First diagnosis of fetal SETD5 mutation during pregnancy，demonstrating an association with congenital heart disease

First diagnosis of fetal SETD5 mutation during pregnancy，demonstrating an association with congenital heart disease | 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 First diagnosis of fetal SETD5 mutation during pregnancy，demonstrating an association with congenital heart disease Jiaqi Fan, Hairui Sun, Huan Jiang, Siyao Zhang, Hongmei Xia, Yihua He This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4542929/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 Mutations in the SETD5 gene lead to the autosomal dominant disorder termed Mental retardation type 23. Limited clinical reports have made it challenging to comprehensively delineate the clinical outcomes and mutation spectrum associated with this gene. Case presentation: In this study, a fetal case presenting an ostium primum atrial septal defect, a presumed upper ventricular septal defect was identified through fetal cardiac ultrasound. Following this discovery, an in-depth genetic assessment, encompassing whole exome sequencing, was executed on the fetus and both parents to pinpoint potential genetic origins. From the exome data, a previously undocumented variant (exon21: c.3601_3605del: p. W1201Efs*2) in the SETD5 gene (NM_001080517.3) surfaced. Lineage analysis validated this as a de novo variant. This mutation disrupts the gene's open reading frame, consequently affecting protein functionality. This is the first prenatal diagnosis of a fetus with a SETD5 mutation, advancing the time of diagnosis while broadening our understanding of the gene's mutation spectrum and clinical manifestations. Conclusions Our study confirms that congenital heart disease, including atrial and ventricular septal defects, is a prenatal clinical feature caused by mutations in this gene. Fetal cardiac ultrasound can be used as a means of early screening for such disorders, and the importance of prenatal whole-exome sequencing technology was emphasized. SETD5 congenital heart disease gene mutation Figures Figure 1 Figure 2 Background SETD5 , or SET domain containing protein 5 (OMIM:615743), operates as a DNA methyltransferase crucial in guiding histone modifications of DNA along with transcriptional regulators [ 1 , 2 ]. Although it's established that variants of SETD5 can induce the rare developmental ailment termed MRD23 (Mental retardation type 23, MIM:615761) [ 2 , 3 ], the full array of clinical manifestations remains not entirely characterized due to limited clinical documentation. Typically, MRD23 presents with developmental lag, cognitive impairment, microcephaly, and hypotonia. Other noted clinical presentations encompass skeletal deformities, hypospadias, and retinopathy [ 4 – 7 ]. We first diagnosed SETD5 mutant fetuses during pregnancy, presenting only as congenital heart disease (CHD), with fetal cardiac ultrasound findings of an ostium primum atrial septal defect, a superior ventricular septal defect and mild tricuspid regurgitation (excluding tricuspid valve developmental anomalies). Our case expands the spectrum of mutations in the SETD5 gene as well as the clinical features, and through the cases in this article as well as a review of the literature, we confirm that CHD is a prenatal clinical feature of SETD5 defects with a low penetrance, and that the cardiac phenotype is most commonly characterized by atrioventricular septal defects. Case presentation A woman aged 31 years, primigravida, in optimal health and abstaining from medication during her gestation, presented with no familial cardiovascular disease history. Notably, she had no consanguineous relation with her spouse. A fetal ultrasound was performed at 23 + 6 weeks gestation, for the ultrasound evaluations, the General Electric Voluson E8 system equipped with transabdominal curvilinear transducers operating at a frequency range of 2–4 MHz (GE Healthcare Ultrasound, Milwaukee, WI, USA) was employed. An all-encompassing fetal echocardiographic assessment was undertaken, adhering to the procedural criteria delineated by the American Society of Echocardiography. This thorough assessment integrated the use of two-dimensional (2D) imaging, M-mode, along with color and pulse Doppler echocardiographic methodologies [ 8 ]. Fetal ultrasound examination showed that the width of the posterior Angle of the lateral ventricle of the fetus was 0.8cm, which was the normal internal high value. The fetal cardiac ultrasound elucidated specific abnormalities: within the four-chamber perspective, there was an evident interruption of echogenicity at the interatrial septum's inferior portion, spanning approximately 2.79 mm with bidirectional shunting (Fig. 1 ). Additionally, the upper section of the interventricular septum displayed diminished echogenicity with an echogenicity gap measuring about 1.1 mm. While the mitral and tricuspid valves displayed regular morphology, position, and function, regurgitation was evident in the tricuspid valve covering an area of roughly 1.2 square centimeters. Notably absent was pericardial effusion. These cardiac ultrasonography findings were indicative of atrial and ventricular septal defects. In addition, ultrasonography showed no other significant structural abnormalities. After detailed counselling, the couple decided to terminate the pregnancy and undergo genetic testing, but refused an autopsy. Utilizing previously delineated methodologies, three distinct sets of CNV-seq and whole exome sequencing were conducted for both the fetus and parents [ 9 – 14 ]. The pathogenicity assessment of the detected variants was executed based on ACMG's existing guidelines [ 15 ], with variants deemed pathogenic or likely pathogenic taken as confirmatory genetic outcomes. Validation of these pivotal genetic results was done through Sanger sequencing. The analyses did not reveal any chromosomal irregularities or pathogenic variations within well-known CHD genes. However, an undiscovered variant emerged within the SETD5 gene, specifically at exon21: c.3601_3605del: p. W1201Efs*2 (Fig. 2 ). This particular variant was absent in multiple reference populations such as 1000 Genomes (1000G), the Shenzhou Genome Database, the Human Exome Database (ExAC), and the Population Genome Mutation Frequency Database (gnomAD). Subsequent lineage analysis confirmed its status as a de novo mutation. Bioinformatics predictions indicate that this variant likely disrupts the gene's open reading frame, potentially modifying protein functionality. A previous report noted a loss of function (LOF) variant in the SETD5 gene linked with a familial atrial septal and ventricular septal defects case [ 16 ]. Collating this data, the inference is that the identified variant holds pathogenic properties and might elucidate the observed fetal cardiac aberration. Discussion We first diagnosed SETD5 mutated fetuses prenatal, manifesting clinically with an ostium primum atrial septal defect, potential upper ventricular septal anomaly, and slight tricuspid regurgitation. An extensive exploration of both literature and public repositories was undertaken to accumulate insights on prior clinical instances related to SETD5 mutations (refer to Table 1 ). Congenital heart disease was present in 43.3% of the SEDT5 patients we enumerated, cystic hygroma was present in 3.3%, Intellectual disability/Developmental delay was present in 86.7%, Ritualized behavior and/or autism was present in 20%, Hypotonia/Epilepsy was present in 53.3%, Facial Dysmorphism was present in 96.7%, Postaxial polydactyly was present in 26.7%, Scoliosis, kyphosis or lordosis was present in 26.7%, Gastrointestinal abnormalities was present in 23.3% and Genitourinary defects was present in 10%。 Recent studies have underscored the pivotal influence of setd5 during embryonic maturation and growth phases. Notably, embryos devoid of setd5 manifest pronounced irregularities in areas such as neural tube organization, cardiac morphology, and the process of somitogenesis. A focused exploration into cardiovascular anomalies emphasized that close to half of the Setd5 null embryos manifested active cardiac pulsations by E9.5. This observation received validation through the comprehensive staining of cardinal cardiac differentiation indicators. In parallel, the absence of Setd5 in embryonic stem cells led to hindered cellular growth, augmented apoptotic activity, erratic cell cycle transitions, curtailed cardiomyocyte differentiation potential, and notable gene expression modulations [ 17 ]. A research endeavor led by Michelle Yu-Qing Cheung [ 18 ] employing a murine model unveiled the indispensability of setd5 in heart morphogenesis within the cardiopharyngeal mesoderm, with its haploinsufficiency culminating in outflow tract malformations in rodents. Synthesizing insights from our study with extant literature, there emerges a hypothesis positioning the SETD5 gene as a potential influencer in congenital heart disease etiology. Yet, the intricate pathways and modalities through which SETD5 steers cardiac morphogenesis and operationality are yet to be comprehensively delineated. As such, there is a pressing need for expanded research efforts focusing on the pathobiological intricacies linked with SETD5 variant manifestations. In a pioneering documentation by Krzysztof Szczałuba [ 16 ], a unique familial instance of SETD5 mutation was brought to light, observed in a pair of siblings. The progenitor of this mutation was their father, manifesting only subtle cognitive challenges. Among the siblings, one exhibited a myriad of clinical features including a combined partial atrioventricular septal defect, patent ductus arteriosus, persistent left superior vena cava, alongside other morphological anomalies. The other sibling demonstrated a partial atrioventricular septal defect complemented by distinct developmental irregularities. In a separate study by Zöe Powis[ 19 ], an examination of 14 individuals with variations in the SETD5 gene was conducted. Predominantly, individuals in this grouping displayed overlapping phenotypes previously identified, encapsulating developmental lags and psychiatric challenges. Interestingly, within this group, two individuals were diagnosed with an accompanying partial atrioventricular septal defect, while another had a ventricular septal anomaly. Another notable contribution was from Lettie E. et al [ 20 ], highlighting an infantile case wherein SETD5 variations culminated in an echocardiographically-detected ventricular septal defect. Based on the above findings and the clinical characteristics of the cases reported in this study, we confirm that congenital heart disease, including atrial and ventricular septal defects, is a prenatal clinical feature caused by mutations in this gene. In addition to the prenatal case reported here, a case of prenatal cystic hygroma in early pregnancy associated with a mutation in SETD5 has been reported in the literature [ 21 ], which presented with cystic hygroma and a thickened nuchal fold during gestation, and the results of Microarray analysis of placental DNA were normal, however, facial deformities and early neurodevelopmental syndrome appeared in less than two years of age, and the analysis was performed by whole-exome sequencing, which revealed that there was a mutation in SETD5 . Therefore, SETD5 mutations may manifest as atrial and ventricular septal defects and cystic hygroma in the prenatal period, and physicians should be alerted to the presence of these two phenotypes in the fetus during the prenatal period. In this prenatal case, clinical manifestations such as atrial septal defect and the possibility of an upper ventricular septal defect were observed. Such conditions, which are prevalent within congenital heart diseases, are potentially manageable through surgical interventions postnatally, usually resulting in improved prognoses. Intriguingly, the implicated gene, SETD5 , has been established as a significant contributor to neurodevelopmental anomalies, including intellectual disability (ID), autism spectrum disorders, and KBG syndromes. This gene also constitutes a vital component of the 3p25.3 microdeletion syndrome, particularly associated with three genes (THUMPD3, SETD5 , and THUMPD3-AS1) [ 3 , 22 – 24 ]. Detrimental alterations within SETD5 can profoundly influence patient survival and life quality. In the absence of comprehensive genetic testing for this case, cardiac ultrasonography might have been the sole criterion, fetal prognosis may be grossly misjudged based on cardiac ultrasound findings alone. With a plethora of clinical syndromes linked to congenital heart disease, the implementation of prenatal whole exome sequencing technology is pivotal. It lays the foundation for meticulous counseling, greatly enhancing the precision in prenatal diagnostic and prognostic assessments [ 25 ]. Table 1 Comparison of the Clinical Features Observed by previous study and in our case Clinical feature Our patient (n = 1) Min Pan et al. (2020) (n = 1) Szczaluba et al. al.(2016) (n = 3) Grozeva et al. (2015) (n = 7) Kuechler et al. (2015) (n = 2) Powis et al. (2017) (n = 14) Pascolini et al. (2022) (n = 1) Rawlins et al. (2017) (n = 1) Age at last examination fetus 16 months varied varied varied varied 8 years 4 weeks Congenital heart defects + - 2 2 0 8 + + cystic hygroma - + 0 0 0 0 - - Intellectual disability /Developmental delay NA + 3 7 2 11 + + Ritualized behavior and/or autism NA NA 0 5 0 NA - + Hypotonia/Epilepsy NA NA 2 NA 0 14 - - Facial Dysmorphism NA + 3 7 2 14 + + Postaxial polydactyly NA NA 2 1 0 4 + - Scoliosis, kyphosis or lordosis NA NA 0 4 0 4 - - Gastrointestinal abnormalities NA NA 0 5 0 2 - - Genitourinary defects NA NA 2 0 0 1 - - +, positive; -, negative; NA, not available Conclusions This is the first prenatal diagnosis of a fetus with a SETD5 mutation, which broadens the known mutation range and clinical manifestations linked to the SETD5 gene. We confirm that mutations in this gene associated with congenital heart diseases, notably atrial and ventricular septal anomalies, exhibiting as a distinct prenatal clinical phenotype with a low penetrance. Consequently, understanding the pathophysiological implications of SETD5 mutations becomes imperative. When anomalies surface during prenatal cardiac ultrasonography, there's a strong recommendation to pursue additional genetic assessments. This will ascertain if the detected mutation can be attributed to a causative gene, help eliminate concerns over other genetic aberrations, and facilitate early interventions for optimal outcomes. Declarations Acknowledgements The authors extend their gratitude to the parents of the fetus for their valuable contribution in this study. Authors’ contributions The study was designed by HX and YH. JF, HS and HJ were responsible for the collection of study materials or samples. HJ and HX provided fetal echocardiograms. The sequencing experiments were conducted by JF and SZ. Data collection and aggregation were performed by FJ, HS and HJ. Data analysis and interpretation were carried out by JF, HS, and HJ. The manuscript was written by JF and HS. All authors, JF, HS, and HJ made equal contributions to this work. The final manuscript was read and approved by all authors. Funding This work was supported by the National Natural Science Foundation of China (U21A20523) to YH which played the role in the collection, analysis and interpretation of data and in writing the manuscript. Availability of data and materials The raw data obtained from whole-exome sequencing of the family in this study cannot be publicly accessed due to the need to protect participant confidentiality. Furthermore, in accordance with the regulations of the People's Republic of China on the management of human Genetic Resources, the original data of genetic resources involving clinical patients cannot be disclosed without approval. However, re-analysis of the whole-exome sequencing data can be made available upon reasonable request, and interested parties can contact Prof. Yihua He (Email: [email protected] ) at the Department of Echocardiography in Beijing Anzhen Hospital, Capital Medical University, Beijing, China. Ethics approval and consent to participate This study was approved by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University. The parents agreed to participate in this study and provided signed informed consent. Consent for publication The present research secured approval from the Beijing Anzhen Hospital's Ethics Committee, affiliated with Capital Medical University. The parents have provided informed written consent for publication. Competing interests The authors declare no conflicts of interest. References Li M, Hou Y, Zhang Z, Zhang B, Huang T, Sun A, Shao G, Lin Q. Structure, activity and function of the lysine methyltransferase SETD5. Front Endocrinol(Lausanne). 2023;14:1089527. Kellogg G, Sum J, Wallerstein R. Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features with further definition of a critical region. Am J Med Genet A. 2013;161:1405–8. Grozeva D, Carss K, Spasic-Boskovic O, Parker MJ, Archer H, Firth HV, et al. De novo loss-of-function mutations in SETD5,encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability. Am J Hum Genet. 2014;94(4):618–24. Iwagawa T, Kawabata R, Fukushima M, Kuribayashi H, Watanabe S. Setd5, but not Setd2, is indispensable for retinal cell survival and proliferation. FEBS Lett. 2023;597(3):427–36. Kuechler A, Zink AM, Wieland T, Lüdecke HJ, Cremer K, Salviati L, et al. Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome. Eur J Hum Genet. 2015;23(6):753–60. Ahsan N, Desai A, Siddiqui O, Powers K. Expanding the Genotype and Phenotype of SETD5-Related Neurodevelopmental Syndrome. Pediatr Neurol. 2023;138:25–6. Anderson E, Lam Z, Arundel P, Parker M, Balasubramanian M. Expanding the phenotype of SETD5-related disorder and presenting a novel association with bone fragility. Clin Genet. 2021;100(3):352–4. Rychik J, Ayres N, Cuneo B, Gotteiner N, Hornberger L, Spevak PJ, et al. American Society of Echocardiography Guidelines and Standards for Performance of the Fetal Echocardiogram. J Am Soc Echocardiography. 2004;17(7):803–10. Sun H, et al. Genetics and clinical features of noncompaction cardiomyopathy in the fetal population. Front Cardiovasc Med. 2021;7:617561. Sun H, et al. Contribution of single-gene defects to congenital cardiac lef-sided lesions in the prenatal setting. Ultrasound Obst Gyn. 2020;56:225–32. Li H, Durbin R. Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics. 2009;25:1754–60. Riggs ER, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020;22:245–57. McKenna A, et al. Te genome analysis toolkit: A mapreduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303. Wang K, Li M, Hakonarson HANNOVAR. Functional annotation of genetic variants from high-throughput sequencing DATA. Nucleic Acids Res. 2010;38:e164. Richards S, 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 Med. 2015;17:405–23. Szczałuba K, Brzezinska M, Kot J, Rydzanicz M, Walczak A, Stawiński P, Werner B, Płoski R. SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression. Am J Med Genet A. 2016;170(9):2322–7. Osipovich AB, Gangula R, Vianna PG, Magnuson MA. Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation. Development. 2016;143(24):4595–607. Cheung MY, Roberts C, Scambler P, Stathopoulou A. Setd5 is required in cardiopharyngeal mesoderm for heart development and its haploinsufficiency is associated with outflow tract defects in mouse. Genesis. 2021;59(7–8):e23421. Powis Z, Farwell Hagman KD, Mroske C, McWalter K, Cohen JS, Colombo R, et al. Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance. Clin Genet. 2018;93(4):752–61. Rawlins LE, Stals KL, Eason JD, Turnpenny PD. De novo SETD5 nonsense mutation associated with diaphragmatic hernia and severe cerebral cortical dysplasia. Clin Dysmorphol. 2017;26(2):95–7. Pan M, Liu YN, Xu LL, Li DZ. First-trimester cystic hygroma and neurodevelopmental disorders: The association to remember. Taiwan J Obstet Gynecol. 2020;59(6):960–2. Fernandes IR, Cruz ACP, Ferrasa A, Phan D, Herai RH, Muotri AR. Genetic variations on SETD5 underlying autistic conditions. Dev Neurobiol. 2018;78(5):500–518. 10.1002/dneu.22584 . Epub 2018 Mar 5. Grozeva D, Carss K, Spasic-Boskovic O, Tejada MI, Gecz J, Shaw M, Italian X-linked Mental Retardation Project; GOLD Consortium;, Hurles M, Raymond FL et al. Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability. Hum Mutat. 2015;36(12):1197 – 204. Nakagawa T, Hattori S, Hosoi T, Nakayama K. Neurobehavioral characteristics of mice with SETD5 mutations as models of IDD23 and KBG syndromes. Front Genet. 2023;13:1022339. Xue Y, Ankala A, Wilcox WR, Hegde MR. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med. 2015;17:444–51. 10.1038/gim.2014.122 . Pascolini G, Gnazzo M, Novelli A, Grammatico P. Clinical refinement of the SETD5-associated phenotype in a child displaying novel features and KBG syndrome-like appearance. Am J Med Genet A. 2022;188(5):1623–5. 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-4542929","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":312419076,"identity":"b07eeea8-b1f9-48cd-9098-8a78c577a30f","order_by":0,"name":"Jiaqi Fan","email":"","orcid":"","institution":"Maternal-Fetal Consultation Center of Congenital Heart Disease","correspondingAuthor":false,"prefix":"","firstName":"Jiaqi","middleName":"","lastName":"Fan","suffix":""},{"id":312419079,"identity":"af65f52c-9f5e-41e5-bd7e-dcdb9ba0ca4e","order_by":1,"name":"Hairui Sun","email":"","orcid":"","institution":"Maternal-Fetal Consultation Center of 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02:10:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4542929/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4542929/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":59219121,"identity":"ebb940d6-4207-4be8-830a-1777c830b767","added_by":"auto","created_at":"2024-06-27 19:57:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":554996,"visible":true,"origin":"","legend":"\u003cp\u003eThe echocardiography of the fetus identified atrial septal defect\u003c/p\u003e","description":"","filename":"FIGURE1.png","url":"https://assets-eu.researchsquare.com/files/rs-4542929/v1/2da1c8bc715fdd933482b54e.png"},{"id":59219283,"identity":"f81af48f-85f8-4993-aa82-91b296bd5d05","added_by":"auto","created_at":"2024-06-27 20:05:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":174303,"visible":true,"origin":"","legend":"\u003cp\u003eSanger sequencing shows a novel frameshift variant in the fetus\u003c/p\u003e","description":"","filename":"FIGURE2.png","url":"https://assets-eu.researchsquare.com/files/rs-4542929/v1/9661658bcf4a0a49774afd81.png"},{"id":59219402,"identity":"896bdd61-6b4f-46f3-af47-78388039a4f6","added_by":"auto","created_at":"2024-06-27 20:13:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1078472,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4542929/v1/f8afbe14-01f2-43b6-b0b3-309c2aeb3c1a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"First diagnosis of fetal SETD5 mutation during pregnancy，demonstrating an association with congenital heart disease","fulltext":[{"header":"Background","content":"\u003cp\u003e \u003cem\u003eSETD5\u003c/em\u003e, or SET domain containing protein 5 (OMIM:615743), operates as a DNA methyltransferase crucial in guiding histone modifications of DNA along with transcriptional regulators [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although it's established that variants of \u003cem\u003eSETD5\u003c/em\u003e can induce the rare developmental ailment termed MRD23 (Mental retardation type 23, MIM:615761) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], the full array of clinical manifestations remains not entirely characterized due to limited clinical documentation. Typically, MRD23 presents with developmental lag, cognitive impairment, microcephaly, and hypotonia. Other noted clinical presentations encompass skeletal deformities, hypospadias, and retinopathy [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe first diagnosed \u003cem\u003eSETD5\u003c/em\u003e mutant fetuses during pregnancy, presenting only as congenital heart disease (CHD), with fetal cardiac ultrasound findings of an ostium primum atrial septal defect, a superior ventricular septal defect and mild tricuspid regurgitation (excluding tricuspid valve developmental anomalies). Our case expands the spectrum of mutations in the \u003cem\u003eSETD5\u003c/em\u003e gene as well as the clinical features, and through the cases in this article as well as a review of the literature, we confirm that CHD is a prenatal clinical feature of \u003cem\u003eSETD5\u003c/em\u003e defects with a low penetrance, and that the cardiac phenotype is most commonly characterized by atrioventricular septal defects.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA woman aged 31 years, primigravida, in optimal health and abstaining from medication during her gestation, presented with no familial cardiovascular disease history. Notably, she had no consanguineous relation with her spouse.\u003c/p\u003e \u003cp\u003eA fetal ultrasound was performed at 23\u0026thinsp;+\u0026thinsp;6 weeks gestation, for the ultrasound evaluations, the General Electric Voluson E8 system equipped with transabdominal curvilinear transducers operating at a frequency range of 2\u0026ndash;4 MHz (GE Healthcare Ultrasound, Milwaukee, WI, USA) was employed. An all-encompassing fetal echocardiographic assessment was undertaken, adhering to the procedural criteria delineated by the American Society of Echocardiography. This thorough assessment integrated the use of two-dimensional (2D) imaging, M-mode, along with color and pulse Doppler echocardiographic methodologies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Fetal ultrasound examination showed that the width of the posterior Angle of the lateral ventricle of the fetus was 0.8cm, which was the normal internal high value. The fetal cardiac ultrasound elucidated specific abnormalities: within the four-chamber perspective, there was an evident interruption of echogenicity at the interatrial septum's inferior portion, spanning approximately 2.79 mm with bidirectional shunting (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Additionally, the upper section of the interventricular septum displayed diminished echogenicity with an echogenicity gap measuring about 1.1 mm. While the mitral and tricuspid valves displayed regular morphology, position, and function, regurgitation was evident in the tricuspid valve covering an area of roughly 1.2 square centimeters. Notably absent was pericardial effusion. These cardiac ultrasonography findings were indicative of atrial and ventricular septal defects. In addition, ultrasonography showed no other significant structural abnormalities. After detailed counselling, the couple decided to terminate the pregnancy and undergo genetic testing, but refused an autopsy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eUtilizing previously delineated methodologies, three distinct sets of CNV-seq and whole exome sequencing were conducted for both the fetus and parents [\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The pathogenicity assessment of the detected variants was executed based on ACMG's existing guidelines [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], with variants deemed pathogenic or likely pathogenic taken as confirmatory genetic outcomes. Validation of these pivotal genetic results was done through Sanger sequencing. The analyses did not reveal any chromosomal irregularities or pathogenic variations within well-known CHD genes. However, an undiscovered variant emerged within the \u003cem\u003eSETD5\u003c/em\u003e gene, specifically at exon21: c.3601_3605del: p. W1201Efs*2 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This particular variant was absent in multiple reference populations such as 1000 Genomes (1000G), the Shenzhou Genome Database, the Human Exome Database (ExAC), and the Population Genome Mutation Frequency Database (gnomAD). Subsequent lineage analysis confirmed its status as a de novo mutation. Bioinformatics predictions indicate that this variant likely disrupts the gene's open reading frame, potentially modifying protein functionality. A previous report noted a loss of function (LOF) variant in the \u003cem\u003eSETD5\u003c/em\u003e gene linked with a familial atrial septal and ventricular septal defects case [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Collating this data, the inference is that the identified variant holds pathogenic properties and might elucidate the observed fetal cardiac aberration.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe first diagnosed \u003cem\u003eSETD5\u003c/em\u003e mutated fetuses prenatal, manifesting clinically with an ostium primum atrial septal defect, potential upper ventricular septal anomaly, and slight tricuspid regurgitation. An extensive exploration of both literature and public repositories was undertaken to accumulate insights on prior clinical instances related to \u003cem\u003eSETD5\u003c/em\u003e mutations (refer to Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Congenital heart disease was present in 43.3% of the \u003cem\u003eSEDT5\u003c/em\u003e patients we enumerated, cystic hygroma was present in 3.3%, Intellectual disability/Developmental delay was present in 86.7%, Ritualized behavior and/or autism was present in 20%, Hypotonia/Epilepsy was present in 53.3%, Facial Dysmorphism was present in 96.7%, Postaxial polydactyly was present in 26.7%, Scoliosis, kyphosis or lordosis was present in 26.7%, Gastrointestinal abnormalities was present in 23.3% and Genitourinary defects was present in 10%。\u003c/p\u003e \u003cp\u003eRecent studies have underscored the pivotal influence of \u003cem\u003esetd5\u003c/em\u003e during embryonic maturation and growth phases. Notably, embryos devoid of \u003cem\u003esetd5\u003c/em\u003e manifest pronounced irregularities in areas such as neural tube organization, cardiac morphology, and the process of somitogenesis. A focused exploration into cardiovascular anomalies emphasized that close to half of the \u003cem\u003eSetd5\u003c/em\u003e null embryos manifested active cardiac pulsations by E9.5. This observation received validation through the comprehensive staining of cardinal cardiac differentiation indicators. In parallel, the absence of \u003cem\u003eSetd5\u003c/em\u003e in embryonic stem cells led to hindered cellular growth, augmented apoptotic activity, erratic cell cycle transitions, curtailed cardiomyocyte differentiation potential, and notable gene expression modulations [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A research endeavor led by Michelle Yu-Qing Cheung [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] employing a murine model unveiled the indispensability of \u003cem\u003esetd5\u003c/em\u003e in heart morphogenesis within the cardiopharyngeal mesoderm, with its haploinsufficiency culminating in outflow tract malformations in rodents. Synthesizing insights from our study with extant literature, there emerges a hypothesis positioning the \u003cem\u003eSETD5\u003c/em\u003e gene as a potential influencer in congenital heart disease etiology. Yet, the intricate pathways and modalities through which \u003cem\u003eSETD5\u003c/em\u003e steers cardiac morphogenesis and operationality are yet to be comprehensively delineated. As such, there is a pressing need for expanded research efforts focusing on the pathobiological intricacies linked with \u003cem\u003eSETD5\u003c/em\u003e variant manifestations.\u003c/p\u003e \u003cp\u003eIn a pioneering documentation by Krzysztof Szczałuba [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], a unique familial instance of \u003cem\u003eSETD5\u003c/em\u003e mutation was brought to light, observed in a pair of siblings. The progenitor of this mutation was their father, manifesting only subtle cognitive challenges. Among the siblings, one exhibited a myriad of clinical features including a combined partial atrioventricular septal defect, patent ductus arteriosus, persistent left superior vena cava, alongside other morphological anomalies. The other sibling demonstrated a partial atrioventricular septal defect complemented by distinct developmental irregularities. In a separate study by Z\u0026ouml;e Powis[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], an examination of 14 individuals with variations in the \u003cem\u003eSETD5\u003c/em\u003e gene was conducted. Predominantly, individuals in this grouping displayed overlapping phenotypes previously identified, encapsulating developmental lags and psychiatric challenges. Interestingly, within this group, two individuals were diagnosed with an accompanying partial atrioventricular septal defect, while another had a ventricular septal anomaly. Another notable contribution was from Lettie E. et al [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], highlighting an infantile case wherein \u003cem\u003eSETD5\u003c/em\u003e variations culminated in an echocardiographically-detected ventricular septal defect.\u003c/p\u003e \u003cp\u003eBased on the above findings and the clinical characteristics of the cases reported in this study, we confirm that congenital heart disease, including atrial and ventricular septal defects, is a prenatal clinical feature caused by mutations in this gene.\u003c/p\u003e \u003cp\u003eIn addition to the prenatal case reported here, a case of prenatal cystic hygroma in early pregnancy associated with a mutation in \u003cem\u003eSETD5\u003c/em\u003e has been reported in the literature [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], which presented with cystic hygroma and a thickened nuchal fold during gestation, and the results of Microarray analysis of placental DNA were normal, however, facial deformities and early neurodevelopmental syndrome appeared in less than two years of age, and the analysis was performed by whole-exome sequencing, which revealed that there was a mutation in \u003cem\u003eSETD5\u003c/em\u003e. Therefore, \u003cem\u003eSETD5\u003c/em\u003e mutations may manifest as atrial and ventricular septal defects and cystic hygroma in the prenatal period, and physicians should be alerted to the presence of these two phenotypes in the fetus during the prenatal period.\u003c/p\u003e \u003cp\u003eIn this prenatal case, clinical manifestations such as atrial septal defect and the possibility of an upper ventricular septal defect were observed. Such conditions, which are prevalent within congenital heart diseases, are potentially manageable through surgical interventions postnatally, usually resulting in improved prognoses. Intriguingly, the implicated gene, \u003cem\u003eSETD5\u003c/em\u003e, has been established as a significant contributor to neurodevelopmental anomalies, including intellectual disability (ID), autism spectrum disorders, and KBG syndromes. This gene also constitutes a vital component of the 3p25.3 microdeletion syndrome, particularly associated with three genes (THUMPD3, \u003cem\u003eSETD5\u003c/em\u003e, and THUMPD3-AS1) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Detrimental alterations within \u003cem\u003eSETD5\u003c/em\u003e can profoundly influence patient survival and life quality. In the absence of comprehensive genetic testing for this case, cardiac ultrasonography might have been the sole criterion, fetal prognosis may be grossly misjudged based on cardiac ultrasound findings alone. With a plethora of clinical syndromes linked to congenital heart disease, the implementation of prenatal whole exome sequencing technology is pivotal. It lays the foundation for meticulous counseling, greatly enhancing the precision in prenatal diagnostic and prognostic assessments [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\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\u003eComparison of the Clinical Features Observed by previous study and in our case\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical feature\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOur patient\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMin Pan et al.\u003c/p\u003e \u003cp\u003e(2020) \u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSzczaluba et al. al.(2016) \u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGrozeva et al. (2015)\u003c/p\u003e \u003cp\u003e (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eKuechler et al. (2015) \u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePowis et al. (2017) \u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePascolini et al. (2022) \u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eRawlins\u003c/p\u003e \u003cp\u003eet al. (2017) \u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at last examination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003efetus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003evaried\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003evaried\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003evaried\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003evaried\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4 weeks\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongenital heart defects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecystic hygroma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntellectual disability\u003c/p\u003e \u003cp\u003e /Developmental delay\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRitualized behavior \u003c/p\u003e \u003cp\u003eand/or autism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypotonia/Epilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFacial Dysmorphism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostaxial polydactyly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScoliosis, kyphosis or lordosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal abnormalities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenitourinary defects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003e\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003e\u003cem\u003e+, positive; -, negative; NA, not available\u003c/em\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis is the first prenatal diagnosis of a fetus with a \u003cem\u003eSETD5\u003c/em\u003e mutation, which broadens the known mutation range and clinical manifestations linked to the \u003cem\u003eSETD5\u003c/em\u003e gene. We confirm that mutations in this gene associated with congenital heart diseases, notably atrial and ventricular septal anomalies, exhibiting as a distinct prenatal clinical phenotype with a low penetrance. Consequently, understanding the pathophysiological implications of \u003cem\u003eSETD5\u003c/em\u003e mutations becomes imperative. When anomalies surface during prenatal cardiac ultrasonography, there's a strong recommendation to pursue additional genetic assessments. This will ascertain if the detected mutation can be attributed to a causative gene, help eliminate concerns over other genetic aberrations, and facilitate early interventions for optimal outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors extend their gratitude to the parents of the fetus for their valuable contribution in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was designed by HX and YH. JF, HS and HJ were responsible for the collection of study materials or samples. HJ and HX provided fetal echocardiograms. The sequencing experiments were conducted by JF and SZ. Data collection and aggregation were performed by FJ, HS and HJ. Data analysis and interpretation were carried out by JF, HS, and HJ. The manuscript was written by JF and HS. All authors, JF, HS, and HJ \u0026nbsp; made equal contributions to this work. The final manuscript was read and approved by all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (U21A20523) to YH which played the role in the collection, analysis and interpretation of data and in writing the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe raw data obtained from whole-exome sequencing of the family in this study cannot be publicly accessed due to the need to protect participant confidentiality. Furthermore, in accordance with the regulations of the People\u0026apos;s Republic of China on the management of human Genetic Resources, the original data of genetic resources involving clinical patients cannot be disclosed without approval. However, re-analysis of the whole-exome sequencing data can be made available upon reasonable request, and interested parties can contact Prof. Yihua He (Email: [email protected]) at the Department of Echocardiography in Beijing Anzhen Hospital, Capital Medical University, Beijing, China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Beijing Anzhen Hospital,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCapital Medical University. The parents agreed to participate in this study and\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eprovided signed informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present research secured approval from the Beijing Anzhen Hospital\u0026apos;s Ethics Committee, affiliated with Capital Medical University. The parents have provided informed written consent for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLi M, Hou Y, Zhang Z, Zhang B, Huang T, Sun A, Shao G, Lin Q. Structure, activity and function of the lysine methyltransferase SETD5. Front Endocrinol(Lausanne). 2023;14:1089527.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKellogg G, Sum J, Wallerstein R. Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features with further definition of a critical region. Am J Med Genet A. 2013;161:1405\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrozeva D, Carss K, Spasic-Boskovic O, Parker MJ, Archer H, Firth HV, et al. 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Pediatr Neurol. 2023;138:25\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnderson E, Lam Z, Arundel P, Parker M, Balasubramanian M. Expanding the phenotype of SETD5-related disorder and presenting a novel association with bone fragility. Clin Genet. 2021;100(3):352\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRychik J, Ayres N, Cuneo B, Gotteiner N, Hornberger L, Spevak PJ, et al. American Society of Echocardiography Guidelines and Standards for Performance of the Fetal Echocardiogram. J Am Soc Echocardiography. 2004;17(7):803\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun H, et al. Genetics and clinical features of noncompaction cardiomyopathy in the fetal population. Front Cardiovasc Med. 2021;7:617561.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun H, et al. Contribution of single-gene defects to congenital cardiac lef-sided lesions in the prenatal setting. Ultrasound Obst Gyn. 2020;56:225\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi H, Durbin R. Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics. 2009;25:1754\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiggs ER, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020;22:245\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcKenna A, et al. Te genome analysis toolkit: A mapreduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297\u0026ndash;303.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang K, Li M, Hakonarson HANNOVAR. Functional annotation of genetic variants from high-throughput sequencing DATA. 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Clin Dysmorphol. 2017;26(2):95\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan M, Liu YN, Xu LL, Li DZ. First-trimester cystic hygroma and neurodevelopmental disorders: The association to remember. Taiwan J Obstet Gynecol. 2020;59(6):960\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFernandes IR, Cruz ACP, Ferrasa A, Phan D, Herai RH, Muotri AR. Genetic variations on SETD5 underlying autistic conditions. Dev Neurobiol. 2018;78(5):500\u0026ndash;518. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/dneu.22584\u003c/span\u003e\u003cspan address=\"10.1002/dneu.22584\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2018 Mar 5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrozeva D, Carss K, Spasic-Boskovic O, Tejada MI, Gecz J, Shaw M, Italian X-linked Mental Retardation Project; GOLD Consortium;, Hurles M, Raymond FL et al. Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability. Hum Mutat. 2015;36(12):1197\u0026thinsp;\u0026ndash;\u0026thinsp;204.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakagawa T, Hattori S, Hosoi T, Nakayama K. Neurobehavioral characteristics of mice with SETD5 mutations as models of IDD23 and KBG syndromes. Front Genet. 2023;13:1022339.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXue Y, Ankala A, Wilcox WR, Hegde MR. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med. 2015;17:444\u0026ndash;51. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/gim.2014.122\u003c/span\u003e\u003cspan address=\"10.1038/gim.2014.122\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePascolini G, Gnazzo M, Novelli A, Grammatico P. Clinical refinement of the SETD5-associated phenotype in a child displaying novel features and KBG syndrome-like appearance. Am J Med Genet A. 2022;188(5):1623\u0026ndash;5.\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":"SETD5, congenital heart disease, gene mutation","lastPublishedDoi":"10.21203/rs.3.rs-4542929/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4542929/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMutations in the \u003cem\u003eSETD5\u003c/em\u003e gene lead to the autosomal dominant disorder termed Mental retardation type 23. Limited clinical reports have made it challenging to comprehensively delineate the clinical outcomes and mutation spectrum associated with this gene.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e \u003cp\u003eIn this study, a fetal case presenting an ostium primum atrial septal defect, a presumed upper ventricular septal defect was identified through fetal cardiac ultrasound. Following this discovery, an in-depth genetic assessment, encompassing whole exome sequencing, was executed on the fetus and both parents to pinpoint potential genetic origins. From the exome data, a previously undocumented variant (exon21: c.3601_3605del: p. W1201Efs*2) in the SETD5 gene (NM_001080517.3) surfaced. Lineage analysis validated this as a de novo variant. This mutation disrupts the gene's open reading frame, consequently affecting protein functionality. This is the first prenatal diagnosis of a fetus with a SETD5 mutation, advancing the time of diagnosis while broadening our understanding of the gene's mutation spectrum and clinical manifestations.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur study confirms that congenital heart disease, including atrial and ventricular septal defects, is a prenatal clinical feature caused by mutations in this gene. Fetal cardiac ultrasound can be used as a means of early screening for such disorders, and the importance of prenatal whole-exome sequencing technology was emphasized.\u003c/p\u003e","manuscriptTitle":"First diagnosis of fetal SETD5 mutation during pregnancy，demonstrating an association with congenital heart disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-27 19:57:15","doi":"10.21203/rs.3.rs-4542929/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":"6eaad6c6-8652-4554-be9b-0cd169b96aae","owner":[],"postedDate":"June 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-27T19:57:17+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-27 19:57:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4542929","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4542929","identity":"rs-4542929","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}