Bryant-Li-Bhoj neurodevelopmental syndrome: a case report in China and literature review

Bryant-Li-Bhoj neurodevelopmental syndrome: a case report in China and literature review | 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 Bryant-Li-Bhoj neurodevelopmental syndrome: a case report in China and literature review Ying Wei, Kun Dai, Jinzhi Gao, Ling Chen, Zhihui Rong This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4393513/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 Bryant-Li-Bhoj’s neurodevelopmental syndrome is an extremely rare neurodevelopmental disorder caused by germline variation of the H3-3A or H3-3B gene. Similar reports have not been found in China, and there are only two similar reports in the world. Case presentation: A female child, full-term cesarean section, had intermittent convulsions and feeding difficulties shortly after birth. She had special facial features such as a small jaw, a narrow forehead, and a narrow palatal arch. The skin of the head and neck was loose and redundant. The muscle tone of the limbs was reduced, the primitive reflex was weakened, and hearing and vision were impaired. Genetic testing revealed a heterozygous missense mutation in the H3-3A gene, c.365C > G ( p.P122R ), which indicated the diagnosis of Bryant-Li-Bhoj neurodevelopmental syndrome type 1. The disease is extremely rare and has not been reported in China. Conclusion: The prognosis and progression of Bryant-Li-Bhoj’s neurodevelopmental syndrome are still unknown. Early genetic testing can help make an early diagnosis and clarify the direction of diagnosis and treatment. Bryant-Li-Bhoj neurodevelopmental syndrome h3-3A gene mutations histone case report Background Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) is an extremely rare neurodevelopmental disorder characterized by the generalized developmental delay with impaired mental development, poor or absent language development, and delayed motor development. BRYLIB is an autosomal dominant genetic disease. The disease was first reported by Laura Bryant, Dong Li, and Elizabeth J. Bhoj in 2020, so it was named Bryant-Li-Bhoj neurodevelopmental syndrome after them 1 . The disease is mainly caused by germline mutations in the embryonic H3-3A gene or H3-3B gene, mostly missense mutations. Histone H3.3 encoded by these two genes is the core component of nucleosomes and plays a central role in transcriptional regulation, DNA repair, DNA replication, and chromosome stability. At present, cases of neurodevelopmental syndromes caused by germline variation of the H3-3A or H3-3B gene are extremely rare. Similar reports have not been found in China, and there are only two similar reports in the world 1,2 . Therefore, this paper retrospectively analyzed the clinical data and genetic variation characteristics of a child with BRYLIB diagnosed and treated in Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, and analyzed the literature. Case presentation The child, female, G2P2, was a test-tube baby at 37W + 2 gestation with a birth weight of 3.85kg. She was delivered by cesarean section due to the mother's scar uterus. The amniotic fluid was slightly cloudy at birth, and there were no abnormalities in the umbilical cord and placenta. There was no asphyxia at birth, and the Apgar scores of 1 minute and 5 minutes were 8 points and 9 points. The parents and the first child were healthy, and there was no history of genetic or metabolic diseases or epilepsy in the family. The child was hospitalized in the local neonatal department for intermittent convulsions at the age of 3 days. The local blood routine, C-reactive protein, procalcitonin, liver and kidney function, myocardial enzyme spectrum, electrolyte, coagulation function, urine, and stool routine were normal. The cerebrospinal fluid(CSF) was colorless transparent and clear liquid, in which the number of nucleated cells was 3 * 10 ^ 6/L, the CSF protein was 0.62 g/L, the CSF glucose was 3.17 mmol/L, and the CSF chloride ion was 111.70 mmol/L. There were no abnormalities in the sputum smear, sputum culture, and blood culture. High-throughput sequencing of blood and cerebrospinal fluid were negative. Color Doppler ultrasound of the liver, spleen and bilateral kidneys were normal. Color Doppler echocardiography showed patent ductus arteriosus and patent foramen ovale. Magnetic Resonance Imaging(MRI) plain scan and diffusion-weighted imaging(DWI) of the head suggested the possibility of softening lesions near the anterior horn of bilateral ventricles. Clinical seizures and electrical seizures were only occasionally seen during the first seizure, and no electrical seizures were found in the subsequent multiple reexaminations of video electroencephalogram(EEG). She was given symptomatic and supportive treatment such as nasal catheter oxygen inhalation, anti-infection (ceftazidime + piperacillin-tazobactam), control of convulsions (phenobarbital and levetiracetam), supplementation of high-dose vitamin B6, and mannitol to reduce intracranial pressure. The patient's condition did not improve, and there were still intermittent convulsions. She was transferred to the Department of Neonatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology at 12 days of age. Physical examination showed that the body temperature was 37.3℃, the respiration rate was 56 beats/min, the pulse rate was 150 beats/min, the blood pressure was 76/43 mmHg, and the weight was 4.02kg. She was unresponsive and lethargic, with some special features, such as loose and redundant skin on the head and neck, a slightly narrow forehead on both sides, a small jaw, and a high and narrow palate arch. Her anterior fontanel was about 2.0cm * 2.0cm. The Bilateral pupils were equal and round, sensitive to light reflex. There was no congestion in the pharynx. The breath sounds were coarse in both lungs, and a little phlegm could be heard in both lungs. The heart sounds were vigorous and rhythmic, and no pathological murmurs were heard. The abdomen was flat and soft, the liver and spleen were not palpable under the ribs, and bowel sounds were normal. The limb muscle tension was low, and the original reflex was weakened. Laboratory tests after admission showed normal blood routine, C-reactive protein, procalcitonin, liver and kidney function, myocardial enzymes, electrolytes, urine and stool routine. Blood ammonia, lactate, and pyruvate levels were normal. There was no abnormality in the sputum smear, sputum culture, and blood culture. At 14 days of age, reexamination of the head MRI showed a thin corpus callosum and a softening focus beside the body of the left lateral ventricle. Video EEG showed moderate abnormalities, with two electrical seizures, with a small number of spikes and sharp waves in the bilateral temporal, occipital, and central midline regions. The background maturity of the EEG was also moderately behind the corresponding gestational age. The patient failed binaural otoacoustic emission and auditory brainstem response, did not chase objects. Her neurobehavioral ability assessment was only 24 points, indicating severe neurodevelopmental delay. After admission, the children were treated with nasal catheter oxygen inhalation, nasal feeding tube feeding, oral swallowing function training, strengthening the nursing of turning over and patting back, phenobarbital, vitamin B6, and gradually adding levetiracetam antispasmodic treatment. The child had no convulsions, but still had a poor response, lethargy and progressive reduction of muscle tension. The sucking and swallowing function was slightly improved, and the oral feeding ranged from 10 to 30ml. The remaining milk was still dependent on nasal feeding, and nasal catheter oxygen inhalation was still needed to maintain stable blood oxygen saturation. Finally, the family members of the child requested that the treatment was abandoned and the patient was discharged from the hospital with the signature of the nasal feeding tube, self-made oxygen generator, and monitor due to economic pressure. During hospitalization, in order to find out the cause of the disease, the peripheral blood of the child and his parents were tested by high-precision clinical exome family testing (Guangzhou JiaJian Medical Testing Company, China). Whole exome sequencing was performed on the genomic DNA of the patient and his parents. Based on the next generation sequencing data, point variation, small fragment indels and large fragment copy number variations (CNV) were analyzed. The results showed that the heterozygous mutation of the H3-3A gene, c.365C > G (p.P121R), was detected in the patient, which was a de novo variant in the patient and not carried by his parents. This mutation had been reported in related clinical cases, which was an autosomal dominant inheritance. The clinical manifestations of the patients in the reported case were mainly developmental retardation, epilepsy, etc. After discharge, the patient was followed up by telephone in our department. After nasal feeding, the child had repeated milk reflux and choking and died of cardiac arrest at 39 days of age due to choking asphyxia. Discussion and Conclusions The patient had intermittent convulsions and feeding difficulties soon after birth. He had special facial features such as a small jaw, a narrow forehead, and a narrow palatal arch. The skin of the head and neck was relaxed and redundant, the muscle tension of the limbs was reduced, and the primitive reflex was weakened. The patient failed in bilateral otoacoustic emission and auditory brainstem response, and did not follow up with the target. The neurological behavior ability evaluation was only 24 points, suggesting that the development of the nervous system was seriously backward. Combined with the results of high-precision clinical exome family detection, there was a heterozygous missense mutation of the H3-3A gene, c.365C > G (p.P121R). The diagnosis of Bryant-Li-Bhoj neurodevelopmental syndrome type 1 was clear. The clinical phenotype of Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) is highly variable and is mainly characterized by moderate to severe global developmental delay, accompanied by impaired intellectual development, low or absent language ability, and delayed motor development. Most patients have decreased muscle tone (a few patients have peripheral hypertonia). Common features include abnormal head shape, facial deformity, oculomotor nerve abnormalities, feeding difficulties, and non-specific brain imaging abnormalities. Other features may include hearing impairment, seizures, short stature, and mild bone defects 1 . Bryant-Li-Bhoj’s neurodevelopmental syndrome is divided into two types, type 1 (BRYLIB1) caused by H3F-3A gene mutation, and type 2 ( BRYLIB2 ) caused by H3F-3B gene mutation. There were no significant differences in clinical phenotypes between the two types except for the difference in gene mutation sites. The H3F-3A gene and H3F-3B gene mainly encode a histone, which is the core component of nucleosome 3 . Nucleosome is the basic unit of chromatin, which is composed of the histone octamer and two DNA supercoils wrapped around it. A histone octamer contains four core histones-H2A, H2B, H3, and H4, which are composed of two molecules of the above four histones 4 . DNA connection between nucleosomes is linked by histone H1. Histones are not only structural proteins, but also powerful regulators of almost all cellular functions exhibited by DNA, and play an important role in epigenetic regulation of chromatin compaction, gene transcription, and DNA damage repair. 4,5 . Core and linker histones are affected by a large number of post-translational modifications, which affect chromatin status and DNA stability 6,7 . The H3 histone family includes seven identified human H3 variants: two typical H3.1 and H3.2 proteins, independently replicated H3.3 protein, centromere protein A (CENP-A ), testis-specific histone H3t, and primate-specific histones H3.X and H3.Y 4 . Histone H3 is composed of typical subtypes H3.1 and H3.2. H3.1 and H3.2 can be replaced by multiple H3 variants, such as H3.3. H3.3 is encoded by two genes, H3-3A(also known as H3F3A) and H3-3B(also known as H3F3B), which can encode the same H3.3 protein after intron cleavage in embryos and differentiated cells 3 . Animal studies have shown that knockout of H3F-3A leads to incomplete death of embryos, and surviving animals show reduced growth rate and partial male sterility 8,9 . The phenotype appears to be more severe in the H3F-3B homozygous knockout mice, and simultaneous knockout of two H3F-3B alleles can lead to fetal death before or immediately after delivery 9 . In conclusion, both H3F-3A and H3F-3B deletions lead to premature oocyte death, which further highlights the importance of H3.3 in development 9 . But their effects on human development are not yet fully understood. Recent genome-wide sequencing studies have identified that mutations occurred in both genes encoding H3.3 (H3F3A and B in humans) in several cancers 10 − 12 . H3.3 K27M and G34R/G34V somatic mutations are frequently found in H3F-3A in pediatric glioblastoma. K27M substitutions have also been found in children with thalamic gliomas or pontine-derived gliomas 10 − 12 . The G34W and G34L mutations in the H3F-3A gene are also present in giant cell tumors of the bone, while the K36M mutation in the H3F-3B gene is characteristic of most chondroblastomas 10−12 . The somatic mutation of the H3.3 gene promotes tumorigenesis by interfering with the epigenetic function of H3.3 chromatin, while the effects of germline mutation on human development are still poorly studied. However, studies suggest that genes involved in chromatin regulation and histone remodeling are associated with many multi-system neurodevelopmental syndromes 13 . Neurodevelopmental disorders are clinically and genetically heterogeneous disease that affects about 2% of children and young people 13 . Today, advances in genome-wide high-throughput technologies have accelerated the discovery of genes associated with chromatin dysregulation in Mendelian syndrome 14,15 . Bryant et al. 1 reported that germline mutations in histone 3 family 3A and 3B caused a previously undiscovered neurodegenerative disease in 46 patients. Most individuals had overall developmental delay, accompanied by hypotonia (67%), seizures (50%), short stature (33%), microcephaly (26%), and abnormal brain imaging (73%). Volkan Okur et al. 2 also reported the presence of germline H3F-3A (n = 6) and H3F-3B (n = 6) de novo missense variants in 12 patients, and moderate to severe global developmental delay was also observed in all individuals, often affectting all three major areas of psychomotor development, as well as hypotonia (80%), gait abnormalities (70%), microcephaly (60%), variable structure brain abnormalities (57%) and seizures (40%). The above studies all confirmed that the new variants of H3F-3A and H3F-3B were associated with neurodevelopmental delay, malformation characteristics, and brain structural abnormalities. The variation sites reported so far are shown in Table 1 . Table 1 The reported variant sites. Genes The literature Locus of variation H3F-3A Bryant 1 p.R8S, p.R8G, p.A15G, p.R17G, p.T22I, p.A29T, p.S31F, p.K36E, p.H39Y, p.A114G, p.T45I, p.L61R, p.D77N, p.D81H, p.R83C, p.G90R, p.N108S, p.I112L, p.I112V, p.V117L, p.M120I, p.M120K, p.P121L, p.P121R, p.Q125R, p.R128C H3F-3A Volkan Okur 2 p.R41C, p.Q56K, p.G91R, p.M121I, p.P122L, p.R129H H3F-3B Bryant 1 p.P121R, p.Q125R, p.S146X, p.M120V, p.N108S, p.L48R, p.H39R, p.G34V, p.A29P, p.G13R, p.S10P, p.R8C H3F-3B Volkan Okur 2 p.A8V, p.R9C, p.K10E, p.T23K, p.I52N, p.*137Cext*9 Bryant L, Li D, Cox SG, et al. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients. Sci Adv 2020;6(49). DOI: 10.1126/sciadv.abc9207 . Okur V, Chen Z, Vossaert L, et al. De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities. NPJ Genom Med 2021;6( 1 ):104. DOI: 10.1038/s41525-021-00268-8 . The mutation site identified in this study was also reported in the study of Bryant et al. 1 . In his study, Case 28 also carried a missense mutation of H3F-3A p. P121R, which was characterized by convulsions and feeding difficulties. He had special facial features such as small jaw, narrow forehead and short neck. The skin of the head and neck was redundant, the muscle tension of the limbs was reduced, the primitive reflex was weakened, the hearing and vision were impaired, and the neurobehavioral development was backward. At the age of 8 months, he was still dependent on gastric tube feeding, and often had milk regurgitation, and was still unable to sit alone. The clinical manifestations of the child in this case report were consistent with the above study, but the child died at 39 days of age due to milk choking and family economy. Since Bryant-Li-Bhoj neurodevelopmental syndrome is rarely reported, the current treatment is mainly symptomatic and supportive treatment. The prognosis and whether the neurodevelopmental retardation is progressive are not yet clear. Therefore, more clinical reports and related studies are needed to further confirm. This case remind clinicians that genetic related diseases should be highly suspected when full-term infants have special facial features, feeding difficulties, unexplained convulsions, and developmental lag. Early genetic testing can help make an early diagnosis, guide treatment and prognosis. Abbreviations Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) cerebrospinal fluid(CSF) Magnetic Resonance Imaging(MRI) diffusion-weighted imaging(DWI) electroencephalogram(EEG) copy number variations (CNV) centromere protein A (CENP-A ) Declarations Ethics approval and consent to participate The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. This study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Consent to Participate declaration The patient's father signed an informed consent, agreeing to publish the patient's diagnosis and treatment information in a public journal without revealing his identity, in order to provide research value. Availability of data and materials The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Competing interests The authors have no conflicts of interest to declare. Funding This study was also supported by the Hubei Provincial Science Foundation (WJ2019M125). Authors' contributions ZHR conceived and designed the study. KD had roles in data collection. YW was also responsible for writing and revising the article. JZG and LC were responsible for review and revision. All authors reviewed and revised the manuscript and approved the final version. Acknowledgements Thanks to the family of the patient for their understanding and consent to publish the diagnosis and treatment data of the child. References Bryant L, Li D, Cox SG, et al. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients. Sci Adv. 2020;6(49). 10.1126/sciadv.abc9207 . Okur V, Chen Z, Vossaert L, et al. De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities. NPJ Genom Med. 2021;6(1):104. 10.1038/s41525-021-00268-8 . Filipescu D, Muller S, Almouzni G. Histone H3 variants and their chaperones during development and disease: contributing to epigenetic control. Annu Rev Cell Dev Biol. 2014;30:615–46. 10.1146/annurev-cellbio-100913-013311 . Bano D, Piazzesi A, Salomoni P, et al. The histone variant H3.3 claims its place in the crowded scene of epigenetics. Aging. 2017;9(3):602–14. 10.18632/aging.101194 . Banaszynski LA, Allis CD, Lewis PW. Histone variants in metazoan development. Dev Cell. 2010;19(5):662–74. 10.1016/j.devcel.2010.10.014 . Graff J, Tsai LH. Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci. 2013;14(2):97–111. 10.1038/nrn3427 . Penney J, Tsai LH. Histone deacetylases in memory and cognition. Sci Signal. 2014;7(355):re12. 10.1126/scisignal.aaa0069 . Couldrey C, Carlton MB, Nolan PM, et al. A retroviral gene trap insertion into the histone 3.3A gene causes partial neonatal lethality, stunted growth, neuromuscular deficits, and male sub-fertility in transgenic mice. Hum Mol Genet. 1999;8(13):2489–95. 10.1093/hmg/8.13.2489 . Tang MC, Jacobs SA, Mattiske DM, et al. Contribution of the two genes encoding histone variant h3.3 to viability and fertility in mice. PLoS Genet. 2015;11(2):e1004964. 10.1371/journal.pgen.1004964 . Behjati S, Tarpey PS, Presneau N, et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumors of bone. Nat Genet. 2013;45(12):1479–82. 10.1038/ng.2814 . Wu G, Broniscer A, McEachron TA, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet. 2012;44(3):251–3. 10.1038/ng.1102 . Schwartzentruber J, Korshunov A, Liu XY, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482(7384):226–31. 10.1038/nature10833 . Larizza L, Finelli P. Developmental disorders with intellectual disability driven by chromatin dysregulation: Clinical overlaps and molecular mechanisms. Clin Genet. 2019;95(2):231–40. 10.1111/cge.13365 . Maver A, Cuturilo G, Ruml SJ, et al. Clinical Next Generation Sequencing Reveals an H3F3A Gene as a New Potential Gene Candidate for Microcephaly Associated with Severe Developmental Delay, Intellectual Disability and Growth Retardation. Balkan J Med Genet. 2019;22(2):65–8. 10.2478/bjmg-2019-0028 . Soshnev AA, Josefowicz SZ, Allis CD. Greater Than the Sum of Parts: Complexity of the Dynamic Epigenome. Mol Cell. 2016;62(5):681–94. 10.1016/j.molcel.2016.05.004 . 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-4393513","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":304861032,"identity":"927d1970-1470-4b3c-9b1e-8b08a4848aaa","order_by":0,"name":"Ying Wei","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Wei","suffix":""},{"id":304861034,"identity":"31451426-5085-4efe-a1e2-1704bd317045","order_by":1,"name":"Kun Dai","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Kun","middleName":"","lastName":"Dai","suffix":""},{"id":304861037,"identity":"95f1b281-913a-4c42-9d8f-c1b56726cb1c","order_by":2,"name":"Jinzhi Gao","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Jinzhi","middleName":"","lastName":"Gao","suffix":""},{"id":304861039,"identity":"ba7d8ec7-40ab-4bd7-afa9-eafba7addbef","order_by":3,"name":"Ling Chen","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Ling","middleName":"","lastName":"Chen","suffix":""},{"id":304861040,"identity":"ac41a446-c64d-4a4b-abad-fe6b74d062cc","order_by":4,"name":"Zhihui Rong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYLACxgaJBAZm/scPPhjY2JGihYfNcEZBWjKxWhgSGBh4GKR5PhwCsgkA8/bewy9/7rDIMzjOe8DYxuAAMwP74aMb8GmROXMuzULyjESxwWG+hMc5Bnf4GHjS0m7g0yIhkWNmYNgmkbjhMIOBcY7BM2YGCR4zwloSoVqkLQwOA4OCsBbjBwfBWngMpBmI0sJzxoyxEahl5mG2NMMeg7RkNoJ+Ye8x/vizrS6x7/zhww9+/LGx42c/fAyvFiBgk0DlElAOAswfiFA0CkbBKBgFIxkAALW6ShRMwEvUAAAAAElFTkSuQmCC","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":true,"prefix":"","firstName":"Zhihui","middleName":"","lastName":"Rong","suffix":""}],"badges":[],"createdAt":"2024-05-09 07:52:47","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4393513/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4393513/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58019450,"identity":"55cd9fec-d2c1-4906-8749-dcf42eddb4b4","added_by":"auto","created_at":"2024-06-10 04:45:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":245248,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4393513/v1/c90a4d59-23e2-4151-9619-fee036deb5c1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Bryant-Li-Bhoj neurodevelopmental syndrome: a case report in China and literature review","fulltext":[{"header":"Background","content":"\u003cp\u003eBryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) is an extremely rare neurodevelopmental disorder characterized by the generalized developmental delay with impaired mental development, poor or absent language development, and delayed motor development. BRYLIB is an autosomal dominant genetic disease. The disease was first reported by Laura Bryant, Dong Li, and Elizabeth J. Bhoj in 2020, so it was named Bryant-Li-Bhoj neurodevelopmental syndrome after them\u003csub\u003e1\u003c/sub\u003e. The disease is mainly caused by germline mutations in the embryonic H3-3A gene or H3-3B gene, mostly missense mutations. Histone H3.3 encoded by these two genes is the core component of nucleosomes and plays a central role in transcriptional regulation, DNA repair, DNA replication, and chromosome stability. At present, cases of neurodevelopmental syndromes caused by germline variation of the H3-3A or H3-3B gene are extremely rare. Similar reports have not been found in China, and there are only two similar reports in the world\u003csub\u003e1,2\u003c/sub\u003e. Therefore, this paper retrospectively analyzed the clinical data and genetic variation characteristics of a child with BRYLIB diagnosed and treated in Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, and analyzed the literature.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eThe child, female, G2P2, was a test-tube baby at 37W\u0026thinsp;+\u0026thinsp;2 gestation with a birth weight of 3.85kg. She was delivered by cesarean section due to the mother's scar uterus. The amniotic fluid was slightly cloudy at birth, and there were no abnormalities in the umbilical cord and placenta. There was no asphyxia at birth, and the Apgar scores of 1 minute and 5 minutes were 8 points and 9 points. The parents and the first child were healthy, and there was no history of genetic or metabolic diseases or epilepsy in the family.\u003c/p\u003e \u003cp\u003eThe child was hospitalized in the local neonatal department for intermittent convulsions at the age of 3 days. The local blood routine, C-reactive protein, procalcitonin, liver and kidney function, myocardial enzyme spectrum, electrolyte, coagulation function, urine, and stool routine were normal. The cerebrospinal fluid(CSF) was colorless transparent and clear liquid, in which the number of nucleated cells was 3 * 10 ^ 6/L, the CSF protein was 0.62 g/L, the CSF glucose was 3.17 mmol/L, and the CSF chloride ion was 111.70 mmol/L. There were no abnormalities in the sputum smear, sputum culture, and blood culture. High-throughput sequencing of blood and cerebrospinal fluid were negative. Color Doppler ultrasound of the liver, spleen and bilateral kidneys were normal. Color Doppler echocardiography showed patent ductus arteriosus and patent foramen ovale. Magnetic Resonance Imaging(MRI) plain scan and diffusion-weighted imaging(DWI) of the head suggested the possibility of softening lesions near the anterior horn of bilateral ventricles. Clinical seizures and electrical seizures were only occasionally seen during the first seizure, and no electrical seizures were found in the subsequent multiple reexaminations of video electroencephalogram(EEG). She was given symptomatic and supportive treatment such as nasal catheter oxygen inhalation, anti-infection (ceftazidime\u0026thinsp;+\u0026thinsp;piperacillin-tazobactam), control of convulsions (phenobarbital and levetiracetam), supplementation of high-dose vitamin B6, and mannitol to reduce intracranial pressure. The patient's condition did not improve, and there were still intermittent convulsions. She was transferred to the Department of Neonatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology at 12 days of age.\u003c/p\u003e \u003cp\u003ePhysical examination showed that the body temperature was 37.3℃, the respiration rate was 56 beats/min, the pulse rate was 150 beats/min, the blood pressure was 76/43 mmHg, and the weight was 4.02kg. She was unresponsive and lethargic, with some special features, such as loose and redundant skin on the head and neck, a slightly narrow forehead on both sides, a small jaw, and a high and narrow palate arch. Her anterior fontanel was about 2.0cm * 2.0cm. The Bilateral pupils were equal and round, sensitive to light reflex. There was no congestion in the pharynx. The breath sounds were coarse in both lungs, and a little phlegm could be heard in both lungs. The heart sounds were vigorous and rhythmic, and no pathological murmurs were heard. The abdomen was flat and soft, the liver and spleen were not palpable under the ribs, and bowel sounds were normal. The limb muscle tension was low, and the original reflex was weakened. Laboratory tests after admission showed normal blood routine, C-reactive protein, procalcitonin, liver and kidney function, myocardial enzymes, electrolytes, urine and stool routine. Blood ammonia, lactate, and pyruvate levels were normal. There was no abnormality in the sputum smear, sputum culture, and blood culture. At 14 days of age, reexamination of the head MRI showed a thin corpus callosum and a softening focus beside the body of the left lateral ventricle. Video EEG showed moderate abnormalities, with two electrical seizures, with a small number of spikes and sharp waves in the bilateral temporal, occipital, and central midline regions. The background maturity of the EEG was also moderately behind the corresponding gestational age. The patient failed binaural otoacoustic emission and auditory brainstem response, did not chase objects. Her neurobehavioral ability assessment was only 24 points, indicating severe neurodevelopmental delay.\u003c/p\u003e \u003cp\u003eAfter admission, the children were treated with nasal catheter oxygen inhalation, nasal feeding tube feeding, oral swallowing function training, strengthening the nursing of turning over and patting back, phenobarbital, vitamin B6, and gradually adding levetiracetam antispasmodic treatment. The child had no convulsions, but still had a poor response, lethargy and progressive reduction of muscle tension. The sucking and swallowing function was slightly improved, and the oral feeding ranged from 10 to 30ml. The remaining milk was still dependent on nasal feeding, and nasal catheter oxygen inhalation was still needed to maintain stable blood oxygen saturation. Finally, the family members of the child requested that the treatment was abandoned and the patient was discharged from the hospital with the signature of the nasal feeding tube, self-made oxygen generator, and monitor due to economic pressure.\u003c/p\u003e \u003cp\u003eDuring hospitalization, in order to find out the cause of the disease, the peripheral blood of the child and his parents were tested by high-precision clinical exome family testing (Guangzhou JiaJian Medical Testing Company, China). Whole exome sequencing was performed on the genomic DNA of the patient and his parents. Based on the next generation sequencing data, point variation, small fragment indels and large fragment copy number variations (CNV) were analyzed. The results showed that the heterozygous mutation of the \u003cem\u003eH3-3A\u003c/em\u003e gene, c.365C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.P121R), was detected in the patient, which was a de novo variant in the patient and not carried by his parents. This mutation had been reported in related clinical cases, which was an autosomal dominant inheritance. The clinical manifestations of the patients in the reported case were mainly developmental retardation, epilepsy, etc.\u003c/p\u003e \u003cp\u003eAfter discharge, the patient was followed up by telephone in our department. After nasal feeding, the child had repeated milk reflux and choking and died of cardiac arrest at 39 days of age due to choking asphyxia.\u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003eThe patient had intermittent convulsions and feeding difficulties soon after birth. He had special facial features such as a small jaw, a narrow forehead, and a narrow palatal arch. The skin of the head and neck was relaxed and redundant, the muscle tension of the limbs was reduced, and the primitive reflex was weakened. The patient failed in bilateral otoacoustic emission and auditory brainstem response, and did not follow up with the target. The neurological behavior ability evaluation was only 24 points, suggesting that the development of the nervous system was seriously backward. Combined with the results of high-precision clinical exome family detection, there was a heterozygous missense mutation of the \u003cem\u003eH3-3A\u003c/em\u003e gene, c.365C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.P121R). The diagnosis of Bryant-Li-Bhoj neurodevelopmental syndrome type 1 was clear.\u003c/p\u003e \u003cp\u003eThe clinical phenotype of Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) is highly variable and is mainly characterized by moderate to severe global developmental delay, accompanied by impaired intellectual development, low or absent language ability, and delayed motor development. Most patients have decreased muscle tone (a few patients have peripheral hypertonia). Common features include abnormal head shape, facial deformity, oculomotor nerve abnormalities, feeding difficulties, and non-specific brain imaging abnormalities. Other features may include hearing impairment, seizures, short stature, and mild bone defects \u003csub\u003e1\u003c/sub\u003e. Bryant-Li-Bhoj\u0026rsquo;s neurodevelopmental syndrome is divided into two types, type 1 (BRYLIB1) caused by \u003cem\u003eH3F-3A\u003c/em\u003e gene mutation, and type 2 ( BRYLIB2 ) caused by \u003cem\u003eH3F-3B\u003c/em\u003e gene mutation. There were no significant differences in clinical phenotypes between the two types except for the difference in gene mutation sites.\u003c/p\u003e \u003cp\u003eThe H3F-3A gene and H3F-3B gene mainly encode a histone, which is the core component of nucleosome \u003csub\u003e3\u003c/sub\u003e. Nucleosome is the basic unit of chromatin, which is composed of the histone octamer and two DNA supercoils wrapped around it. A histone octamer contains four core histones-H2A, H2B, H3, and H4, which are composed of two molecules of the above four histones\u003csub\u003e4\u003c/sub\u003e. DNA connection between nucleosomes is linked by histone H1. Histones are not only structural proteins, but also powerful regulators of almost all cellular functions exhibited by DNA, and play an important role in epigenetic regulation of chromatin compaction, gene transcription, and DNA damage repair.\u003csub\u003e4,5\u003c/sub\u003e. Core and linker histones are affected by a large number of post-translational modifications, which affect chromatin status and DNA stability\u003csub\u003e6,7\u003c/sub\u003e.\u003c/p\u003e \u003cp\u003eThe H3 histone family includes seven identified human H3 variants: two typical H3.1 and H3.2 proteins, independently replicated H3.3 protein, centromere protein A (CENP-A ), testis-specific histone H3t, and primate-specific histones H3.X and H3.Y\u003csub\u003e4\u003c/sub\u003e. Histone H3 is composed of typical subtypes H3.1 and H3.2. H3.1 and H3.2 can be replaced by multiple H3 variants, such as H3.3. H3.3 is encoded by two genes, H3-3A(also known as H3F3A) and H3-3B(also known as H3F3B), which can encode the same H3.3 protein after intron cleavage in embryos and differentiated cells\u003csub\u003e3\u003c/sub\u003e.\u003c/p\u003e \u003cp\u003eAnimal studies have shown that knockout of H3F-3A leads to incomplete death of embryos, and surviving animals show reduced growth rate and partial male sterility \u003csub\u003e8,9\u003c/sub\u003e. The phenotype appears to be more severe in the H3F-3B homozygous knockout mice, and simultaneous knockout of two H3F-3B alleles can lead to fetal death before or immediately after delivery\u003csub\u003e9\u003c/sub\u003e. In conclusion, both H3F-3A and H3F-3B deletions lead to premature oocyte death, which further highlights the importance of H3.3 in development\u003csub\u003e9\u003c/sub\u003e. But their effects on human development are not yet fully understood.\u003c/p\u003e \u003cp\u003eRecent genome-wide sequencing studies have identified that mutations occurred in both genes encoding H3.3 (H3F3A and B in humans) in several cancers\u003csub\u003e10\u0026thinsp;\u0026minus;\u0026thinsp;12\u003c/sub\u003e. H3.3 K27M and G34R/G34V somatic mutations are frequently found in H3F-3A in pediatric glioblastoma. K27M substitutions have also been found in children with thalamic gliomas or pontine-derived gliomas\u003csub\u003e10\u0026thinsp;\u0026minus;\u0026thinsp;12\u003c/sub\u003e. The G34W and G34L mutations in the H3F-3A gene are also present in giant cell tumors of the bone, while the K36M mutation in the H3F-3B gene is characteristic of most chondroblastomas \u003csub\u003e10\u0026minus;12\u003c/sub\u003e. The somatic mutation of the H3.3 gene promotes tumorigenesis by interfering with the epigenetic function of H3.3 chromatin, while the effects of germline mutation on human development are still poorly studied.\u003c/p\u003e \u003cp\u003eHowever, studies suggest that genes involved in chromatin regulation and histone remodeling are associated with many multi-system neurodevelopmental syndromes\u003csub\u003e13\u003c/sub\u003e. Neurodevelopmental disorders are clinically and genetically heterogeneous disease that affects about 2% of children and young people\u003csub\u003e13\u003c/sub\u003e. Today, advances in genome-wide high-throughput technologies have accelerated the discovery of genes associated with chromatin dysregulation in Mendelian syndrome \u003csub\u003e14,15\u003c/sub\u003e. Bryant et al.\u003csub\u003e1\u003c/sub\u003e reported that germline mutations in histone 3 family 3A and 3B caused a previously undiscovered neurodegenerative disease in 46 patients. Most individuals had overall developmental delay, accompanied by hypotonia (67%), seizures (50%), short stature (33%), microcephaly (26%), and abnormal brain imaging (73%). Volkan Okur et al.\u003csub\u003e2\u003c/sub\u003e also reported the presence of germline H3F-3A (n\u0026thinsp;=\u0026thinsp;6) and H3F-3B (n\u0026thinsp;=\u0026thinsp;6) de novo missense variants in 12 patients, and moderate to severe global developmental delay was also observed in all individuals, often affectting all three major areas of psychomotor development, as well as hypotonia (80%), gait abnormalities (70%), microcephaly (60%), variable structure brain abnormalities (57%) and seizures (40%). The above studies all confirmed that the new variants of H3F-3A and H3F-3B were associated with neurodevelopmental delay, malformation characteristics, and brain structural abnormalities. The variation sites reported so far are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe reported variant sites.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThe literature\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLocus of variation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH3F-3A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBryant\u003csub\u003e1\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep.R8S, p.R8G, p.A15G, p.R17G, p.T22I, p.A29T, p.S31F, p.K36E, p.H39Y, p.A114G, p.T45I, p.L61R, p.D77N, p.D81H, p.R83C, p.G90R, p.N108S, p.I112L, p.I112V, p.V117L, p.M120I, p.M120K, p.P121L, p.P121R, p.Q125R, p.R128C\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH3F-3A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVolkan Okur\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep.R41C, p.Q56K, p.G91R, p.M121I, p.P122L, p.R129H\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH3F-3B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBryant\u003csub\u003e1\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep.P121R, p.Q125R, p.S146X, p.M120V, p.N108S, p.L48R, p.H39R, p.G34V, p.A29P, p.G13R, p.S10P, p.R8C\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eH3F-3B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVolkan Okur\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep.A8V, p.R9C, p.K10E, p.T23K, p.I52N, p.*137Cext*9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e Bryant L, Li D, Cox SG, et al. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients. Sci Adv 2020;6(49). DOI: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1126/sciadv.abc9207\u003c/span\u003e\u003cspan address=\"10.1126/sciadv.abc9207\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eOkur V, Chen Z, Vossaert L, et al. De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities. NPJ Genom Med 2021;6(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e):104. DOI: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41525-021-00268-8\u003c/span\u003e\u003cspan address=\"10.1038/s41525-021-00268-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eThe mutation site identified in this study was also reported in the study of Bryant et al. \u003csub\u003e1\u003c/sub\u003e. In his study, Case 28 also carried a missense mutation of H3F-3A p. P121R, which was characterized by convulsions and feeding difficulties. He had special facial features such as small jaw, narrow forehead and short neck. The skin of the head and neck was redundant, the muscle tension of the limbs was reduced, the primitive reflex was weakened, the hearing and vision were impaired, and the neurobehavioral development was backward. At the age of 8 months, he was still dependent on gastric tube feeding, and often had milk regurgitation, and was still unable to sit alone. The clinical manifestations of the child in this case report were consistent with the above study, but the child died at 39 days of age due to milk choking and family economy.\u003c/p\u003e \u003cp\u003eSince Bryant-Li-Bhoj neurodevelopmental syndrome is rarely reported, the current treatment is mainly symptomatic and supportive treatment. The prognosis and whether the neurodevelopmental retardation is progressive are not yet clear. Therefore, more clinical reports and related studies are needed to further confirm. This case remind clinicians that genetic related diseases should be highly suspected when full-term infants have special facial features, feeding difficulties, unexplained convulsions, and developmental lag. Early genetic testing can help make an early diagnosis, guide treatment and prognosis.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB)\u003c/p\u003e\n\u003cp\u003ecerebrospinal fluid(CSF)\u003c/p\u003e\n\u003cp\u003eMagnetic Resonance Imaging(MRI)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ediffusion-weighted imaging(DWI)\u003c/p\u003e\n\u003cp\u003eelectroencephalogram(EEG)\u003c/p\u003e\n\u003cp\u003ecopy number variations (CNV)\u003c/p\u003e\n\u003cp\u003ecentromere protein A (CENP-A )\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. This study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent to Participate declaration\u003c/p\u003e\n\u003cp\u003eThe patient\u0026apos;s father signed an informed consent, agreeing to publish the patient\u0026apos;s diagnosis and treatment information in a public journal without revealing his identity, in order to provide research value.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis study was also supported by the Hubei Provincial Science Foundation (WJ2019M125).\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eZHR conceived and designed the study. KD had roles in data collection. YW was also responsible for writing and revising the article. JZG and LC were responsible for review and revision. All authors reviewed and revised the manuscript and approved the final version.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eThanks to the family of the patient for their understanding and consent to publish the diagnosis and treatment data of the child.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBryant L, Li D, Cox SG, et al. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients. 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Mol Cell. 2016;62(5):681\u0026ndash;94. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.molcel.2016.05.004\u003c/span\u003e\u003cspan address=\"10.1016/j.molcel.2016.05.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"Bryant-Li-Bhoj neurodevelopmental syndrome, h3-3A gene, mutations, histone, case report","lastPublishedDoi":"10.21203/rs.3.rs-4393513/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4393513/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e Bryant-Li-Bhoj’s neurodevelopmental syndrome is an extremely rare neurodevelopmental disorder caused by germline variation of the H3-3A or H3-3B gene. Similar reports have not been found in China, and there are only two similar reports in the world.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation:\u003c/strong\u003e A female child, full-term cesarean section, had intermittent convulsions and feeding difficulties shortly after birth. She had special facial features such as a small jaw, a narrow forehead, and a narrow palatal arch. The skin of the head and neck was loose and redundant. The muscle tone of the limbs was reduced, the primitive reflex was weakened, and hearing and vision were impaired. Genetic testing revealed a heterozygous missense mutation in the H3-3A gene, c.365C \u0026gt; G ( p.P122R ), which indicated the diagnosis of Bryant-Li-Bhoj neurodevelopmental syndrome type 1. The disease is extremely rare and has not been reported in China.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e The prognosis and progression of Bryant-Li-Bhoj’s neurodevelopmental syndrome are still unknown. Early genetic testing can help make an early diagnosis and clarify the direction of diagnosis and treatment.\u003c/p\u003e","manuscriptTitle":"Bryant-Li-Bhoj neurodevelopmental syndrome: a case report in China and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-22 11:29:33","doi":"10.21203/rs.3.rs-4393513/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":"fd046255-c5ae-4f0d-8a09-62affed8ca67","owner":[],"postedDate":"May 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-10T04:37:24+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-22 11:29:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4393513","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4393513","identity":"rs-4393513","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}