (MIM 615075), and FEVR (MIM 617572). Among patients with previously reported \u003cem\u003eCTNNB1\u003c/em\u003e-related neurodevelopmental disorders, many suffer from ocular abnormalities, including strabismus, hyperopia, and astigmatism, which are associated with vitreoretinopathy\u003csup\u003e[15]\u003c/sup\u003e. Among patients with visual defects due to NEDSDV, the prevalence was 78.4% among Chinese and 69.4% among non-Chinese. NEDSDV is an autosome dominant genetic disease, characterized by developmental delay/intellectual delay (DD/ID), language disorder, microcephaly, motor retardation, autism spectrum disorder (ASD), muscle hypotonia, progressive peripheral spasm, craniofacial malformation and visual abnormalities of different degrees\u003csup\u003e[16, 17]\u003c/sup\u003e. It has been found that endothelial \u0026beta;-catenin signaling supports postnatal brain and retinal angiogenesis by promoting sprouting, tip cell formation, VEGFR (Vascular Endothelial Growth Factor Receptor) 2 expression, and Sox17 (and Sox7)\u003csup\u003e[18]\u003c/sup\u003e. In vivo experiments on \u0026beta;-catenin knockout mice have also shown that haploinsufficiency of this gene leads to dyssynaptic plasticity, neuronal network connectivity, and synaptic adhesion, providing a potential pathogenic mechanism for neurodevelopmental disorders\u003csup\u003e[19, 20]\u003c/sup\u003e. Thus, if the Wnt/\u0026beta;-catenin signaling pathway is inactivated, the signaling of VEGF and SOX17 is blocked, which may be the reason why patients have both abnormal retinal vascular development and abnormal neurodevelopment.\u003c/p\u003e\n\u003cp\u003eAs of now, there are few reports of NEDSDV patients in China. In this study, we reported a case of c.1060+1G\u0026gt;A heterozygous mutation of the \u003cem\u003eCTNNB1\u003c/em\u003e gene in Han Chinese, who was diagnosed with FEVR and presented with strabismus, hand-eye coordination disorder, larger ears, poor elbow support, lower limb hypertonia and spasm, DD/ID and other global developmental delays, and some facial abnormalities consistent with previous reports. We found a foreign report related to this mutation reported by Kuechler et al.\u003csup\u003e[21]\u003c/sup\u003e in the Clinvar database, but there was no clinical description of FEVR in their case. So far, there are less than 100 reported functional deletion mutations in the \u003cem\u003eCTNNB1\u003c/em\u003e gene in the literature, mainly from non-Chinese populations. Dixon et al.\u003csup\u003e[22]\u003c/sup\u003e first reported the relationship between \u003cem\u003eCTNNB1\u003c/em\u003e haploid dysfunction and FEVR in 2016, a few cases have been reported, and the majority of patients are of Asian ethnicity\u003csup\u003e[23, 24]\u003c/sup\u003e. In the study of Yan et al.\u003csup\u003e[25]\u003c/sup\u003e, the clinical characteristics and genetic results of 24 patients with \u003cem\u003eCTNNB1\u003c/em\u003e pathogenic variation in the Chinese Mainland were reported. This is currently the largest case series of NEDSDV caused by \u003cem\u003eCTNNB1\u003c/em\u003e mutation in China. Among them, 19 patients had mild visual impairment, and 1 patient had familial exudative vitreoretinopathy. The larger ears of the patients in our study are consistent with those reported by Yan et al. and Ho\u0026apos;s cohort. This phenotype has only been reported in the Chinese population, whether there is a racial difference in the clinical presentation of these larger ears is unknown.\u003c/p\u003e\n\u003cp\u003eIn addition, we also found that in addition to the c.1060+1G\u0026gt;A heterozygous mutation, the patient also had three novel gene mutation sites: the \u003cem\u003eNIPBL\u003c/em\u003e gene c.3130G\u0026gt;A (p.Asp1044Asn), the \u003cem\u003eCNGA1\u003c/em\u003e gene c.568G\u0026gt;T (p.Glu190X), and the \u003cem\u003eFBN2\u003c/em\u003e gene c.5370A\u0026gt;G (p.Ile1790Met). \u003cem\u003eCNGA1\u003c/em\u003e gene is located on chromosome 4p12 and contains 13 Exon. The protein encoded by \u003cem\u003eCNGA1\u003c/em\u003e is involved in K\u003csup\u003e+\u003c/sup\u003e transport, light transduction, visual perception, and response stimulation. This gene is a susceptibility gene for Retinitis pigmentosa (RP), especially for Retinitis pigmentosa Autosome recessive inheritance (ARRP). Its symptoms are mainly chronic progressive visual field loss, night blindness, abnormal electroretinogram, and decreased vision. In the later stages of the disease, central vision loss may occur\u003csup\u003e[26]\u003c/sup\u003e. The ACMG guidelines classify this mutation site as Likely Pathogenic (Table 1). Therefore, it is currently unknown whether the FEVR and other ocular manifestations of this patient have the effect of \u003cem\u003eCNGA1\u003c/em\u003e, and further research is needed to elucidate its specific mechanism.\u003c/p\u003e\n\u003cp\u003eIn this study, we reported a case of FEVR caused by \u003cem\u003eCTNNB1\u0026nbsp;\u003c/em\u003emutation in Chinese Han nationality, which further elucidates that FEVR disease caused by \u003cem\u003eCTNNB1\u003c/em\u003e heterozygous mutation may be related to the loss of Wnt/ \u0026beta;-catenin signaling pathway activity. At the same time, this case also enriched the spectrum of \u003cem\u003eCTNNB1\u003c/em\u003e gene function loss variation in the Chinese population.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe c.1060\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A heterozygous mutation in the \u003cem\u003eCTNNB1\u003c/em\u003e gene can lead to FEVR disease, which expands the spectrum of \u003cem\u003eCTNNB1\u003c/em\u003e gene functional loss mutations in the Chinese population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFEVR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFamilial exudative vitreoretinopathy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cem\u003eCTNNB1\u003c/em\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCatenin beta 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNEDSDV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNeurodevelopmental disorders with spastic diplegia and visual impairment\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDD/ID\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDevelopmental delay/Intellectual delay\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFFA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFundus fluorescein angiography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWES\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWhole exon sequencing\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank all the participants and the staff for their valuable contribution to this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI confirm that the relevant guidelines and regulations performed all methods. The parents of the proband signed an informed consent form. The study was approved by the Ethics Committee of Medical Genetics and Prenatal Diagnosis of Luoyang Maternal and Child Health Hospital. The ethics number is LYFY-YCCZ-2023008.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eObtain the informed consent of the patient and her family, and publish information and images in an online open-access publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analysed during the current study are available in the Genome Sequence Archive for Human repository, and accession number to datasets is HRA005666. It can be accessed from the following link: https://bigd.big.ac.cn/gsa-human/browse/HRA005666.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Department of Genetics and Prenatal Diagnosis of the Luoyang Maternal and Child Health Hospital. The funding agency did not participate in the design or implementation of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eW.Y. brewed and designed experiments, critically reviewed the knowledge content of the article, and obtained research funding. C.Y. and C.Y. performed sequencing and analysis, L.H. and Y.W. prepared figures, Z.W. provides administrative, technical, or material support, and W.Y. and C.Y. wrote the main manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe want to thank all the participants and the staff for contributing to this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYanan Wang (\u003cstrong\u003eCorresponding author; First author\u003c/strong\u003e):\u0026nbsp;Luoyang City;\u0026nbsp;CHINA; Luoyang Maternal and Child Health Hospital; Genetics and Prenatal Diagnosis Department; Chief physician; E-mail: [email protected]\u003c/p\u003e\n\u003cp\u003eYujie Chang:\u0026nbsp;Luoyang City;\u0026nbsp;CHINA; Luoyang Maternal and Child Health Hospital; Genetics and Prenatal Diagnosis Department; E-mail: [email protected]\u003c/p\u003e\n\u003cp\u003eYuqiong Chai: Luoyang City; CHINA; Luoyang Maternal and Child Health Hospital; Genetics and Prenatal Diagnosis Department; E-mail: [email protected]\u003c/p\u003e\n\u003cp\u003eHongtao Lei: Luoyang City; CHINA; Luoyang Maternal and Child Health Hospital; Pediatric Ophthalmology Department; E-mail: [email protected]\u003c/p\u003e\n\u003cp\u003eWeiyan Yan:\u0026nbsp;Luoyang City;\u0026nbsp;CHINA; Luoyang Maternal and Child Health Hospital; Pediatric Ophthalmology Department; E-mail: [email protected]\u003c/p\u003e\n\u003cp\u003eWeiwei Zang:\u0026nbsp;Luoyang City;\u0026nbsp;CHINA; Luoyang Maternal and Child Health Hospital; Genetics and Prenatal Diagnosis Department; E-mail: [email protected]\u003c/p\u003e\n\u003cp\u003eThere is no conflict of interest between the authors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTang H, Li N, Li Z, et al. Fundus examination of 199 851 newborns by digital imaging in China: a multicentre cross-sectional study [J]. Br J Ophthalmol. 2018;102(12):1742\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun W, Xiao X, Li S et al. Pathogenic variants and associated phenotypic spectrum of TSPAN12 based on data from a large cohort [J]. Graefe's Archive for Clinical and Experimental Ophthalmology, 2021, 259(10): 2929\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShukla D, Singh J, Sudheer G, et al. Familial exudative vitreoretinopathy (FEVR). Clinical profile and management [J]. Indian J Ophthalmol. 2003;51(4):323\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Z, Chen C, Sun L et al. Symmetry of folds in FEVR: a genotype-phenotype correlation study [J]. Experimental Eye Research, 2019, 186(107720.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDixon MW, Stem MS, Schuette JL, et al. CTNNB1 mutation associated with familial exudative vitreoretinopathy (FEVR) phenotype [J]. Ophthalmic Genet. 2016;37(4):468\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJoussen A, Gordes R, Heu\u0026szlig;en F, et al. Retinal exudative disease in childhood: Coats' disease and familial exudative vitreoretinopathy (FEVR) [J]. Klin Monbl Augenheilkd. 2013;230(9):902\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoussa RG, Zhao Y, Debenedictis MJ, et al. Novel mutation in CTNNB1 causes familial exudative vitreoretinopathy (FEVR) and microcephaly: case report and review of the literature [J]. Ophthalmic Genet. 2020;41(1):63\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGilmour D. Familial exudative vitreoretinopathy and related retinopathies [J]. Eye. 2015;29(1):1\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Y, Zhang Z, Huang L, et al. Update on the phenotypic and genotypic spectrum of KIF11-Related retinopathy [J]. Genes. 2022;13(4):713.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu H, Zhang S, Huang L, et al. Identification of novel variants in the FZD4 gene associated with familial exudative vitreoretinopathy in Chinese families [J]. Volume 48. Clinical \u0026amp; Experimental Ophthalmology; 2020. pp. 356\u0026ndash;65. 3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeuberger J, Birchmeier W. Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling [J]. Cold Spring Harb Perspect Biol. 2010;2(2):a002915.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClevers H, Nusse R. Wnt/β-catenin signaling and disease [J]. Cell. 2012;149(6):1192\u0026ndash;205.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZechner D, Fujita Y, H\u0026uuml;lsken J, et al. β-Catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system [J]. Dev Biol. 2003;258(2):406\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou Y, Wang Y, Tischfield M, et al. Canonical WNT signaling components in vascular development and barrier formation [J]. J Clin Investig. 2014;124(9):3825\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRossetti LZ, Bekheirnia MR, Lewis AM, et al. Missense variants in CTNNB1 can be associated with vitreoretinopathy\u0026mdash;Seven new cases of CTNNB1-associated neurodevelopmental disorder including a previously unreported retinal phenotype [J]. Volume 9. Molecular Genetics \u0026amp; Genomic Medicine; 2021. p. e1542. 1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Ligt J, Willemsen MH, Van Bon BWM, et al. Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability [J]. N Engl J Med. 2012;367(20):1921\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHo S, Tsang M, H-Y, Fung JL-F, et al. CTNNB1-related neurodevelopmental disorder in a Chinese population: A case series [J]. Am J Med Genet Part A. 2022;188(1):130\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartowicz A, Trusohamn M, Jensen N et al. Endothelial β-catenin signaling supports postnatal brain and retinal angiogenesis by promoting sprouting, tip cell formation, and VEGFR (vascular endothelial growth factor receptor) 2 expression [J]. Arteriosclerosis, thrombosis, and vascular biology, 2019, 39(11): 2273\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTucci V, Kleefstra T, Hardy A, et al. Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features [J]. J Clin Investig. 2014;124(4):1468\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWickham RJ, Alexander JM, Eden LW, et al. Learning impairments and molecular changes in the brain caused by β-catenin loss [J]. Hum Mol Genet. 2019;28(17):2965\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuechler A, Willemsen MH, Albrecht B, et al. De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum [J]. Hum Genet. 2015;134(1):97\u0026ndash;109.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDixon MW, Stem MS, Schuette JL, et al. CTNNB1 mutation associated with familial exudative vitreoretinopathy (FEVR) phenotype [J]. Ophthalmic Genet. 2016;37(4):468\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang H, Zhao Y, Yang L, et al. Identification of a novel splice mutation in CTNNB1 gene in a Chinese family with both severe intellectual disability and serious visual defects [J]. Neurol Sci. 2019;40(8):1701\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi N, Xu Y, Li G, et al. Exome sequencing identifies a de novo mutation of CTNNB1 gene in a patient mainly presented with retinal detachment, lens and vitreous opacities, microcephaly, and developmental delay: Case report and literature review [J]. Med (Baltim). 2017;96(20):e6914.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYan D, Sun Y, Xu N et al. Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants [J]. Molecular Genetics \u0026amp; Genomic Medicine, 2022, 10(11): e2067.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaito K, Gotoh N, Kang I, et al. A case of retinitis pigmentosa homozygous for a rare CNGA1 causal variant [J]. Sci Rep. 2021;11(1):4681.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Detection Results of Gene Mutations.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"585\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.034188034188034%\"\u003e\n \u003cp\u003eGene\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.52991452991453%\"\u003e\n \u003cp\u003eTranscript\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.991452991452991%\"\u003e\n \u003cp\u003eThe location of the genome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.282051282051283%\"\u003e\n \u003cp\u003eZygotic type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.282051282051283%\"\u003e\n \u003cp\u003ePathogenicity rating of ACMG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.034188034188034%\"\u003e\n \u003cp\u003eGenetic mode\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.84615384615385%\"\u003e\n \u003cp\u003eDiseases related to gene mutations\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.034188034188034%\"\u003e\n \u003cp\u003e\u003cem\u003eCTNNB1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.52991452991453%\"\u003e\n \u003cp\u003eNM_001330729\u003c/p\u003e\n \u003cp\u003eExon 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.991452991452991%\"\u003e\n \u003cp\u003echr3:41268844\u003c/p\u003e\n \u003cp\u003ec.1060+1G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.282051282051283%\"\u003e\n \u003cp\u003eHeterozygote\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.282051282051283%\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.034188034188034%\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.84615384615385%\"\u003e\n \u003cp\u003eExudative vitreoretinopathy type 7 (MIM: 617572)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.034188034188034%\"\u003e\n \u003cp\u003e\u003cem\u003eNIPBL\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.52991452991453%\"\u003e\n \u003cp\u003eNM_015384\u003c/p\u003e\n \u003cp\u003eExon 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.991452991452991%\"\u003e\n \u003cp\u003echr5:36995732\u003c/p\u003e\n \u003cp\u003ec.3130G\u0026gt;A\u003c/p\u003e\n \u003cp\u003ep.D1044N\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.282051282051283%\"\u003e\n \u003cp\u003eHeterozygote; Verified; By his father\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.282051282051283%\"\u003e\n \u003cp\u003eUncertain\u003c/p\u003e\n \u003cp\u003esignificance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.034188034188034%\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.84615384615385%\"\u003e\n \u003cp\u003eCornelia de Lange syndrome 1 (MIM: 122470)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.034188034188034%\"\u003e\n \u003cp\u003e\u003cem\u003eCNGA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.52991452991453%\"\u003e\n \u003cp\u003eNM_001142564\u003c/p\u003e\n \u003cp\u003eExon 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.991452991452991%\"\u003e\n \u003cp\u003echr4:47945286\u003c/p\u003e\n \u003cp\u003ec.568G\u0026gt;T\u003c/p\u003e\n \u003cp\u003ep.E190X\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.282051282051283%\"\u003e\n \u003cp\u003eHeterozygote\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.282051282051283%\"\u003e\n \u003cp\u003eLikely pathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.034188034188034%\"\u003e\n \u003cp\u003eunknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.84615384615385%\"\u003e\n \u003cp\u003eRetinitis pigmentosa 49 (MIM: 613756)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.034188034188034%\"\u003e\n \u003cp\u003e\u003cem\u003eFBN2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.52991452991453%\"\u003e\n \u003cp\u003eNM_001999\u003c/p\u003e\n \u003cp\u003eExon 42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.991452991452991%\"\u003e\n \u003cp\u003echr5:127642879\u003c/p\u003e\n \u003cp\u003ec.5370A\u0026gt;G\u003c/p\u003e\n \u003cp\u003ep.I1790M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.282051282051283%\"\u003e\n \u003cp\u003eHeterozygote\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.282051282051283%\"\u003e\n \u003cp\u003eUncertain\u003c/p\u003e\n \u003cp\u003esignificance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.034188034188034%\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.84615384615385%\"\u003e\n \u003cp\u003eContractural arachnodactyly, congenital (MIM: 121050);\u003c/p\u003e\n \u003cp\u003eEarly-onset macular degeneration (MIM: 616118 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eNote:\u003c/strong\u003e AD: Autosomal dominant inheritance; AR: Autosomal recessive inheritance.\u003c/p\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":"Familial exudative vitreoretinopathy, CTNNB1 gene, Heterozygous mutation","lastPublishedDoi":"10.21203/rs.3.rs-3893221/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3893221/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eFamilial exudative vitreoretinopathy (FEVR) is an inherited disorder of retinal vascularization insufficiency caused primarily by genetic mutations. So far, FEVR has been less reported in the Chinese population. This study will provide a case of FEVR due to \u003cem\u003eCTNNB1\u003c/em\u003e splice mutation in a Chinese family, which will be helpful for genetic counseling and clinical diagnosis.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e \u003cp\u003eWe analyzed a case of familial exudative vitreoretinopathy of Chinese Han origin using whole-exome sequencing. The results showed that the patient presents with neurodevelopmental disorders accompanied by spastic diplegia and visual impairment, as well as FEVR. Whole exome sequencing revealed a splicing mutation of c.1060\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A in the \u003cem\u003eCTNNB1\u003c/em\u003e gene of the patient. This may be the reason for the pathogenicity of FEVR observed in this patient. Our analysis indicates that this variant produces a truncated protein that contributes to the development of the disease. Genetic testing confirmed the FEVR diagnosis of patients from the study pedigree.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe c.1060\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A heterozygous mutation in the \u003cem\u003eCTNNB1\u003c/em\u003e gene can lead to FEVR disease, which expands the spectrum of \u003cem\u003eCTNNB1\u003c/em\u003e gene functional loss mutations in the Chinese population.\u003c/p\u003e","manuscriptTitle":"Familial exudative vitreoretinopathy caused by CTNNB1 gene mutation in a Chinese family: A case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-29 20:41:08","doi":"10.21203/rs.3.rs-3893221/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":"47dacee5-9c0c-4e90-b78a-ed2849b328ac","owner":[],"postedDate":"January 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-19T10:18:00+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-29 20:41:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3893221","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3893221","identity":"rs-3893221","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}