Fetal de novo 6q24.3-q25.1 microdeletion encompassing TAB2 gene associated with small left atrium, growth restriction, and urogenital/anal abnormalities: a case report

Fetal de novo 6q24.3-q25.1 microdeletion encompassing TAB2 gene associated with small left atrium, growth restriction, and urogenital/anal abnormalities: a case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Fetal de novo 6q24.3-q25.1 microdeletion encompassing TAB2 gene associated with small left atrium, growth restriction, and urogenital/anal abnormalities: a case report Xiufen Bu, Xu Li, Li Zeng, Rong Tan, Can Peng, Shihao Zhou, Siyuan Linpeng, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6972884/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Deletions involving TAB2 gene have been identified as the cause of a multi - system disorder, including cardiac abnormalities, distinctive facial features, growth abnormalities and connective tissue abnormalities. Cardiac abnormalities are a key feature and are present in nearly all patients. The majority of the reported patients are children or adults, while prenatal cases are rare. Whether cardiac abnormalities are the primary prenatal phenotype of TAB2 deficiency remains unclear. Case presentation: Here, we report a prenatal case where invasive prenatal diagnosis was performed because of thickened NT. The fetus had a normal karyotype. An SNP array analysis of the family revealed a de novo 1.12 Mb deletion on chromosome 6q24.3q25.1, which encompasses TAB2 gene. At 25 weeks of gestation, the fetus was found to have a small left atrium. Trio - based whole exome sequencing detected no pathogenic or likely pathogenic single nucleotide variants; however, it did identify the deletion on 6q24.3q25.1. Six weeks later, an ultrasound once more showed a small left atrium. Moreover, severe intrauterine growth restriction, hypospadias, and anal atresia were detected. The parents decided to terminate the pregnancy after genetic counseling. Subsequently, we reviewed all the TAB2 -related cases with available prenatal ultrasound findings. Conclusion The growth abnormalities resulting from 6q25.1 ( TAB2 ) microdeletion are more severe than cardiac abnormalities prenatally. We identified two new features, namely a small left atrium and anal atresia. Our study expands the spectrum of 6q25.1 ( TAB2 ) microdeletion and could provide evidence for the prenatal genetic counseling. TAB2 small left atrium intrauterine growth restriction anal atresia case report Figures Figure 1 Figure 2 Figure 3 1 Introduction Interstitial microdeletions in chromosome 6q are rare, and 6q24–25 microdeletion encompassing TAB2 gene has been identified as a locus for congenital heart disease (CHD)(Thienpont et al., 2010 ). TAB2 gene has been demonstrated to play a critical role in human cardiac development and is associated with congenital heart defects − 2 (CHTD2) (MIM#614980) according to Online Mendelian Inheritance in Man (OMIM)(Hamosh et al., 2021 ). CHTD2 is characterized by variable congenital heart defects, primarily involving the valves, but also including septal defects or aneurysms, and complex defects. In addition, cardiomyopathy and myocardial noncompaction have been reported in some patients. Some affected individuals exhibit non - cardiac phenotypes such as distinctive facial features, growth abnormalities, hypotonia, developmental delay and connective tissue abnormalities(Thienpont et al., 2010 ;Ackerman et al., 2016 ;Ritelli et al., 2018 ). No substantial phenotypic differences have been reported between patients with TAB2 deletions and those with intragenic variants(Engwerda et al., 2021 ). Heart disease is a key feature of the TAB2 -related phenotype. However, the spectrum of cardiac phenotype varies greatly, with some patients exhibiting severe cardiac abnormalities such as hypoplastic left heart syndrome and tetralogy of Fallot, while some patients have no structural cardiac malformations and only show late onset cardiomyopathy(Cheng et al., 2017 ;Engwerda et al., 2021 ). The majority of the reported patients are children or adults, and prenatal cases are rare. Whether cardiac abnormalities are the most common feature in fetuses carrying TAB2 deletion remains unclear to us. This is a challenge for genetic counseling in prenatal TAB2 deletion cases and it requires the accumulation of a large number of prenatal cases. Here, we identified a de novo deletion on chromosome 6q24.3q25.1 encompassing TAB2 gene in a fetus with a cardiac phenotype showing a small left atrium (LA), along with severe intrauterine growth restriction (IUGR), hypospadias, and anal atresia. 2 Case presentation A healthy 33-year-old woman (gravida 3, induced abortion 1, para 1) was referred to the Department of Medical Genetics at Changsha Hospital for Maternal and Child Health Care for genetic counseling at 16 weeks of gestation due to thickened NT (4.6 mm at 12 weeks and 6 days of gestation). Subsequently, amniocentesis was arranged. Then, both G - banding karyotype analysis (320 bands) and the Affymetrix CytoScan 750K SNP array were carried out on the obtained amniocytes. Karyotype analysis revealed a normal karyotype of 46,XY. The SNP microarray data from this family showed that the fetus had a 1.12 Mb de novo deletion on chromosome 6q24.3q25.1, spanning from position 148,739,085 to 149,802,239 (hg19) (Fig. 1 ). This region completely overlaps with five protein - coding genes: TAB2, SASH1 , SUMO4 , UST and ZC3H12D . Among them, TAB2 is associated with autosomal dominant CHTD2 and is predicted to be haploinsufficient by two or more HI predictors (with %HI < 10% and pLI ≥ 0.9). After genetic counseling, the parents decided to continue with the pregnancy. Subsequently, a fetal echocardiogram, which was arranged at 22 weeks and 5 days of gestation, detected no structural heart malformations. Later, at 25 weeks and 3 days of gestation, a level Ⅳ ultrasound indicated a small LA (7.1 mm) (Fig. 2 Ⅰ ). Given the abnormal result of cardiac ultrasound, we carried out trio-based whole exome sequencing (trio-WES) on the spare uncultured amniocytes. Trio - WES revealed no pathogenic or likely pathogenic single nucleotide variants associated with the phenotype. However, a de novo deletion was detected on chromosome 6q24.3q25.1, which encompassed TAB2 gene, and this finding was in accordance with the SNP array results. At 30 weeks and 3 days of gestation, a level Ⅲ ultrasound once more demonstrated that the LA was small, measuring 7.0 mm (Fig. 2 Ⅱ ). Additionally, the ultrasound revealed that the fetus had hypospadias (Fig. 2 Ⅲ ) and anal atresia (Fig. 2 Ⅳ ). Throughout the pregnancy, we monitored the fetal growth and observed that the fetal abdominal circumference (AC), femur length (FL), and humerus length (HL) were persistently small. Specifically, from 25 weeks and 3 days of gestation, their measurements were less than 5% (AC: 1.4%, FL < 1%, and HL < 1%), while the head circumference and biparietal diameter were in line with the gestational week (Fig. 3 ). We reanalyzed the trio-WES data and found no clinically significant mutations associated with the phenotype, apart from the de novo deletion in the 6q24.3q25.1 region. Taking into account the poor prognosis of the fetus, following genetic counseling, the parents made the decision to terminate the pregnancy. At 32 weeks of gestation, a male stillbirth was delivered, and the parents refused to consent to a fetal autopsy. Table 1 Summary of TAB2 deleted cases with available prenatal ultrasound findings. Case number Gender Age at genetic diagnosis Genetic abnormalities Size (Mb) Mode of inheritance Prenatal ultrasound findings Cardiac abnormality IUGR Genitourinary abnormality Others Present case M Prenatal arr[GRCh37]6q24.3q25.1(148739085_149802239)x1 1.06 De novo Small left atria Yes Hypospadias Thickened NT, anal atresia Case 1(Karmegaraj, 2024 ) Unknown Prenatal 471.5 - kb deletion on 6q25.1 ( TAB2 gene) by WES 0.47 Unkown Cardiomegaly, myxomatous tricuspid, mitral valve leaflets, thickened pulmonary valve, bicuspid aortic valves - - - Case 2(Nowaczyk et al., 2008 ) Patient 2 F Prenatal 46, XX, del(6)(q25.1q25.3). ish del (6)(wcp6+) 10.37 De novo Left axial displacement of the heart chambers, large patent foramen ovale, secundum atrial septal defect Yes - - Case 3(Cheng et al., 2017 ) (P2) F Newborn arr[GRCh37]6q25.1(149398652_149654593) 0.26 De novo Irregular fetal heart rate - - - Case 4(Cheng et al., 2017 ) (P10) F 1 years arr[GRCh37]6q24.3q25.1(148684126_150469060) 1.78 Unknown Fetal heart decelerations Yes - - Case 5(Cheng et al., 2017 ) (P11) F Newborn arr[GRCh37]6q24.3q25.1(148607207_151405588)x1 2.80 De novo Fetal heart decelerations Yes - - Case 6(Cheng et al., 2017 ) (P12) F 3 years arr[GRCh37]6q24.1q25.1(140073077_151572200)x1 11.5 De novo - Yes - - Case 7(Cheng et al., 2017 ) (P13) F 4 months arr[GRCh37]6q24.1q25.2(141004908_152822158)x1 11.82 De novo - Yes - - Case 8(Weiss et al., 2015 ) F 5 months arr[GRCh37]6q25.1(149580983_149861981)x1 0.28 Inherited TOF, short segment pulmonary atresia, severe prolapsing of the mitral and tricuspid valves - - - Case 9(Salpietro et al., 2015 ) F 6 years arr[GRCh37]6q25.1(149396427_150024732)x1 0.63 De novo - Yes - - Case 10(Nowaczyk et al., 2008 ) Patient 1 M 4 years 46, XY, del(6)(q25.1q25.3). ish del(6)(57H24x2) 10.13 De novo Apparent cardiomegaly Yes - - Case 11(Thienpont et al., 2010 )Patient A NA NA Breakpoint regions on chromosome 6: 143.72-143.74 Mb (proximal) to 150.21-150.22 Mb (distal) 6.4 De novo Hypopl aortic arch, coarctation of the aorta, ventricular septal defect Yes Hypospadias - Case 12(Stagi et al., 2015 ) M 1 years arr[GRCh37]6q24.2q25.2(143297976_154039064)x1 10.74 De novo Apparent cardiomegaly Yes - - Case 13(Cheng et al., 2020 ) M Newborn arr[GRCh37]6q24.3q25.1(148684028_150448233)x1 1.76 Inherited HLHS Yes Horseshoe kidney Short long bones Summary incidence 11/14 (78.4%) 11/14 (78.4%) 3/14 (21.4%) 2/14 (14.3%) M, male; F, female; NA, not available; WES, whole exome sequencing; IUGR, intrauterine growth restriction; TOF, tetralogy of Fallot; HLHS, hypoplastic left heart syndrome. 3 Discussion Table 2 encodes TGF beta-activated kinase 1-binding protein 2 (TAB-2), which consists of 693 amino acids. TAB2 deficiency has been associated with CHD and cardiomyopathy. In the reported patients, 100% presented with a primary cardiomyopathy characterized by reduced systolic function, while CHD was detected in 71% of the patients(Cheng et al., 2017 ). Atrial septal defects and/or ventricular septal defects are reported to be more prevalent in cases of TAB2 deletions compared to those with TAB2 mutations(Engwerda et al., 2021 ). Besides cardiac defects, 64% of individuals with the disease caused by TAB2 variants present with one or more extra - cardiac manifestations, among which the most frequent features are skeletal manifestations (including short stature, small extremities, short limbs, and pes planus) (63%), facial dysmorphism ( long and/or round face, a high forehead, almond-shaped eyes/dystopia canthorum, a prominent nose and columella, maxillary hypoplasia, and a long philtrum) (54%), and connective tissue disorders (54%)(Hanson et al., 2022a ). However, among patients who have TAB2 deletions, nearly every one of them exhibits a composite extra-cardiac phenotype(Cheng et al., 2017 ). Distinctive facial features (88%-100%), short stature (disproportionate in most reports) (73% − 84%) and connective tissue abnormalities (48% − 82%) are the most frequent non - cardiac characteristics(Engwerda et al., 2021 ). Nevertheless, the majority of the reported patients were children or adults, while prenatal cases were rare. It remains unclear what the main prenatal phenotypes of fetuses with TAB2 deficiency are, which poses a significant challenge for prenatal genetic counseling. In our case, the fetus showed a small left heart atrium. Decreased volumes of left heart atrium have been attributed to several different etiologies(Opotowsky et al., 2012 ;Lang et al., 2015 ;Aviram et al., 2016 ). It may be due to the presence of space occupying lesions, such as intra-atrial tumors and extracardiac tumors. In other cases, it might be caused by reversible factors, such as intravascular volume depletion and a reduction in the LA preload. In our case, we essentially ruled out the presence of space-occupying lesions in our fetus by echocardiography and systematic ultrasonography. Invisible vascular or valve abnormalities may be the cause of the small left atrium. Unfortunately, there was no autopsy in our case, so the exact cause of the small LA remains unknown. Nevertheless, it has been demonstrated that even when an apparent etiology for small LA is not detected, the prognosis remains poor and has a high risk of mortality(Rozenbaum et al., 2023 ). None of the other four protein-coding genes within the deletion region, which we described previously, were associated with cardiac development, and we also excluded other mutations in cardiac-associated genes using trio-WES. Based on these findings, the cardiac features in our case can be attributed to TAB2 haploinsufficiency. Our report is the first report associating TAB2 haploinsufficiency with a small LA. We comprehensively reviewed mutations or deletions in the TAB2 gene. It was noted that in the majority of cases, there were no reported abnormalities detected by prenatal ultrasound, or there was a lack of available phenotypic descriptions. In the literature, among approximately 70 reported cases with TAB2 gene mutations, about 6 cases had descriptions of prenatal phenotypes which were respectively manifested as CHD(Liu et al., 2020 ;Koene et al., 2022 ), short legs(Deng et al., 2023 ), and supraventricular tachycardia accompanied by a small pericardial effusion (Hanson et al., 2022b ). Upon our review, we discovered that, out of around 50 deletion cases reported in the literature, about 13 cases had available descriptions of prenatal phenotypes and the size of the deletions varied from 0.28 Mb to 11.82 Mb (Table 1 ). Our findings revealed that, including our present case, 78.6% (11/14) of these cases manifested a prenatal cardiac phenotype. Among these 11 cases with a cardiac phenotype, 3 cases demonstrated only mild soft - marker abnormalities like fetal heart decelerations or an irregular fetal heart rate ( Cases 3 to 5 ). Therefore, the cardiac phenotype may not be the most distinctive characteristic of the affected fetuses. Moreover, we discovered that IUGR was observed in 78.6% (11/14) of the fetuses with deletions. The other three fetuses that did not develop IUGR carried the smallest deletion fragments, with the sizes varying from 0.26 Mb to 0.47 Mb ( Case 1 , Case 3 and Case 8 ). Most of the reported cases in the TAB2 deletions spectrum exhibited earlier and more severe growth abnormalities compared to the TAB2 mutations, and we therefore hypothesize the likely presence of at least one gene responsible for physiological growth processes within this deleted region that acts in conjunction with TAB2 to jointly affect the growth of individuals(Woods et al., 2022 ). Most literature focuses on cardiac and common extra - cardiac abnormalities, yet provides little clinical information on other systemic malformations. Genitourinary abnormalities (such as horseshoe kidney, testicular dysgenesis and cryptorchidism) and gastrointestinal abnormalities (such as feeding difficulties, abdominal mesentery morphology and jejunostomy) can also be seen in some TAB2 -related cases(Cheng et al., 2020 ;Woods et al., 2022 ;Deng et al., 2023 ). These malformations may be caused by other mutations or may be manifestations of TAB2 -associated syndromes. Hypospadias was found in our case, which has been occasionally reported in other literature(Thienpont et al., 2010 ;Woods et al., 2022 ). Our case also presented a gastrointestinal malformation, namely anal atresia, which was not previously reported in other cases. When other variants have been eliminated, and the cases of TAB2 deficiency exhibit more severe phenotypes compared to mutant cases, it is reasonable to believe that anal atresia may be another clinical manifestation of TAB2 -deficiency syndrome. In summary, unique features of this subject included underdevelopment of a small LA and anal atresia, which were not reported among previously published individuals with 6q25.1 microdeletion syndrome. We summarized previously reported cases and discovered that growth abnormalities resulting from 6q25.1 ( TAB2 ) microdeletion are more severe than cardiac abnormalities prenatally. Our study expands the mutation spectrum of the TAB2 gene deletion and can offer evidence for prenatal genetic counseling. Abbreviations CHD Congenital heart disease LA Left atrium IUGR Intrauterine growth restriction trio-WES trio-based Whole exome sequencing TOF Tetralogy of Fallot HLHS Hypoplastic left heart syndrome. Declarations Ethics approval and consent to participate This study was approved by the Changsha Hospital for Maternal & Child Healthcare. The studies were conducted in accordance with the local legislation and institutional requirements. Consent for publication All the patients/legal guardians provided written informed consent to participate in this study, including review of relevant medical records and consent for publication. Availability of data and materials The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2021) in National Genomics Data Center (Nucleic Acids Res 2024), China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA012182) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human. Competing interests 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. Funding The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Program of Health Commission of Hunan Province (No. 202301036352 and 202305026432). Authors' contributions XB: Writing–original draft. XL: Writing–original draft. LZ: Writing–review and editing, Conceptualization, Data curation, Formal Analysis, Methodology, Project administration, Supervision, Validation. RT: Writing–review and editing, Investigation, Methodology, Project administration, Resources, Supervision, Validation. CP: Writing–review and editing, Data curation, Investigation, Methodology, Project administration, Resources. SZ: Writing–review and editing; Data curation; Methodology; Formal Analysis. SL: Investigation, Methodology, Resources, Supervision, Validation, Writing–review and editing. JL: Supervision, Validation, Writing–review and editing, Conceptualization, Formal Analysis, Funding acquisition, Project administration, Resources. Acknowledgments We would like to thank Berry-Beijing (China) for their technical contributions to this study. References Ackerman JP, Smestad JA, Tester DJ, Qureshi MY, Crabb BA, Mendelsohn NJ, Ackerman MJ. 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09:23:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6972884/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6972884/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91830468,"identity":"dc8e480c-3369-4733-bc32-f9b71660bfed","added_by":"auto","created_at":"2025-09-22 09:03:00","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":334236,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-6972884/v1/d58dc742d1cd5ab3a3338fc9.docx"},{"id":91826734,"identity":"0fc6a160-e1e4-4c07-ab4d-59b380a4de90","added_by":"auto","created_at":"2025-09-22 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08:39:00","extension":"xml","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":95312,"visible":true,"origin":"","legend":"","description":"","filename":"e885b85cacb84e679019c608c9c375531structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-6972884/v1/847fe474052d91c8e0e0b250.xml"},{"id":91826747,"identity":"8040cb4d-127c-4d52-b02d-d454106884d0","added_by":"auto","created_at":"2025-09-22 08:39:00","extension":"html","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":102508,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-6972884/v1/5736b3d80be958af839e72a7.html"},{"id":91827357,"identity":"53058905-ccf4-4265-b9ad-1085504e373e","added_by":"auto","created_at":"2025-09-22 08:47:00","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":86700,"visible":true,"origin":"","legend":"\u003cp\u003eA 1.12 Mb \u003cem\u003ede novo\u003c/em\u003e deletion on chromosome 6q24.3q25.1. SNP array analysis revealed that the parental chromosomes were normal, whereas the fetus had a 1.12 Mb deletion at the 6q24.3q25.1 locus. (The color of orange represents the result of the fetus. The color of green represents the result of the mother. The color of purple represents the result of the father. The red block indicates the position of the 6q24.3q25.1 deletion.)\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6972884/v1/e5346a6e052dcb10a26223eb.jpeg"},{"id":91827354,"identity":"243f883c-870f-4dfd-b839-73bb4f53e0b8","added_by":"auto","created_at":"2025-09-22 08:47:00","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":71707,"visible":true,"origin":"","legend":"\u003cp\u003eSonographic image of the fetus. I: Sonographic image of the fetus at 25 weeks and 5 days of \u003ca href=\"https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/pregnancy\" title=\"Learn more about gestation from ScienceDirect's AI-generated Topic Pages\"\u003egestation\u003c/a\u003e shows a small size of left atrium (left: 7.1 mm, right: 9.6mm). II: Sonographic image of the fetus at 30 weeks and 3 days of \u003ca href=\"https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/pregnancy\" title=\"Learn more about gestation from ScienceDirect's AI-generated Topic Pages\"\u003egestation\u003c/a\u003e shows a small size of left atrium (left: 7.0 mm, right: 11.2mm). III: Sonographic image of the fetus at 30 weeks and 3 days of \u0026nbsp;\u003ca href=\"https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/pregnancy\" title=\"Learn more about gestation from ScienceDirect's AI-generated Topic Pages\"\u003egestation\u003c/a\u003e shows hypospadias. IV: Sonographic image of the fetus at 30 weeks and 3 days of \u003ca href=\"https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/pregnancy\" title=\"Learn more about gestation from ScienceDirect's AI-generated Topic Pages\"\u003egestation\u003c/a\u003e shows anal atresia.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6972884/v1/879efcf4e5515ba99d88efbc.jpeg"},{"id":91826736,"identity":"27fdffee-c675-4f7e-8814-f68663527fc9","added_by":"auto","created_at":"2025-09-22 08:39:00","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":66918,"visible":true,"origin":"","legend":"\u003cp\u003eThe growth curve of the fetus spanning from 17 to 30 weeks of gestation. (A) The trend of the abdominal circumference increasing with the age of the fetus. (B) The trend of the femur length increasing with the age of the fetus. (C) The trend of the humerus length increasing with the age of the fetus. (D) The trend of the head circumference increasing with the age of the fetus, according to the fetal growth standard of Asians from the National Institute of Child Health and Human Development (Buck Louis et al., 2015).\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6972884/v1/2ee8f537b12f8c10b4cd4a29.jpeg"},{"id":91831755,"identity":"23203571-b645-4fc4-9c38-dfff136d86a2","added_by":"auto","created_at":"2025-09-22 09:11:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":952632,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6972884/v1/b3a1a455-66c4-461f-805e-e6735b452dac.pdf"},{"id":91827351,"identity":"19bda6d1-4305-4910-a9c7-c3301d9d170e","added_by":"auto","created_at":"2025-09-22 08:47:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":534216,"visible":true,"origin":"","legend":"","description":"","filename":"CAREchecklist.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6972884/v1/26641946b9f58b7d1ebc1bdb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Fetal de novo 6q24.3-q25.1 microdeletion encompassing TAB2 gene associated with small left atrium, growth restriction, and urogenital/anal abnormalities: a case report","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eInterstitial microdeletions in chromosome 6q are rare, and 6q24\u0026ndash;25 microdeletion encompassing \u003cem\u003eTAB2\u003c/em\u003e gene has been identified as a locus for congenital heart disease (CHD)(Thienpont et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). \u003cem\u003eTAB2\u003c/em\u003e gene has been demonstrated to play a critical role in human cardiac development and is associated with congenital heart defects \u0026minus;\u0026thinsp;2 (CHTD2) (MIM#614980) according to Online Mendelian Inheritance in Man (OMIM)(Hamosh et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). CHTD2 is characterized by variable congenital heart defects, primarily involving the valves, but also including septal defects or aneurysms, and complex defects. In addition, cardiomyopathy and myocardial noncompaction have been reported in some patients. Some affected individuals exhibit non - cardiac phenotypes such as distinctive facial features, growth abnormalities, hypotonia, developmental delay and connective tissue abnormalities(Thienpont et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2010\u003c/span\u003e;Ackerman et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2016\u003c/span\u003e;Ritelli et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). No substantial phenotypic differences have been reported between patients with \u003cem\u003eTAB2\u003c/em\u003e deletions and those with intragenic variants(Engwerda et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Heart disease is a key feature of the \u003cem\u003eTAB2\u003c/em\u003e-related phenotype. However, the spectrum of cardiac phenotype varies greatly, with some patients exhibiting severe cardiac abnormalities such as hypoplastic left heart syndrome and tetralogy of Fallot, while some patients have no structural cardiac malformations and only show late onset cardiomyopathy(Cheng et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2017\u003c/span\u003e;Engwerda et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). The majority of the reported patients are children or adults, and prenatal cases are rare. Whether cardiac abnormalities are the most common feature in fetuses carrying \u003cem\u003eTAB2\u003c/em\u003e deletion remains unclear to us. This is a challenge for genetic counseling in prenatal \u003cem\u003eTAB2\u003c/em\u003e deletion cases and it requires the accumulation of a large number of prenatal cases.\u003c/p\u003e\u003cp\u003eHere, we identified a \u003cem\u003ede novo\u003c/em\u003e deletion on chromosome 6q24.3q25.1 encompassing \u003cem\u003eTAB2\u003c/em\u003e gene in a fetus with a cardiac phenotype showing a small left atrium (LA), along with severe intrauterine growth restriction (IUGR), hypospadias, and anal atresia.\u003c/p\u003e"},{"header":"2 Case presentation","content":"\u003cp\u003eA healthy 33-year-old woman (gravida 3, induced abortion 1, para 1) was referred to the Department of Medical Genetics at Changsha Hospital for Maternal and Child Health Care for genetic counseling at 16 weeks of gestation due to thickened NT (4.6 mm at 12 weeks and 6 days of gestation). Subsequently, amniocentesis was arranged. Then, both G - banding karyotype analysis (320 bands) and the Affymetrix CytoScan 750K SNP array were carried out on the obtained amniocytes. Karyotype analysis revealed a normal karyotype of 46,XY. The SNP microarray data from this family showed that the fetus had a 1.12 Mb \u003cem\u003ede novo\u003c/em\u003e deletion on chromosome 6q24.3q25.1, spanning from position 148,739,085 to 149,802,239 (hg19) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This region completely overlaps with five protein - coding genes: \u003cem\u003eTAB2, SASH1\u003c/em\u003e, \u003cem\u003eSUMO4\u003c/em\u003e, \u003cem\u003eUST\u003c/em\u003e and \u003cem\u003eZC3H12D\u003c/em\u003e. Among them, \u003cem\u003eTAB2\u003c/em\u003e is associated with autosomal dominant CHTD2 and is predicted to be haploinsufficient by two or more HI predictors (with %HI\u0026thinsp;\u0026lt;\u0026thinsp;10% and pLI\u0026thinsp;\u0026ge;\u0026thinsp;0.9). After genetic counseling, the parents decided to continue with the pregnancy. Subsequently, a fetal echocardiogram, which was arranged at 22 weeks and 5 days of gestation, detected no structural heart malformations. Later, at 25 weeks and 3 days of gestation, a level Ⅳ ultrasound indicated a small LA (7.1 mm) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003eⅠ\u003c/b\u003e). Given the abnormal result of cardiac ultrasound, we carried out trio-based whole exome sequencing (trio-WES) on the spare uncultured amniocytes. Trio - WES revealed no pathogenic or likely pathogenic single nucleotide variants associated with the phenotype. However, a \u003cem\u003ede novo\u003c/em\u003e deletion was detected on chromosome 6q24.3q25.1, which encompassed \u003cem\u003eTAB2\u003c/em\u003e gene, and this finding was in accordance with the SNP array results. At 30 weeks and 3 days of gestation, a level Ⅲ ultrasound once more demonstrated that the LA was small, measuring 7.0 mm (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003eⅡ\u003c/b\u003e). Additionally, the ultrasound revealed that the fetus had hypospadias (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003eⅢ\u003c/b\u003e) and anal atresia (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003eⅣ\u003c/b\u003e). Throughout the pregnancy, we monitored the fetal growth and observed that the fetal abdominal circumference (AC), femur length (FL), and humerus length (HL) were persistently small. Specifically, from 25 weeks and 3 days of gestation, their measurements were less than 5% (AC: 1.4%, FL\u0026thinsp;\u0026lt;\u0026thinsp;1%, and HL\u0026thinsp;\u0026lt;\u0026thinsp;1%), while the head circumference and biparietal diameter were in line with the gestational week (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). We reanalyzed the trio-WES data and found no clinically significant mutations associated with the phenotype, apart from the \u003cem\u003ede novo\u003c/em\u003e deletion in the 6q24.3q25.1 region. Taking into account the poor prognosis of the fetus, following genetic counseling, the parents made the decision to terminate the pregnancy. At 32 weeks of gestation, a male stillbirth was delivered, and the parents refused to consent to a fetal autopsy.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\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\u003eSummary of \u003cem\u003eTAB2\u003c/em\u003e deleted cases with available prenatal ultrasound findings.\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=\"char\" char=\".\" 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\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eCase number\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eAge at genetic diagnosis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eGenetic abnormalities\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSize\u003c/p\u003e\u003cp\u003e(Mb)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eMode\u0026nbsp;of\u003c/p\u003e\u003cp\u003einheritance\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c10\" namest=\"c7\"\u003e\u003cp\u003ePrenatal ultrasound findings\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCardiac abnormality\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eIUGR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eGenitourinary abnormality\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePresent case\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM\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\u003earr[GRCh37]6q24.3q25.1(148739085_149802239)x1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eDe novo\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSmall left atria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHypospadias\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eThickened NT, anal atresia\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 1(Karmegaraj, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2024\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnknown\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\u003e471.5 - kb deletion on 6q25.1 (\u003cem\u003eTAB2\u003c/em\u003e gene) by WES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eUnkown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCardiomegaly, myxomatous tricuspid, mitral valve leaflets, thickened pulmonary valve, bicuspid aortic valves\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 2(Nowaczyk et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2008\u003c/span\u003e) Patient 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\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\u003e46, XX, del(6)(q25.1q25.3). ish del (6)(wcp6+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e10.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eDe novo\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLeft axial displacement of the heart chambers, large patent foramen ovale, secundum atrial septal defect\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 3(Cheng et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2017\u003c/span\u003e) (P2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNewborn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003earr[GRCh37]6q25.1(149398652_149654593)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eDe novo\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eIrregular fetal heart rate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 4(Cheng et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2017\u003c/span\u003e) (P10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003earr[GRCh37]6q24.3q25.1(148684126_150469060)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFetal heart decelerations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 5(Cheng et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2017\u003c/span\u003e) (P11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNewborn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003earr[GRCh37]6q24.3q25.1(148607207_151405588)x1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eDe novo\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFetal heart decelerations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 6(Cheng et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2017\u003c/span\u003e) (P12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003earr[GRCh37]6q24.1q25.1(140073077_151572200)x1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e11.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eDe novo\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 7(Cheng et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2017\u003c/span\u003e) (P13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003earr[GRCh37]6q24.1q25.2(141004908_152822158)x1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e11.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eDe novo\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 8(Weiss et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2015\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003earr[GRCh37]6q25.1(149580983_149861981)x1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eInherited\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTOF, short segment pulmonary atresia, severe prolapsing of the mitral and tricuspid valves\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 9(Salpietro et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2015\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003earr[GRCh37]6q25.1(149396427_150024732)x1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eDe novo\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 10(Nowaczyk et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2008\u003c/span\u003e) Patient 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e46, XY, del(6)(q25.1q25.3). ish del(6)(57H24x2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e10.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eDe novo\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eApparent cardiomegaly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 11(Thienpont et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2010\u003c/span\u003e)Patient A\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\u003eBreakpoint\u0026nbsp;regions\u0026nbsp;on\u0026nbsp;chromosome\u0026nbsp;6: 143.72-143.74 Mb (proximal) to 150.21-150.22 Mb (distal)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eDe novo\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHypopl aortic arch, coarctation of the aorta, ventricular septal defect\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHypospadias\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 12(Stagi et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2015\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003earr[GRCh37]6q24.2q25.2(143297976_154039064)x1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e10.74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eDe novo\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eApparent cardiomegaly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase 13(Cheng et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2020\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNewborn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003earr[GRCh37]6q24.3q25.1(148684028_150448233)x1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eInherited\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHLHS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHorseshoe kidney\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eShort long bones\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSummary incidence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e11/14\u003c/p\u003e\u003cp\u003e(78.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e11/14 (78.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3/14\u003c/p\u003e\u003cp\u003e(21.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e2/14\u003c/p\u003e\u003cp\u003e(14.3%)\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\u003eM, male; F, female; NA, not available; WES, whole exome sequencing; IUGR, intrauterine growth restriction; TOF, tetralogy of Fallot; HLHS, hypoplastic left heart syndrome.\u003c/p\u003e"},{"header":"3 Discussion","content":"\u003cp\u003e\u003cem\u003eTable\u0026nbsp;2\u003c/em\u003e encodes TGF beta-activated kinase 1-binding protein 2 (TAB-2), which consists of 693 amino acids. \u003cem\u003eTAB2\u003c/em\u003e deficiency has been associated with CHD and cardiomyopathy. In the reported patients, 100% presented with a primary cardiomyopathy characterized by reduced systolic function, while CHD was detected in 71% of the patients(Cheng et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Atrial septal defects and/or ventricular septal defects are reported to be more prevalent in cases of \u003cem\u003eTAB2\u003c/em\u003e deletions compared to those with \u003cem\u003eTAB2\u003c/em\u003e mutations(Engwerda et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Besides cardiac defects, 64% of individuals with the disease caused by \u003cem\u003eTAB2\u003c/em\u003e variants present with one or more extra - cardiac manifestations, among which the most frequent features are skeletal manifestations (including short stature, small extremities, short limbs, and pes planus) (63%), facial dysmorphism ( long and/or round face, a high forehead, almond-shaped eyes/dystopia canthorum, a prominent nose and columella, maxillary hypoplasia, and a long philtrum) (54%), and connective tissue disorders (54%)(Hanson et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2022a\u003c/span\u003e). However, among patients who have \u003cem\u003eTAB2\u003c/em\u003e deletions, nearly every one of them exhibits a composite extra-cardiac phenotype(Cheng et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Distinctive facial features (88%-100%), short stature (disproportionate in most reports) (73% \u0026minus;\u0026thinsp;84%) and connective tissue abnormalities (48% \u0026minus;\u0026thinsp;82%) are the most frequent non - cardiac characteristics(Engwerda et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Nevertheless, the majority of the reported patients were children or adults, while prenatal cases were rare. It remains unclear what the main prenatal phenotypes of fetuses with \u003cem\u003eTAB2\u003c/em\u003e deficiency are, which poses a significant challenge for prenatal genetic counseling.\u003c/p\u003e\u003cp\u003eIn our case, the fetus showed a small left heart atrium. Decreased volumes of left heart atrium have been attributed to several different etiologies(Opotowsky et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2012\u003c/span\u003e;Lang et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2015\u003c/span\u003e;Aviram et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). It may be due to the presence of space occupying lesions, such as intra-atrial tumors and extracardiac tumors. In other cases, it might be caused by reversible factors, such as intravascular volume depletion and a reduction in the LA preload. In our case, we essentially ruled out the presence of space-occupying lesions in our fetus by echocardiography and systematic ultrasonography. Invisible vascular or valve abnormalities may be the cause of the small left atrium. Unfortunately, there was no autopsy in our case, so the exact cause of the small LA remains unknown. Nevertheless, it has been demonstrated that even when an apparent etiology for small LA is not detected, the prognosis remains poor and has a high risk of mortality(Rozenbaum et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). None of the other four protein-coding genes within the deletion region, which we described previously, were associated with cardiac development, and we also excluded other mutations in cardiac-associated genes using trio-WES. Based on these findings, the cardiac features in our case can be attributed to \u003cem\u003eTAB2\u003c/em\u003e haploinsufficiency. Our report is the first report associating \u003cem\u003eTAB2\u003c/em\u003e haploinsufficiency with a small LA.\u003c/p\u003e\u003cp\u003eWe comprehensively reviewed mutations or deletions in the \u003cem\u003eTAB2\u003c/em\u003e gene. It was noted that in the majority of cases, there were no reported abnormalities detected by prenatal ultrasound, or there was a lack of available phenotypic descriptions. In the literature, among approximately 70 reported cases with \u003cem\u003eTAB2\u003c/em\u003e gene mutations, about 6 cases had descriptions of prenatal phenotypes which were respectively manifested as CHD(Liu et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2020\u003c/span\u003e;Koene et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), short legs(Deng et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), and supraventricular tachycardia accompanied by a small pericardial effusion (Hanson et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2022b\u003c/span\u003e). Upon our review, we discovered that, out of around 50 deletion cases reported in the literature, about 13 cases had available descriptions of prenatal phenotypes and the size of the deletions varied from 0.28 Mb to 11.82 Mb (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Our findings revealed that, including our present case, 78.6% (11/14) of these cases manifested a prenatal cardiac phenotype. Among these 11 cases with a cardiac phenotype, 3 cases demonstrated only mild soft - marker abnormalities like fetal heart decelerations or an irregular fetal heart rate (\u003cb\u003eCases 3 to 5\u003c/b\u003e). Therefore, the cardiac phenotype may not be the most distinctive characteristic of the affected fetuses. Moreover, we discovered that IUGR was observed in 78.6% (11/14) of the fetuses with deletions. The other three fetuses that did not develop IUGR carried the smallest deletion fragments, with the sizes varying from 0.26 Mb to 0.47 Mb (\u003cb\u003eCase 1\u003c/b\u003e, \u003cb\u003eCase 3\u003c/b\u003e and \u003cb\u003eCase 8\u003c/b\u003e). Most of the reported cases in the \u003cem\u003eTAB2\u003c/em\u003e deletions spectrum exhibited earlier and more severe growth abnormalities compared to the \u003cem\u003eTAB2\u003c/em\u003e mutations, and we therefore hypothesize the likely presence of at least one gene responsible for physiological growth processes within this deleted region that acts in conjunction with \u003cem\u003eTAB2\u003c/em\u003e to jointly affect the growth of individuals(Woods et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eMost literature focuses on cardiac and common extra - cardiac abnormalities, yet provides little clinical information on other systemic malformations. Genitourinary abnormalities (such as horseshoe kidney, testicular dysgenesis and cryptorchidism) and gastrointestinal abnormalities (such as feeding difficulties, abdominal mesentery morphology and jejunostomy) can also be seen in some \u003cem\u003eTAB2\u003c/em\u003e-related cases(Cheng et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2020\u003c/span\u003e;Woods et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2022\u003c/span\u003e;Deng et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). These malformations may be caused by other mutations or may be manifestations of \u003cem\u003eTAB2\u003c/em\u003e-associated syndromes. Hypospadias was found in our case, which has been occasionally reported in other literature(Thienpont et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2010\u003c/span\u003e;Woods et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Our case also presented a gastrointestinal malformation, namely anal atresia, which was not previously reported in other cases. When other variants have been eliminated, and the cases of \u003cem\u003eTAB2\u003c/em\u003e deficiency exhibit more severe phenotypes compared to mutant cases, it is reasonable to believe that anal atresia may be another clinical manifestation of \u003cem\u003eTAB2\u003c/em\u003e-deficiency syndrome.\u003c/p\u003e\u003cp\u003eIn summary, unique features of this subject included underdevelopment of a small LA and anal atresia, which were not reported among previously published individuals with 6q25.1 microdeletion syndrome. We summarized previously reported cases and discovered that growth abnormalities resulting from 6q25.1 (\u003cem\u003eTAB2\u003c/em\u003e) microdeletion are more severe than cardiac abnormalities prenatally. Our study expands the mutation spectrum of the \u003cem\u003eTAB2\u003c/em\u003e gene deletion and can offer evidence for prenatal genetic counseling.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCHD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCongenital heart disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLeft atrium\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIUGR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIntrauterine growth restriction\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003etrio-WES\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003etrio-based Whole exome sequencing\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTOF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTetralogy of Fallot\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHLHS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHypoplastic left heart syndrome.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Changsha Hospital for Maternal \u0026amp; Child Healthcare. The studies were conducted in accordance with the local legislation and institutional requirements.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the patients/legal guardians provided written informed consent to participate in this study, including review of relevant medical records and consent for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (Genomics, Proteomics \u0026amp; Bioinformatics 2021) in National Genomics Data Center (Nucleic Acids Res 2024), China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA012182) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests \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\n\u003cp\u003e\u003cstrong\u003eFunding \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Program of Health Commission of Hunan Province (No. 202301036352 and 202305026432).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXB: Writing\u0026ndash;original draft. XL: Writing\u0026ndash;original draft. LZ: Writing\u0026ndash;review and editing, Conceptualization, Data curation, Formal Analysis, Methodology, Project administration, Supervision, Validation. RT: Writing\u0026ndash;review and editing, Investigation, Methodology, Project administration, Resources, Supervision, Validation. CP: Writing\u0026ndash;review and editing, Data curation, Investigation, Methodology, Project administration, Resources. SZ: Writing\u0026ndash;review and editing; Data curation; Methodology; Formal Analysis. SL: Investigation, Methodology, Resources, Supervision, Validation, Writing\u0026ndash;review and editing. JL: Supervision, Validation, Writing\u0026ndash;review and editing, Conceptualization, Formal Analysis, Funding acquisition, Project administration, Resources.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Berry-Beijing (China) for their technical contributions to this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAckerman JP, Smestad JA, Tester DJ, Qureshi MY, Crabb BA, Mendelsohn NJ, Ackerman MJ. Whole Exome Sequencing, Familial Genomic Triangulation, and Systems Biology Converge to Identify a Novel Nonsense Mutation in TAB2-encoded TGF-beta Activated Kinase 1 in a Child with Polyvalvular Syndrome. Congenit Heart Dis. 2016;11:452\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAviram G, Soikher E, Bendet A, Shmueli H, Ziv-Baran T, Amitai Y, Friedensohn L, Berliner S, Meilik A, Topilsky Y. Prediction of Mortality in Pulmonary Embolism Based on Left Atrial Volume Measured on CT Pulmonary Angiography. Chest. 2016;149:667\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBuck Louis GM, Grewal J, Albert PS, Sciscione A, Wing DA, Grobman WA, Newman RB, Wapner R, D'alton ME, Skupski D, Nageotte MP, Ranzini AC, Owen J, Chien EK, Craigo S, Hediger ML, Kim S, Zhang C, Grantz KL. (2015). Racial/ethnic standards for fetal growth: the NICHD Fetal Growth Studies. \u003cem\u003eAm J Obstet Gynecol\u003c/em\u003e 213, 449.e441-449.e441.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCheng A, Dinulos MBP, Neufeld-Kaiser W, Rosenfeld J, Kyriss M, Madan-Khetarpal S, Risheg H, Byers PH, Liu YJ. 6q25.1 (TAB2) microdeletion syndrome: Congenital heart defects and cardiomyopathy. 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Eur J Hum Genet. 2021;29:1669\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHamosh A, Amberger JS, Bocchini C, Scott AF, Rasmussen SA. Online Mendelian Inheritance in Man (OMIM\u0026reg;): Victor McKusick's magnum opus. Am J Med Genet A. 2021;185:3259\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHanson J, Brezavar D, Hughes S, Amudhavalli S, Fleming E, Zhou D, Alaimo JT, Bonnen PE. TAB2 variants cause cardiovascular heart disease, connective tissue disorder, and developmental delay. Clin Genet. 2022a;101:214\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHanson J, Brezavar D, Hughes S, Amudhavalli S, Fleming E, Zhou D, Alaimo JT, Bonnen PE. (2022b). TAB2 variants cause cardiovascular heart disease, connective tissue disorder, and developmental delay. 101, 214\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKarmegaraj B. 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Am J Med Genet A. 2008;146a:354\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOpotowsky AR, Ojeda J, Rogers F, Prasanna V, Clair M, Moko L, Vaidya A, Afilalo J, Forfia PR. A simple echocardiographic prediction rule for hemodynamics in pulmonary hypertension. Circ Cardiovasc Imaging. 2012;5:765\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRitelli M, Morlino S, Giacopuzzi E, Bernardini L, Torres B, Santoro G, Ravasio V, Chiarelli N, D'angelantonio D, Novelli A, Grammatico P, Colombi M, Castori M. A recognizable systemic connective tissue disorder with polyvalvular heart dystrophy and dysmorphism associated with TAB2 mutations. Clin Genet. 2018;93:126\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRozenbaum Z, Sapir O, Granot Y, Arnold JH, Biner S, Topilsky Y, Laufer-Perl M. Implications of Indeterminate and Determined Etiologies Leading to Small Left Atria. Isr Med Assoc J. 2023;25:468\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSalpietro V, Ruggieri M, Mankad K, Di Rosa G, Granata F, Loddo I, Moschella E, Calabro MP, Capalbo A, Bernardini L, Novelli A, Polizzi A, Seidler DG, Arrigo T, Briuglia S. A de novo 0.63 Mb 6q25.1 deletion associated with growth failure, congenital heart defect, underdeveloped cerebellar vermis, abnormal cutaneous elasticity and joint laxity. Am J Med Genet A. 2015;167a:2042\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStagi S, Lapi E, Pantaleo M, Carella M, Petracca A, De Crescenzo A, Zelante L, Riccio A, De Martino M. A new case of de novo 6q24.2-q25.2 deletion on paternal chromosome 6 with growth hormone deficiency: a twelve-year follow-up and literature review. 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Expanding the phenotype of TAB2 variants and literature review. Am J Med Genet A. 2022;188:3331\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"TAB2, small left atrium, intrauterine growth restriction, anal atresia, case report","lastPublishedDoi":"10.21203/rs.3.rs-6972884/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6972884/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eDeletions involving \u003cem\u003eTAB2\u003c/em\u003e gene have been identified as the cause of a multi - system disorder, including cardiac abnormalities, distinctive facial features, growth abnormalities and connective tissue abnormalities. Cardiac abnormalities are a key feature and are present in nearly all patients. The majority of the reported patients are children or adults, while prenatal cases are rare. Whether cardiac abnormalities are the primary prenatal phenotype of \u003cem\u003eTAB2\u003c/em\u003e deficiency remains unclear.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e\u003cp\u003eHere, we report a prenatal case where invasive prenatal diagnosis was performed because of thickened NT. The fetus had a normal karyotype. An SNP array analysis of the family revealed a \u003cem\u003ede novo\u003c/em\u003e 1.12 Mb deletion on chromosome 6q24.3q25.1, which encompasses \u003cem\u003eTAB2\u003c/em\u003e gene. At 25 weeks of gestation, the fetus was found to have a small left atrium. Trio - based whole exome sequencing detected no pathogenic or likely pathogenic single nucleotide variants; however, it did identify the deletion on 6q24.3q25.1. Six weeks later, an ultrasound once more showed a small left atrium. Moreover, severe intrauterine growth restriction, hypospadias, and anal atresia were detected. The parents decided to terminate the pregnancy after genetic counseling. Subsequently, we reviewed all the \u003cem\u003eTAB2\u003c/em\u003e-related cases with available prenatal ultrasound findings.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThe growth abnormalities resulting from 6q25.1 (\u003cem\u003eTAB2\u003c/em\u003e) microdeletion are more severe than cardiac abnormalities prenatally. We identified two new features, namely a small left atrium and anal atresia. Our study expands the spectrum of 6q25.1 (\u003cem\u003eTAB2\u003c/em\u003e) microdeletion and could provide evidence for the prenatal genetic counseling.\u003c/p\u003e","manuscriptTitle":"Fetal de novo 6q24.3-q25.1 microdeletion encompassing TAB2 gene associated with small left atrium, growth restriction, and urogenital/anal abnormalities: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-22 08:38:55","doi":"10.21203/rs.3.rs-6972884/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-10-12T13:32:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"197761359312376850859257967392617047528","date":"2025-09-21T20:25:05+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-10T11:35:12+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-19T11:02:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-24T07:42:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-24T02:16:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cardiovascular Disorders","date":"2025-07-24T02:14:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3c62b9bb-19d1-4c83-9f66-df0b7a760d8f","owner":[],"postedDate":"September 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-09-22T08:38:56+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-22 08:38:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6972884","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6972884","identity":"rs-6972884","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}