A Novel Mutation of NONO-Associated X-linked Syndromic Intellectual Developmental Disorder-34 in a Fetus

A Novel Mutation of NONO-Associated X-linked Syndromic Intellectual Developmental Disorder-34 in a Fetus | 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 A Novel Mutation of NONO-Associated X-linked Syndromic Intellectual Developmental Disorder-34 in a Fetus Ruchun Huang, Siqi Wu, Hongke Ding, Liping Wu, Huichun Pi, Weiqiang Liu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4348501/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 The NONO gene is located on chromosome Xq13.1 and encodes a nuclear protein involved in RNA synthesis, transcriptional regulation, and DNA repair. Hemizygous loss-of-function variants in NONO reportedly cause X-linked syndromic intellectual developmental disorder-34 (MRXS34) in males. At present, there are few clinical reports related to MRXS34, and the mutation spectrum of NONO-related diseases has not been completely determined. Methods We report the case of a fetus with noncompaction cardiomyopathy, a short anteroposterior diameter of the corpus callosum and relative macrocephaly. Genotyping examination, including chromosome microarray analysis (CMA) and trio-medical exon sequencing, was performed. Results Medical exon sequencing revealed a de novo hemizygous nonsense mutation (c.214 C > T, p.Gln72Ter) in exon 4 of the NONO gene. A review of previous literature suggested that noncompaction cardiomyopathy, abnormalities of the corpus callosum, and macrocephaly are consistent phenotypes of MRXS34. Conclusion The mutation (c.214 C > T, p.Gln72Ter) in the NONO gene was present in a fetus with MRXS34. This study expands the mutation spectrum of NONO-related diseases and enlarges noncompaction cardiomyopathy, abnormalities of the corpus callosum and macrocephaly to the phenotype of MRXS34 in fetuses. noncompaction cardiomyopathy NONO X-linked syndromic intellectual developmental disorder-34 (MRXS34) exome sequencing Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Hemizygous loss-of-function variants in the non-POU domain-containing octamer-binding gene ( NONO ) cause X-linked syndromic intellectual developmental disorder-34 (MRXS34; OMIM 300967). MRXS34 was first described as an X-linked recessive disorder in 2015 by Mircsof et al. (Mircsof et al., 2015), and to date, more than 30 male patients have been reported[ 1 – 7 ]. These patients are characterized by intellectual developmental disorders, delayed language development, special facial features, feeding difficulties, and brain anomalies, including an abnormal corpus callosum, relative macrocephaly/macrocephaly, congenital heart defects (CHDs) and cardiomyopathy, such as left ventricular noncompaction cardiomyopathy (LVNC). Seven male fetuses with cardiac anomalies, including LVNC, carrying loss-of-function variants in NONO have also been described [ 5 , 6 ]. However, there is a lack of information on the intrauterine phenotypes and spectra of NONO-related MRXS34. Here, we report a fetus with noncompaction cardiomyopathy, a short anteroposterior diameter of the corpus callosum and relative macrocephaly carrying a de novo and novel hemizygous mutation in NONO. Our report expands the mutation spectrum of NONO and the phenotypes of MRXS34 in fetuses. CLINICAL REPORT A 42-year-old multipara was transferred to our department for prenatal ultrasound at 26 gestational weeks due to fetal cardiac heart problems. The woman gave birth to a healthy baby with no unfavorable pregnancy history, and there was no drug use during pregnancy. The couple was not biologically related and healthy, with no family history. A detailed prenatal ultrasound diagnosis revealed noncompaction cardiomyopathy, mild ventriculomegaly (10 millimeters) and relative macrocephaly (95th percentile) (Fig. 1 ). Consistent with the prenatal sonographic findings, fetal echocardiography revealed noncompaction cardiomyopathy involving both the left and right ventricles. Myocardial thickening was characterized by both apical involvement and pathologically prominent trabeculations and demonstrated a typical honeycombing appearance. Magnetic resonance imaging (MRI) revealed mild ventriculomegaly (10.6 mm) and a short anteroposterior diameter of the corpus callosum (the ratio between the corpus callosum length and the internal cranial occipitofrontal dimension (CC/ICOFD) = 0.3) (Fig. 2 ). After receiving detailed genetic counseling and informed consent, the couple decided to receive genetic testing. The amniotic fluid was obtained from the women by amniocentesis. Genomic DNA was extracted from amniotic fluid specimens and parental peripheral blood lymphocyte specimens for chromosomal microarray analysis and trio-medical exome sequencing. Chromosomal microarray analysis revealed any chromosomal copy number abnormalities. Sequencing was performed using the HiSeq2000 sequencing system (Illumina, Inc., San Diego, CA). Medical exome sequencing revealed 4,000 clinical pathogenic genes with known functions, which included 50,584 coding regions and 8,421,879 base pairs. The average sequencing depth was greater than 100-fold, and the highest sequencing depth was 200-fold. A coverage interval greater than 10-fold accounted for 98.9% of the pathogenic genes, and coverage greater than 20-fold accounted for 98.5% of the pathogenic genes. The pathogenicity of variants was classified according to the American College of Medical Genetics and Genomics guidelines[ 8 ]. The constructed genome was referred to as hg19/GRch37. A de novo hemizygous mutation (NM_007363.5: c.214C > T, p.Gln72Ter) in NONO was found. Sanger sequencing of the PCR products of the proband confirmed the de novo mutation c.214C > T (p.Gln72Ter) in exon 4 (Fig. 3 A), which could lead to protein truncation. This nonsense mutation was not registered in the dbSNP150, 1000 Genomes Project or Human Genetic Variation Database and was not detected in 3000 Chinese Han control subjects in our local variant database (which was derived from an exome-sequencing experiment), suggesting that it was not a polymorphism. The mutation was not detected in the couples. The couple chose to terminate the pregnancy, but unfortunately, they refused to autopsy the fetus for personal reasons. DISCUSSION This study describes a fetus with noncompaction cardiomyopathy, a short anteroposterior diameter of the corpus callosum and relative macrocephaly that carried a nonsense mutation in exon 4 of the NONO gene (NM_007363.5:c.214C > T; p.Gln72Ter). This de novo mutation has not been previously reported as pathogenic or benign and has not been detected in the general population (dbSNP150, 1000 Genomes Project, gnomAD). A literature review revealed that phenotypes, including noncompaction cardiomyopathy, abnormalities of the corpus callosum and macrocephaly, are consistent features of MRXS34. This mutation turned the 72nd Gln into a stop codon. The loss of protein from this allele was expected to occur through nonsense-mediated mRNA decay. Therefore, we classified this mutation in NONO as pathogenic according to the American College of Medical Genetics and Genomics guidelines[ 8 ]. Loss-of-function variants in NONO might predispose males to CHD and LVNC. The gene had a haploinsufficiency index of 4.11 according to DECIPHER, and the probability of loss-of-function intolerance (pLI) was 0.99 according to GnomAD. We report a fetus with a de novo mutation, c.214C > T, p.Gln72Ter, which was classified as pathogenic and predicted to undergo nonsense-mediated mRNA decay, ultimately leading to loss of function in NONO. In addition, noncompaction cardiomyopathy involving both the left and right ventricles was the only cardiac phenotype in this patient. LVNC was the most common cardiac phenotype. We also found that LVNC is diagnosed early in almost all individuals (Table 1 ): six individuals who were pregnant, including the fetus we reported[ 6 ], four individuals who were in the neonatal period[ 3 , 5 ], and three individuals who were in infancy[ 2 , 4 , 9 ], indicating that LVNC is an early clue for diagnosing MRXS34 and emphasizing the importance of fetal echocardiography for identifying cardiac structural anomalies in NONO-related fetuses. Table 1 Craniocerebral and cardiomyopathy of fetuses with NONO mutations. Study, patient identifier, age NONO variant (NM_001145408.2), inheritance age at diagnosis Brain anomalies Macrocephaly (relative or + 2 SD) Cardiomyopathy Sewani et al ., S3, 2019 c.457C > T, p.(Arg153*), de novo prenatal (16 weeks gestation) ND ND Cardiomegaly Sun et al., S(A1), 2020 c.246_249del, p.Pro83Thrfs*7 prenatal ND ND LVNC Sun et al., S(A2), 2020 c.246_249del, p.Pro83Thrfs*7 prenatal ND ND LVNC Sun et al., S(A3), 2020 c.246_249del, p.Pro83Thrfs*7 prenatal ND ND LVNC Sun et al., S(B1), 2020 c.471del, p.Gln157Hisfs*18 prenatal dysplasia of the corpus callosum ND LVNC Sun et al., S(B2), 2020 c.471del, p.Gln157Hisfs*18 prenatal ND ND LVNC Sun et al.,S1, 2020 c.154 + 9A > G, p.Asn52Serfs*3 prenatal (26 week gestation) ND ND ND This study,S1,2022 C.214C > T, p.Gln75Ter prenatal (30 week gestation) Short anteroposterior diameter of corpus callosum, mild ventriculomegaly relative macrocephaly Myocardial thickening, ventricular noncompaction of myocardium Abbreviations: LVNC, left ventricular noncompaction; ND, not determined/not reported; S, subject. In addition to congenital heart defects and LVNC, minor cerebral structural anomalies and intellectual developmental disorders are other symptoms in male patients with loss-of-function mutations in NONO. Brain MRI of male patients with NONO mutations may indicate abnormalities of the corpus callosum, the most common phenotype. However, based on a review of the literature by Roessler et al.[ 7 ], among nine MRXS34 patients for whom antenatal ultrasound data were available, eight were diagnosed with corpus callosum agenesis (CCA) postnatally. However, prenatal diagnosis of CCA was made in only four patients out of the night patients with postnatal diagnosis of CCA. This means that the CCA is missed prenatally in nearly half of patients, which is limited by the use of prenatal ultrasound and the proficiency of sonographers. For evaluating brain development, prenatal ultrasound can only assess intracranial structures and morphology[ 10 ] but cannot detect functional abnormalities, including mental retardation, psychomotor development delay, and speech impediment, which are characterized phenotypes of MRXS34[ 1 ]. Indeed, prenatal cranial MRI provides clearer visualization of intracranial structures and improves the diagnosis of neurological abnormalities such as CCA[ 11 ]. MRI revealed that the corpus callosum was abnormal in our patient. Therefore, this study emphasizes the role of prenatal MRI for the identification of CCA in patients with MRXS34. In addition, macrocephaly or relative macrocephaly (relative or + 2 SD) is another common feature. Macrocephaly or relative macrocephaly was observed in 10 (91%) of the 11 male patients. One of the males with macrocephaly was reported to have undergone multiple prenatal ultrasound examinations during pregnancy[ 5 ]. This suggests that the proportion of mothers with this phenotype appearing before childbirth is relatively small. However, in regard to fetal macrocephaly in the prenatal setting, in addition to MRXS34, Beckwith-Wiedemann syndrome, which is a rare overgrowth syndrome manifesting as macrocephaly, needs to be excluded[ 12 ]. Surprisingly, prenatal intrauterine growth restriction (IUGR) with or without short long bones was found in 6 MRXS34 patients (75%)[ 7 ], stressing the significance of biological measurements for prenatal diagnosis of MRXS34. Moreover, IUGR, which is caused by multiple factors, such as placental and maternal factors, as well as genetic factors, such as aneuploidy, pathogenic copy number variation, and monogenic genetic diseases, is not uncommon in prenatal diagnosis[ 13 ]. Moreover, supravalvular stenosis and intrauterine growth restriction are features of 7q11.23 microdeletion syndrome[ 14 ]. It is very interesting to investigate the contribution of phenotypic associations such as LNVC or CCA with FGR to the prenatal diagnosis of MRXS34. This study has several limitations. The fetus is most likely to have MRXS34 according to its NONO mutation and the phenotypes of noncompaction cardiomyopathy, relative macrocephaly and short anteroposterior diameter of the corpus callosum, but we cannot confirm whether the mild ventriculomegaly revealed by prenatal ultrasound diagnosis and MRI is related to MRXS34. In addition, we cannot determine microsturctural abnormalities using prenatal ultrasound and fetal MRI, and some phenotypes, especially intellectual developmental disorders, cannot be evaluated before delivery. Therefore, even if the fetus has the brain phenotype of relative acrocephaly, an abnormal corpus callosum and mild ventriculomegaly, we cannot determine whether the fetus would have an intellectual developmental disorder of MRXS34 after birth. The fetus was identified as having a de novo mutation in NONO, but maternal germline mosaicism cannot be excluded. CONCLUSION We identified a novel causative NONO mutation, c.214C > T (p.Gln72Ter), in a fetus with MRXS34. Our findings expand the NONO mutation spectrum of MRXS34 and further expand noncompaction cardiomyopathy, abnormalities of the corpus callosum and macrocephaly to the phenotype of MRXS34 in fetuses. Declarations Data availability statement Data sharing: no additional data available. ETHICS STATEMENT The studies involving human participants were reviewed and approved by The ethics committee of Longgang District Maternity＆Child Healthcare Hospital of Shenzhen City. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. AUTHOR CONTRIBUTIONS All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. INSTITUTIONAL REVIEW BOARD STATEMENT The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Longgang District Maternity＆Child Healthcare Hospital of Shenzhen City with approval code LGFYYXLLL-2020-002. FUNDING This study was supported (or partially supported) by Shenzhen Longgang District Science and Technology Innovation Bureau (LGKCYLWS2023016). ACKNOWLEDGMENTS The authors kindly acknowledge the participation of the family members and the staff members in the Prenatal Diagnosis Center of Longgang District Maternity＆Child Healthcare Hospital of Shenzhen City, Guangdong Province, China. The authors would also like to thank the Genome Aggregation database (gnomAD) for providing genome variant data. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References Mircsof D, Langouët M, Rio M, Moutton S, Siquier-Pernet K, Bole-Feysot C, Cagnard N, Nitschke P, Gaspar L, Žnidarič M, et al. Mutations in NONO lead to syndromic intellectual disability and inhibitory synaptic defects. Nat Neurosci. 2015;18(12):1731–6. Reinstein E, Tzur S, Cohen R, Bormans C, Behar DM. Intellectual disability and non-compaction cardiomyopathy with a de novo NONO mutation identified by exome sequencing. Eur J Hum genetics: EJHG. 2016;24(11):1635–8. Scott DA, Hernandez-Garcia A, Azamian MS, Jordan VK, Kim BJ, Starkovich M, Zhang J, Wong LJ, Darilek SA, Breman AM, et al. Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO. J Med Genet. 2017;54(1):47–53. Carlston CM, Bleyl SB, Andrews A, Meyers L, Brown S, Bayrak-Toydemir P, Bale JF, Botto LD. Expanding the genetic and clinical spectrum of the NONO-associated X-linked intellectual disability syndrome. Am J Med Genet Part A. 2019;179(5):792–6. Sewani M, Nugent K, Blackburn PR, Tarnowski JM, Hernandez-Garcia A, Amiel J, Whalen S, Keren B, Courtin T, Rosenfeld JA, et al. Further delineation of the phenotypic spectrum associated with hemizygous loss-of-function variants in NONO. Am J Med Genet Part A. 2020;182(4):652–8. Sun H, Hao X, Wang X, Zhou X, Zhang Y, Liu X, Han J, Gu X, Sun L, Zhao Y, et al. Genetics and Clinical Features of Noncompaction Cardiomyopathy in the Fetal Population. Front Cardiovasc Med. 2020;7:617561. Roessler F, Beck AE, Susie B, Tobias B, Begtrup A, Biskup S, Caluseriu O, Delanty N, Fröhlich C, Gtrureally MT, et al. Genetic and phenotypic spectrum in the NONO-associated syndromic disorder. Am J Med Genet Part A. 2023;191(2):469–78. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet medicine: official J Am Coll Med Genet. 2015;17(5):405–24. Coetzer KC, Moosa S. Novel hemizygous loss-of-function variant in NONO identified in a South African boy. Am J Med Genet Part A. 2022;188(1):373–6. Rosenbloom JI, Yaeger LH, Porat S. Reference Ranges for Corpus Callosum and Cavum Septi Pellucidi Biometry on Prenatal Ultrasound: Systematic Review and Meta-Analysis. J ultrasound medicine: official J Am Inst Ultrasound Med. 2022;41(9):2135–48. Pugash D, Brugger PC, Bettelheim D, Prayer D. Prenatal ultrasound and fetal MRI: the comparative value of each modality in prenatal diagnosis. Eur J Radiol. 2008;68(2):214–26. Gai S, Wang L, Zheng W. Comparison of prenatal ultrasound with MRI in the evaluation and prediction of fetal orofacial clefts. BMC Med Imaging. 2022;22(1):213. Nardozza LM, Caetano AC, Zamarian AC, Mazzola JB, Silva CP, Marçal VM, Lobo TF, Peixoto AB. Araujo Júnior E: Fetal growth restriction: current knowledge. Arch Gynecol Obstet. 2017;295(5):1061–77. Yuan M, Deng L, Yang Y, Sun L. Intrauterine phenotype features of fetuses with Williams-Beuren syndrome and literature review. Ann Hum Genet. 2020;84(2):169–76. Additional Declarations No competing interests reported. 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. 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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-4348501","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":299513335,"identity":"e9609906-0f3b-4232-a9eb-8e1fa6293c27","order_by":0,"name":"Ruchun Huang","email":"","orcid":"","institution":"Longgang District Maternity \u0026 Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical 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10:57:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4348501/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4348501/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56196513,"identity":"d603e506-0682-4798-be3e-e6496f137a31","added_by":"auto","created_at":"2024-05-09 18:10:59","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":42172,"visible":true,"origin":"","legend":"\u003cp\u003eDetailed prenatal ultrasound revealed noncompaction cardiomyopathy (A), mild ventriculomegaly of the left ventricle (10 millimeters) (B) and relative macrocephaly (95th percentile) (C).\u003c/p\u003e\n\u003cp\u003e(A) The echocardiographic findings were consistent with the prenatal ultrasound diagnosis of noncompaction cardiomyopathy involving both the left and right ventricles. Myocardial thickening was characterized by both apical involvement and pathologically prominent trabeculations and demonstrated a typical honeycombing appearance.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4348501/v1/a072a6bcb5e72a147b3f8d34.jpeg"},{"id":56196409,"identity":"082b2b7a-5ae2-4380-84ea-995be25995bc","added_by":"auto","created_at":"2024-05-09 18:10:20","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":35597,"visible":true,"origin":"","legend":"\u003cp\u003eMagnetic resonance imaging (MRI) revealed mild ventriculomegaly (10.6 mm) (A). Short anteroposterior diameter of the corpus callosum (the ratio between the corpus callosum length and the internal cranial occipitofrontal dimension (CC/ICOFD) = 0.3) (B)\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4348501/v1/8544398233f01c17768c1784.jpeg"},{"id":56196441,"identity":"c1089f17-f0de-48df-9d9e-7ca3f658e1de","added_by":"auto","created_at":"2024-05-09 18:10:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":300005,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e: Trio-medical exome sequence identified a de novo and hemizygous nonsense mutation (c.214 C\u0026gt;T, p.Gln72Ter) in exon 4 of the NONO gene. \u003cstrong\u003eB\u003c/strong\u003e: Sanger sequencing of the \u003cem\u003eNONO\u003c/em\u003e gene (reference cDNA sequence, NM_007363.5) revealed that the proband had the de novo mutation c.214C\u0026gt;T in exon 4, and the proband’s father and mother were negative for this mutation.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4348501/v1/964b4ca116c2264456690163.png"},{"id":59998255,"identity":"3fb5c12e-f164-455b-8b7c-bade7ab71d70","added_by":"auto","created_at":"2024-07-10 10:01:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":667248,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4348501/v1/d476f4c8-c32a-4d5f-8aa7-e556b9f5ef06.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Novel Mutation of NONO-Associated X-linked Syndromic Intellectual Developmental Disorder-34 in a Fetus","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eHemizygous loss-of-function variants in the non-POU domain-containing octamer-binding gene (\u003cem\u003eNONO\u003c/em\u003e) cause X-linked syndromic intellectual developmental disorder-34 (MRXS34; OMIM 300967). MRXS34 was first described as an X-linked recessive disorder in 2015 by Mircsof et al. (Mircsof et al., 2015), and to date, more than 30 male patients have been reported[\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. These patients are characterized by intellectual developmental disorders, delayed language development, special facial features, feeding difficulties, and brain anomalies, including an abnormal corpus callosum, relative macrocephaly/macrocephaly, congenital heart defects (CHDs) and cardiomyopathy, such as left ventricular noncompaction cardiomyopathy (LVNC). Seven male fetuses with cardiac anomalies, including LVNC, carrying loss-of-function variants in \u003cem\u003eNONO\u003c/em\u003e have also been described [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, there is a lack of information on the intrauterine phenotypes and spectra of NONO-related MRXS34. Here, we report a fetus with noncompaction cardiomyopathy, a short anteroposterior diameter of the corpus callosum and relative macrocephaly carrying a de novo and novel hemizygous mutation in NONO. Our report expands the mutation spectrum of NONO and the phenotypes of MRXS34 in fetuses.\u003c/p\u003e"},{"header":"CLINICAL REPORT","content":"\u003cp\u003eA 42-year-old multipara was transferred to our department for prenatal ultrasound at 26 gestational weeks due to fetal cardiac heart problems. The woman gave birth to a healthy baby with no unfavorable pregnancy history, and there was no drug use during pregnancy. The couple was not biologically related and healthy, with no family history. A detailed prenatal ultrasound diagnosis revealed noncompaction cardiomyopathy, mild ventriculomegaly (10 millimeters) and relative macrocephaly (95th percentile) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Consistent with the prenatal sonographic findings, fetal echocardiography revealed noncompaction cardiomyopathy involving both the left and right ventricles. Myocardial thickening was characterized by both apical involvement and pathologically prominent trabeculations and demonstrated a typical honeycombing appearance. Magnetic resonance imaging (MRI) revealed mild ventriculomegaly (10.6 mm) and a short anteroposterior diameter of the corpus callosum (the ratio between the corpus callosum length and the internal cranial occipitofrontal dimension (CC/ICOFD)\u0026thinsp;=\u0026thinsp;0.3) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). After receiving detailed genetic counseling and informed consent, the couple decided to receive genetic testing.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe amniotic fluid was obtained from the women by amniocentesis. Genomic DNA was extracted from amniotic fluid specimens and parental peripheral blood lymphocyte specimens for chromosomal microarray analysis and trio-medical exome sequencing. Chromosomal microarray analysis revealed any chromosomal copy number abnormalities. Sequencing was performed using the HiSeq2000 sequencing system (Illumina, Inc., San Diego, CA). Medical exome sequencing revealed 4,000 clinical pathogenic genes with known functions, which included 50,584 coding regions and 8,421,879 base pairs. The average sequencing depth was greater than 100-fold, and the highest sequencing depth was 200-fold. A coverage interval greater than 10-fold accounted for 98.9% of the pathogenic genes, and coverage greater than 20-fold accounted for 98.5% of the pathogenic genes. The pathogenicity of variants was classified according to the American College of Medical Genetics and Genomics guidelines[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The constructed genome was referred to as hg19/GRch37. A de novo hemizygous mutation (NM_007363.5: c.214C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.Gln72Ter) in \u003cem\u003eNONO\u003c/em\u003e was found.\u003c/p\u003e \u003cp\u003eSanger sequencing of the PCR products of the proband confirmed the de novo mutation c.214C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Gln72Ter) in exon 4 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA), which could lead to protein truncation. This nonsense mutation was not registered in the dbSNP150, 1000 Genomes Project or Human Genetic Variation Database and was not detected in 3000 Chinese Han control subjects in our local variant database (which was derived from an exome-sequencing experiment), suggesting that it was not a polymorphism. The mutation was not detected in the couples. The couple chose to terminate the pregnancy, but unfortunately, they refused to autopsy the fetus for personal reasons.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study describes a fetus with noncompaction cardiomyopathy, a short anteroposterior diameter of the corpus callosum and relative macrocephaly that carried a nonsense mutation in exon 4 of the NONO gene (NM_007363.5:c.214C\u0026thinsp;\u0026gt;\u0026thinsp;T; p.Gln72Ter). This de novo mutation has not been previously reported as pathogenic or benign and has not been detected in the general population (dbSNP150, 1000 Genomes Project, gnomAD). A literature review revealed that phenotypes, including noncompaction cardiomyopathy, abnormalities of the corpus callosum and macrocephaly, are consistent features of MRXS34. This mutation turned the 72nd Gln into a stop codon. The loss of protein from this allele was expected to occur through nonsense-mediated mRNA decay. Therefore, we classified this mutation in NONO as pathogenic according to the American College of Medical Genetics and Genomics guidelines[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLoss-of-function variants in NONO might predispose males to CHD and LVNC. The gene had a haploinsufficiency index of 4.11 according to DECIPHER, and the probability of loss-of-function intolerance (pLI) was 0.99 according to GnomAD. We report a fetus with a de novo mutation, c.214C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.Gln72Ter, which was classified as pathogenic and predicted to undergo nonsense-mediated mRNA decay, ultimately leading to loss of function in NONO. In addition, noncompaction cardiomyopathy involving both the left and right ventricles was the only cardiac phenotype in this patient. LVNC was the most common cardiac phenotype. We also found that LVNC is diagnosed early in almost all individuals (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e): six individuals who were pregnant, including the fetus we reported[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], four individuals who were in the neonatal period[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and three individuals who were in infancy[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], indicating that LVNC is an early clue for diagnosing MRXS34 and emphasizing the importance of fetal echocardiography for identifying cardiac structural anomalies in NONO-related fetuses.\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\u003e Craniocerebral and cardiomyopathy of fetuses with NONO mutations.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy, patient identifier, age\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNONO\u003c/em\u003e variant (NM_001145408.2), inheritance\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eage at diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBrain anomalies\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMacrocephaly (relative or +\u0026thinsp;2 SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCardiomyopathy\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSewani et al ., S3, 2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.457C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.(Arg153*), de novo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eprenatal (16 weeks gestation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCardiomegaly\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSun et al., S(A1), 2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.246_249del, p.Pro83Thrfs*7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eprenatal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVNC\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSun et al., S(A2), 2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.246_249del, p.Pro83Thrfs*7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eprenatal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVNC\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSun et al., S(A3), 2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.246_249del, p.Pro83Thrfs*7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eprenatal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVNC\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSun et al., S(B1), 2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.471del, p.Gln157Hisfs*18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eprenatal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003edysplasia of the corpus callosum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVNC\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSun et al., S(B2), 2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.471del, p.Gln157Hisfs*18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eprenatal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVNC\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSun et al.,S1, 2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.154\u0026thinsp;+\u0026thinsp;9A\u0026thinsp;\u0026gt;\u0026thinsp;G, p.Asn52Serfs*3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eprenatal (26 week gestation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThis study,S1,2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC.214C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.Gln75Ter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eprenatal (30 week gestation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eShort anteroposterior diameter of corpus callosum, mild ventriculomegaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003erelative macrocephaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMyocardial thickening, ventricular noncompaction of myocardium\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eAbbreviations: LVNC, left ventricular noncompaction; ND, not determined/not reported; S, subject.\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\u003eIn addition to congenital heart defects and LVNC, minor cerebral structural anomalies and intellectual developmental disorders are other symptoms in male patients with loss-of-function mutations in \u003cem\u003eNONO.\u003c/em\u003e Brain MRI of male patients with NONO mutations may indicate abnormalities of the corpus callosum, the most common phenotype. However, based on a review of the literature by Roessler et al.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], among nine MRXS34 patients for whom antenatal ultrasound data were available, eight were diagnosed with corpus callosum agenesis (CCA) postnatally. However, prenatal diagnosis of CCA was made in only four patients out of the night patients with postnatal diagnosis of CCA. This means that the CCA is missed prenatally in nearly half of patients, which is limited by the use of prenatal ultrasound and the proficiency of sonographers. For evaluating brain development, prenatal ultrasound can only assess intracranial structures and morphology[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] but cannot detect functional abnormalities, including mental retardation, psychomotor development delay, and speech impediment, which are characterized phenotypes of MRXS34[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Indeed, prenatal cranial MRI provides clearer visualization of intracranial structures and improves the diagnosis of neurological abnormalities such as CCA[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. MRI revealed that the corpus callosum was abnormal in our patient. Therefore, this study emphasizes the role of prenatal MRI for the identification of CCA in patients with MRXS34.\u003c/p\u003e \u003cp\u003eIn addition, macrocephaly or relative macrocephaly (relative or +\u0026thinsp;2 SD) is another common feature. Macrocephaly or relative macrocephaly was observed in 10 (91%) of the 11 male patients. One of the males with macrocephaly was reported to have undergone multiple prenatal ultrasound examinations during pregnancy[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This suggests that the proportion of mothers with this phenotype appearing before childbirth is relatively small. However, in regard to fetal macrocephaly in the prenatal setting, in addition to MRXS34, Beckwith-Wiedemann syndrome, which is a rare overgrowth syndrome manifesting as macrocephaly, needs to be excluded[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Surprisingly, prenatal intrauterine growth restriction (IUGR) with or without short long bones was found in 6 MRXS34 patients (75%)[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], stressing the significance of biological measurements for prenatal diagnosis of MRXS34. Moreover, IUGR, which is caused by multiple factors, such as placental and maternal factors, as well as genetic factors, such as aneuploidy, pathogenic copy number variation, and monogenic genetic diseases, is not uncommon in prenatal diagnosis[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Moreover, supravalvular stenosis and intrauterine growth restriction are features of 7q11.23 microdeletion syndrome[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. It is very interesting to investigate the contribution of phenotypic associations such as LNVC or CCA with FGR to the prenatal diagnosis of MRXS34.\u003c/p\u003e \u003cp\u003eThis study has several limitations. The fetus is most likely to have MRXS34 according to its NONO mutation and the phenotypes of noncompaction cardiomyopathy, relative macrocephaly and short anteroposterior diameter of the corpus callosum, but we cannot confirm whether the mild ventriculomegaly revealed by prenatal ultrasound diagnosis and MRI is related to MRXS34. In addition, we cannot determine microsturctural abnormalities using prenatal ultrasound and fetal MRI, and some phenotypes, especially intellectual developmental disorders, cannot be evaluated before delivery. Therefore, even if the fetus has the brain phenotype of relative acrocephaly, an abnormal corpus callosum and mild ventriculomegaly, we cannot determine whether the fetus would have an intellectual developmental disorder of MRXS34 after birth. The fetus was identified as having a de novo mutation in NONO, but maternal germline mosaicism cannot be excluded.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eWe identified a novel causative \u003cem\u003eNONO\u003c/em\u003e mutation, c.214C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Gln72Ter), in a fetus with MRXS34. Our findings expand the \u003cem\u003eNONO\u003c/em\u003e mutation spectrum of MRXS34 and further expand noncompaction cardiomyopathy, abnormalities of the corpus callosum and macrocephaly to the phenotype of MRXS34 in fetuses.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing: no additional data available.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICS STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe studies involving human participants were reviewed and approved by The ethics committee of Longgang District Maternity＆Child Healthcare Hospital of Shenzhen City. Written informed consent to participate in this study was provided by the participants\u0026rsquo; legal guardian/next of kin. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eINSTITUTIONAL REVIEW BOARD STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Longgang District Maternity＆Child Healthcare Hospital of Shenzhen City with approval code LGFYYXLLL-2020-002.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported (or partially supported) by Shenzhen Longgang District Science and Technology Innovation Bureau (LGKCYLWS2023016).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors kindly acknowledge the participation of the family members and the staff members in the Prenatal Diagnosis Center of Longgang District Maternity＆Child Healthcare Hospital of Shenzhen City, Guangdong Province, China. The authors would also like to thank the Genome Aggregation database (gnomAD) for providing genome variant data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMircsof D, Langou\u0026euml;t M, Rio M, Moutton S, Siquier-Pernet K, Bole-Feysot C, Cagnard N, Nitschke P, Gaspar L, Žnidarič M, et al. Mutations in NONO lead to syndromic intellectual disability and inhibitory synaptic defects. Nat Neurosci. 2015;18(12):1731\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReinstein E, Tzur S, Cohen R, Bormans C, Behar DM. Intellectual disability and non-compaction cardiomyopathy with a de novo NONO mutation identified by exome sequencing. Eur J Hum genetics: EJHG. 2016;24(11):1635\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScott DA, Hernandez-Garcia A, Azamian MS, Jordan VK, Kim BJ, Starkovich M, Zhang J, Wong LJ, Darilek SA, Breman AM, et al. Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO. J Med Genet. 2017;54(1):47\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarlston CM, Bleyl SB, Andrews A, Meyers L, Brown S, Bayrak-Toydemir P, Bale JF, Botto LD. Expanding the genetic and clinical spectrum of the NONO-associated X-linked intellectual disability syndrome. Am J Med Genet Part A. 2019;179(5):792\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSewani M, Nugent K, Blackburn PR, Tarnowski JM, Hernandez-Garcia A, Amiel J, Whalen S, Keren B, Courtin T, Rosenfeld JA, et al. Further delineation of the phenotypic spectrum associated with hemizygous loss-of-function variants in NONO. Am J Med Genet Part A. 2020;182(4):652\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun H, Hao X, Wang X, Zhou X, Zhang Y, Liu X, Han J, Gu X, Sun L, Zhao Y, et al. Genetics and Clinical Features of Noncompaction Cardiomyopathy in the Fetal Population. Front Cardiovasc Med. 2020;7:617561.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoessler F, Beck AE, Susie B, Tobias B, Begtrup A, Biskup S, Caluseriu O, Delanty N, Fr\u0026ouml;hlich C, Gtrureally MT, et al. Genetic and phenotypic spectrum in the NONO-associated syndromic disorder. Am J Med Genet Part A. 2023;191(2):469\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRichards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet medicine: official J Am Coll Med Genet. 2015;17(5):405\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoetzer KC, Moosa S. Novel hemizygous loss-of-function variant in NONO identified in a South African boy. Am J Med Genet Part A. 2022;188(1):373\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosenbloom JI, Yaeger LH, Porat S. Reference Ranges for Corpus Callosum and Cavum Septi Pellucidi Biometry on Prenatal Ultrasound: Systematic Review and Meta-Analysis. J ultrasound medicine: official J Am Inst Ultrasound Med. 2022;41(9):2135\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePugash D, Brugger PC, Bettelheim D, Prayer D. Prenatal ultrasound and fetal MRI: the comparative value of each modality in prenatal diagnosis. Eur J Radiol. 2008;68(2):214\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGai S, Wang L, Zheng W. Comparison of prenatal ultrasound with MRI in the evaluation and prediction of fetal orofacial clefts. BMC Med Imaging. 2022;22(1):213.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNardozza LM, Caetano AC, Zamarian AC, Mazzola JB, Silva CP, Mar\u0026ccedil;al VM, Lobo TF, Peixoto AB. Araujo J\u0026uacute;nior E: Fetal growth restriction: current knowledge. Arch Gynecol Obstet. 2017;295(5):1061\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYuan M, Deng L, Yang Y, Sun L. Intrauterine phenotype features of fetuses with Williams-Beuren syndrome and literature review. Ann Hum Genet. 2020;84(2):169\u0026ndash;76.\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":"noncompaction cardiomyopathy, NONO, X-linked syndromic intellectual developmental disorder-34 (MRXS34), exome sequencing","lastPublishedDoi":"10.21203/rs.3.rs-4348501/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4348501/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe \u003cem\u003eNONO\u003c/em\u003e gene is located on chromosome Xq13.1 and encodes a nuclear protein involved in RNA synthesis, transcriptional regulation, and DNA repair. Hemizygous loss-of-function variants in NONO reportedly cause X-linked syndromic intellectual developmental disorder-34 (MRXS34) in males. At present, there are few clinical reports related to MRXS34, and the mutation spectrum of NONO-related diseases has not been completely determined.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe report the case of a fetus with noncompaction cardiomyopathy, a short anteroposterior diameter of the corpus callosum and relative macrocephaly. Genotyping examination, including chromosome microarray analysis (CMA) and trio-medical exon sequencing, was performed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMedical exon sequencing revealed a de novo hemizygous nonsense mutation (c.214 C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.Gln72Ter) in exon 4 of the \u003cem\u003eNONO\u003c/em\u003e gene. A review of previous literature suggested that noncompaction cardiomyopathy, abnormalities of the corpus callosum, and macrocephaly are consistent phenotypes of MRXS34.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe mutation (c.214 C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.Gln72Ter) in the \u003cem\u003eNONO\u003c/em\u003e gene was present in a fetus with MRXS34. This study expands the mutation spectrum of NONO-related diseases and enlarges noncompaction cardiomyopathy, abnormalities of the corpus callosum and macrocephaly to the phenotype of MRXS34 in fetuses.\u003c/p\u003e","manuscriptTitle":"A Novel Mutation of NONO-Associated X-linked Syndromic Intellectual Developmental Disorder-34 in a Fetus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-09 18:08:49","doi":"10.21203/rs.3.rs-4348501/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":"24ca8bc5-5520-46b4-973b-d49cad60a957","owner":[],"postedDate":"May 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-10T09:53:28+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-09 18:08:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4348501","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4348501","identity":"rs-4348501","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}