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BACKGROUND: This study aims to compare the outcomes of transcatheter aortic valve replacement (TAVR) with self-expandable valves for bicuspid aortic valve (BAV) vs. tricuspid aortic valve (TAV) stenosis patients who are at low surgical risk. METHODS: Participants were enrolled from 36 centers in China between January 2017 and December 2021. The primary endpoint event was all-cause mortality and all stroke at 30 days. RESULTS: Among 389 patients at low surgical risk that underwent TAVR, 229 patients were BAV stenosis (mean age, 72.9 years; 65.1% men). There was no significant difference in the rate of all-cause death between two populations at 30 days. However, the rate of all stroke was significantly higher in the BAV group at 30 days (3.3% vs. 0%; odds ratio (OR), 0.97 (95% confidence interval (CI), 0.94 to 0.99); p = 0.044). By multivariate logistic regression analysis, trans-carotid access was associated with a higher all stroke rate at 30 days (OR, 29.20 (95% CI, 3.97 to 215.1); p = 0.001). CONCLUSIONS: In this national registry-based study, patients treated for BAV vs. TAV stenosis had no significant difference in all-cause mortality at 30 days, but trans-carotid access was associated with a higher all stroke rate after TAVR at 30 days.
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Atrioventricular septal defects (AVSD) are a complicated subtype of congenital heart defects for which the genetic basis is poorly understood. Many studies have demonstrated that the transcription factor SOX7 plays a pivotal role in cardiovascular development. However, whether SOX7 single nucleotide variants are involved in AVSD pathogenesis is unclear. To explore the potential pathogenic role of SOX7 variants, we recruited a total of 100 sporadic non-syndromic AVSD Chinese Han patients and screened SOX7 variants in the patient cohort by targeted sequencing. Functional assays were performed to evaluate pathogenicity of nonsynonymous variants of SOX7. We identified three rare SOX7 variants, c.40C > G, c.542G > A, and c.743C > T, in the patient cohort, all of which were found to be highly conserved in mammals. Compared to the wild type, these SOX7 variants had increased mRNA expression and decreased protein expression. In developing hearts, SOX7 and GATA4 were highly expressed in the region of atrioventricular cushions. Moreover, SOX7 overexpression promoted the expression of GATA4 in human umbilical vein endothelial cells. A chromatin immunoprecipitation assay revealed that SOX7 could directly bind to the GATA4 promoter and luciferase assays demonstrated that SOX7 activated the GATA4 promoter. The SOX7 variants had impaired transcriptional activity relative to wild-type SOX7. Furthermore, the SOX7 variants altered the ability of GATA4 to regulate its target genes. In conclusion, our findings showed that deleterious SOX7 variants potentially contribute to human AVSD by impairing its interaction with GATA4. This study provides novel insights into the etiology of AVSD and contributes new strategies to the prenatal diagnosis of AVSD.
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Defectos de los Tabiques Cardíacos , Animales , Factor de Transcripción GATA4/genética , Predisposición Genética a la Enfermedad , Defectos de los Tabiques Cardíacos/genética , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Mamíferos , Factores de Transcripción SOXF/genética , Factores de Transcripción SOXF/metabolismo , Factores de Transcripción/genéticaRESUMEN
Cardiac septum malformations account for the largest proportion in congenital heart defects. The transcription factor Sox7 has critical functions in the vascular development and angiogenesis. It is unclear whether Sox7 also contributes to cardiac septation development. We identified a de novo 8p23.1 deletion with Sox7 haploinsufficiency in an atrioventricular septal defect (AVSD) patient using whole exome sequencing in 100 AVSD patients. Then, multiple Sox7 conditional loss-of-function mice models were generated to explore the role of Sox7 in atrioventricular cushion development. Sox7 deficiency mice embryos exhibited partial AVSD and impaired endothelial to mesenchymal transition (EndMT). Transcriptome analysis revealed BMP signaling pathway was significantly downregulated in Sox7 deficiency atrioventricular cushions. Mechanistically, Sox7 deficiency reduced the expressions of Bmp2 in atrioventricular canal myocardium and Wnt4 in endocardium, and Sox7 binds to Wnt4 and Bmp2 directly. Furthermore, WNT4 or BMP2 protein could partially rescue the impaired EndMT process caused by Sox7 deficiency, and inhibition of BMP2 by Noggin could attenuate the effect of WNT4 protein. In summary, our findings identify Sox7 as a novel AVSD pathogenic candidate gene, and it can regulate the EndMT involved in atrioventricular cushion morphogenesis through Wnt4-Bmp2 signaling. This study contributes new strategies to the diagnosis and treatment of congenital heart defects.
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Proteína Morfogenética Ósea 2/metabolismo , Defectos de los Tabiques Cardíacos/metabolismo , Factores de Transcripción SOXF/metabolismo , Proteína Wnt4/metabolismo , Animales , Estudios de Casos y Controles , Preescolar , Endocardio/embriología , Endocardio/crecimiento & desarrollo , Endocardio/metabolismo , Femenino , Defectos de los Tabiques Cardíacos/genética , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Factores de Transcripción SOXF/deficiencia , Factores de Transcripción SOXF/genética , Transducción de SeñalRESUMEN
BACKGROUND: Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. The concept of precision medicine in CVD therapy today requires the incorporation of individual genetic and environmental variability to achieve personalized disease prevention and tailored treatment. Autophagy, an evolutionarily conserved intracellular degradation process, has been demonstrated to be essential in the pathogenesis of various CVDs. Nonetheless, there have been no effective treatments for autophagy- involved CVDs. Long noncoding RNAs (lncRNAs) are noncoding RNA sequences that play versatile roles in autophagy regulation, but much needs to be explored about the relationship between lncRNAs and autophagy-involved CVDs. SUMMARY: Increasing evidence has shown that lncRNAs contribute considerably to modulate autophagy in the context of CVDs. In this review, we first summarize the current knowledge of the role lncRNAs play in cardiovascular autophagy and autophagy-involved CVDs. Then, recent developments of antisense oligonucleotides (ASOs) designed to target lncRNAs to specifically modulate autophagy in diseased hearts and vessels are discussed, focusing primarily on structure-activity relationships of distinct chemical modifications and relevant clinical trials. PERSPECTIVE: ASOs are promising in cardiovascular drug innovation. We hope that future studies of lncRNA-based therapies would overcome existing technical limitations and help people who suffer from autophagy-involved CVDs.
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Enfermedades Cardiovasculares , Sistema Cardiovascular , ARN Largo no Codificante , Autofagia , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/genética , Corazón , Humanos , ARN Largo no Codificante/genéticaRESUMEN
Our aim was to apply a composite braided biodegradable stent (CBBS) made from poly p-dioxanone (PPDO) and polycaprolactone (PCL) as an alternative to metallic stents for the treatment of pediatric endovascular disease. CBBS properties after adjunctive post-dilatation were assessed using radial force testing. CBBS degradation was assessed using in vitro measurements. Self-expandable CBBSs (8 × 20 mm) were implanted in abdominal aortas with an oversizing ratio of 1.1-1.4 (group A, n = 12) and in common iliac arteries with an oversizing ratio >1.4 (group B, n = 12). Self-expandable metal WALLSTENTs (8 × 21 mm) were implanted in common iliac arteries with an oversizing ratio >1.4 and served as controls (group C, n = 12). Artery evaluations including angiography and histological examinations were performed at 1, 4, 6 and 12 months after stent implantation. Eight millimeter CBBSs delivered in 8Fr sheaths with adjunctive post-dilatation had properties similar to those of metallic benchmark stents and were degraded in 12 months, with mild to moderate inflammation-induced neointimal hyperplasia and vessel restenosis. Post-dilatation and oversizing are suggested when using CBBSs for polymeric strut tissue embedding and optimal wall apposition, but an overextended ratio should be avoided because of the induction of less-desirable neointimal hyperplasia. Mid-term outcomes of CBBSs with adjunctive post-dilatation were better than those of WALLSTENTs in a swine endovascular disease model.
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Aorta Abdominal , Stents , Animales , Aorta Abdominal/cirugía , Niño , Constricción Patológica , Dilatación , Humanos , PorcinosRESUMEN
Conotruncal heart defects (CTDs) are closely related to defective outflow tract (OFT) development, in which cardiac neural crest cells (CNCCs) play an indispensable role. However, the genetic etiology of CTDs remains unclear. Mesoderm posterior 2 (MESP2) is an important transcription factor regulating early cardiogenesis. Nevertheless, MESP2 variants have not been reported in congenital heart defect (CHD) patients. We first identified four MESP2 variants in 601 sporadic nonsyndromic CTD patients that were not detected in 400 healthy controls using targeted sequencing. Reverse transcription-quantitative PCR (RT-qPCR), immunohistochemistry, and immunofluorescence assays revealed MESP2 expression in the OFT of Carnegie stage (CS) 11, CS13, and CS15 human embryos and embryonic day (E) 8.5, E10, and E11.5 mouse embryos. Functional analyses in HEK 293T cells, HL-1 cells, JoMa1 cells, and primary mouse CNCCs revealed that MESP2 directly regulates the transcriptional activities of downstream CTD-related genes and promotes CNCC proliferation by regulating cell cycle factors. Three MESP2 variants, c.346G>C (p.G116R), c.921C>G (p.Y307X), and c.59A>T (p.Q20L), altered the transcriptional activities of MYOCD, GATA4, NKX2.5, and CFC1 and inhibited CNCC proliferation by upregulating p21cip1 or downregulating Cdk4. Based on our findings, MESP2 variants disrupted MESP2 function by interfering with CNCC proliferation during OFT development, which may contribute to CTDs. KEY MESSAGES: This study first analyzed MESP2 variants identified in sporadic nonsyndromic CTD patients. MESP2 is expressed in the OFT of different stages of human and mouse embryos. MESP2 regulates the transcriptional activities of downstream CTD-related genes and promotes CNCC proliferation by regulating cell cycle factor p21cip1 or Cdk4.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proliferación Celular/genética , Variación Genética/genética , Cardiopatías Congénitas/genética , Corazón/fisiopatología , Cresta Neural/patología , Animales , Ciclo Celular/genética , Línea Celular , Regulación hacia Abajo/genética , Embrión de Mamíferos/patología , Regulación de la Expresión Génica/genética , Células HEK293 , Cardiopatías Congénitas/patología , Humanos , Ratones , Miocardio/patología , Organogénesis/genética , Transducción de Señal/genética , Factores de Transcripción/genética , Transcripción Genética/genética , Regulación hacia Arriba/genéticaRESUMEN
OBJECTIVES: Available apical occluders do not fulfil requirements for full-percutaneous transapical valve procedures with large-sized introducer sheaths. A self-expanding closure device designed for closed-chest transapical valve procedures was tested in an animal model to verify safety, efficacy and thrombogenicity. METHODS: Large-sized 21-Fr introducer sheaths (Certitude™ system for Sapien™ valves) were percutaneously placed in the ventricles of nine 3-month old minipigs. To seal the apical access, delivery catheters carrying folded self-expanding plugs were inserted. Then, the plugs were deployed while sheaths were removed. Echocardiograms verified tamponade and cardiac function, drains were not placed and a 3-month long aspirin therapy was administered. After 6 and 9 months, animals were euthanized and organs were analysed for macroembolic lesions search. Histological analysis was also performed. RESULTS: Nine minipigs (weight: 28±3 kg) were used for this study. Eight plugs were successfully deployed in 8 ventricles without cardiac tamponade or ventricular dysfunction (success rate: 88.9%). In a failed procedure (the animal died after 1 month of cardiac tamponade), the outer disc of the apical plug got stuck in the intercostal space and did not correctly deploy. Post-mortem analysis in 8 minipigs at 6 (n = 4) and 9 months (n = 4) confirmed full deployment and good fixation of all plugs with internal surfaces covered by new endocardium. Macroscopic analysis of myocardium and vital organs showed absence of embolic lesions. Histological analysis showed absence of significant inflammatory infiltration and thrombosis. CONCLUSIONS: In this animal model, self-expanding closure devices sealed 21-Fr large percutaneous apical accesses without acute tamponade, thrombosis or embolization. Further tests to evaluate full-percutaneous closed-chest apical procedures are required.
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Cateterismo Cardíaco/instrumentación , Enfermedades de las Válvulas Cardíacas/cirugía , Implantación de Prótesis de Válvulas Cardíacas/instrumentación , Prótesis Valvulares Cardíacas , Ventrículos Cardíacos/cirugía , Animales , Modelos Animales de Enfermedad , Porcinos , Porcinos EnanosRESUMEN
To evaluate the properties and efficacy of a novel braided biodegradable stent (BBS) consisting of poly (p-dioxanone) (PPDO) and polycaprolactone (PCL) for usage in children with congenital cardiovascular diseases. PCL/PPDO composite filaments were fabricated by coating PCL layers onto PPDO filaments, which were fused with PPDO monofilaments to form the BBS. Physical properties of BBSs including elastic recovery rate, deformation rate, and mechanical characteristics with adjunctive post-dilation were evaluated by radial force-tests. Ten BBS stents and 10 metallic wall stents (WS) as controls were implanted into the common carotid arteries of 10 pigs and angiography as well as histological examinations were performed 4 and 8 weeks after implantation. An 8 mm BBS with adjunctive post-dilation had the best morphological retention and dimension stability being similar to an 8 mm WS. Luminal gain percentages of BBS and WS immediately, 4 weeks and 8 weeks after implantation were 20.44 ± 2.82% and 27.08 ± 0.88%, 12.34 ± 0.18% and 17.32 ± 8.24%, as well as -1.76 ± 2.45% and - 0.98 ± 3.23%. Luminal areas, internal elastic laminas, neointimal areas, neointimal thicknesses, and area stenosis were not significantly different at 4 weeks and 8 weeks after implantation. Injury and inflammation were similar in both groups and no malposition, thrombosis or dissection occurred. BBS with adjunctive post-dilation showed good physical properties and mechanical stability noninferior to WS. In vivo evaluations showed that a BBS with post-ballooning had similar short-term outcomes as a WS. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1667-1677, 2019.
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Materiales Biocompatibles/química , Cardiopatías Congénitas/cirugía , Arteria Ilíaca/cirugía , Diseño de Prótesis , Stents , Animales , Elasticidad , Inflamación/patología , Implantación de Prótesis , Stents Metálicos Autoexpandibles , PorcinosRESUMEN
Copy number variants (CNVs) are major variations contributing to the gene heterogeneity of congenital heart diseases (CHD). pulmonary atresia with ventricular septal defect (PA-VSD) is a rare form of cyanotic CHD characterized by complex manifestations and the genetic determinants underlying PA-VSD are still largely unknown. We investigated rare CNVs in a recruited cohort of 100 unrelated patients with PA-VSD, PA-IVS, or TOF and a population-matched control cohort of 100 healthy children using whole-exome sequencing. Comparing rare CNVs in PA-VSD cases and that in PA-IVS or TOF positive controls, we observed twenty-two rare CNVs only in PA-VSD, five rare CNVs only in PA-VSD and TOF as well as thirteen rare CNVs only in PA-VSD and PA-IVS. Six of these CNVs were considered pathogenic or potentially pathogenic to PA-VSD: 16p11.2 del (PPP4C and TBX6), 5q35.3 del (FLT4), 5p13.1 del (RICTOR), 6p21.33 dup (TNXB), 7p15.2 del (HNRNPA2B1), and 19p13.3 dup (FGF22). The gene networks showed that four putative candidate genes for PA-VSD, PPP4C, FLT4, RICTOR, and FGF22 had strong interaction with well-known cardiac genes relevant to heart or blood vessel development. Meanwhile, the analysis of transcriptome array revealed that PPP4C and RICTOR were also significantly expressed in human embryonic heart. In conclusion, three rare novel CNVs were identified only in PA-VSD: 16p11.2 del (PPP4C), 5q35.3 del (FLT4) and 5p13.1 del (RICTOR), implicating novel candidate genes of interest for PA-VSD. Our study provided new insights into understanding for the pathogenesis of PA-VSD and helped elucidate critical genes for PA-VSD.
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BACKGROUND: Conotruncal heart defects (CTDs) are heterogeneous congenital heart malformations that result from outflow tract dysplasia; however, the genetic determinants underlying CTDs remain unclear. Increasing evidence demonstrates that dysfunctional TBX2 and TBX3 result in outflow tract malformations, implying that both of them are involved in CTD pathogenesis. We screened for TBX2 and TBX3 variants in a large cohort of CTD patients (n = 588) and population-matched healthy controls (n = 300) by target sequencing and genetically analyzed the expression and function of these variants. RESULTS: The probably damaging variants p.R608W, p.T249I, and p.R616Q of TBX2 and p.A192T, p.M65L, and p.A562V of TBX3 were identified in CTD patients, but none in controls. All altered amino acids were highly conserved evolutionarily. Moreover, our data suggested that mRNA and protein expressions of TBX2 and TBX3 variants were altered compared with those of the wild-type. We screened PEA3 and MEF2C as novel downstream genes of TBX2 and TBX3, respectively. Functional analysis revealed that TBX2R608W and TBX2R616Q variant proteins further activated HAS2 promoter but failed to activate PEA3 promoter and that TBX3A192T and TBX3A562V variant proteins showed a reduced transcriptional activity over MEF2C promoter. CONCLUSIONS: Our results indicate that the R608W and R616Q variants of TBX2 as well as the A192T and A562V variants of TBX3 contribute to CTD etiology; this was the first association of variants of TBX2 and TBX3 to CTDs based on a large population.
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Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/genética , Proteínas de Dominio T Box/genética , Proteínas E1A de Adenovirus/genética , Preescolar , Estudios de Cohortes , Femenino , Regulación de la Expresión Génica , Cardiopatías Congénitas/fisiopatología , Humanos , Lactante , Factores de Transcripción MEF2/genética , Masculino , Proteínas Mutantes , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-etsRESUMEN
BACKGROUND: Conotruncal heart defect (CTD) is a complex congenital heart disease with a complex and poorly understood etiology. The transcriptional corepressor RIPPLY3 plays a pivotal role in heart development as a negative regulator of the key cardiac transcription factor TBX1. A previous study showed that RIPPLY3 contribute to cardiac outflow tract development in mice, however, the relationship between RIPPLY3 and human cardiac malformation has not been reported. METHODS: 615 unrelated CTD Chinese Han patients were enrolled, we excluded the 22q11.2 deletion/duplication using a modified multiplex ligation-dependent probe amplification method-CNVplex®, and investigated the variants of RIPPLY3 in 577 patients without the 22q11.2 deletion/duplication by target sequencing. Functional assays were performed to testify the potential pathogenicity of nonsynonymous variants found in these CTD patients. RESULTS: Four rare heterozygous nonsynonymous variants (p.P30L, p.T52S, p.D113N and p.V179D) were identified in four CTD patients, the variant NM_018962.2:c.155C>G (p.T52S) is referred as rs745539198, and the variant NM_018962.2:c.337G>A (p.D113N) is referred as rs747419773. However, variants p.P30L and p.V179D were not found in multiple online human gene variation databases. Western blot analysis and immunofluorescence showed that there were no significant difference between wild type RIPPLY3 and these four variants. Luciferase assays revealed that the p.T52S variant altered the inhibition of TBX1 transcriptional activity in vitro, and co-immunoprecipitation assays showed that the p.T52S variant reduced the physical interaction of RIPPLY3 with TBX1. In addition to the results from pathogenicity prediction tools and evolutionary protein conservation, the p.T52S variant was thought to be a potentially deleterious variant. CONCLUSION: Our results provide evidence that deleterious variants in RIPPLY3 are potential molecular mechanisms involved in the pathogenesis of human CTD.
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Anomalías Múltiples/genética , Pueblo Asiatico/genética , Duplicación Cromosómica/genética , Síndrome de DiGeorge/genética , Etnicidad/genética , Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/genética , Mutación con Pérdida de Función/genética , Proteínas Represoras/genética , Factores de Transcripción/genética , Secuencia de Aminoácidos , Cromosomas Humanos Par 22/genética , Estudios de Cohortes , Variaciones en el Número de Copia de ADN/genética , Células HEK293 , Humanos , Mutación Missense/genética , Unión Proteica , Proteínas Represoras/química , Factores de Riesgo , Proteínas de Dominio T Box/genética , Transcripción GenéticaRESUMEN
Conotruncal heart defects (CTDs) represent a group of severe and complicated congenital cardiovascular malformations and require opportune clinical interventions once diagnosed. Occurrence of CTD is related to the functional abnormality of the second heart field (SHF), and variants of genes which regulate the development of the second heart field have been recognized as the main genetic factors leading to CTDs. Previous studies indicated that transcriptional complex SIX1/EYA1 may contribute to SHF development, and SIX1/EYA1 knockout mice exhibited a series of conotruncal malformations. Here, we recruited and sequenced 600 Chinese conotruncal heart defect patients and 300 controls. We screened out one novel SIX1 mutation (SIX1-K134R) and four EYA1 rare mutations (EYA1-A227T, EYA1-R296H, EYA1-Q397R, EYA1-G426S), all variants were present only in the case cohort, and the mutated sites were highly conserved. We then analyzed mutations by software including Sift, PolyPhen-2, PROVEAN, Mutation Taster, HOPE, and SWISS-PdbViewer. The results showed that the mutations had varying degrees of pathogenic risk, protein properties, spatial conformations, and domain functions which might be altered or influenced. Through biological and in silico analyses, our study suggests an association between SIX1/EYA1 mutations and cardiovascular malformations, SIX1/EYA1 mutations might be partially responsible for CTDs.
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Cardiopatías Congénitas/genética , Proteínas de Homeodominio/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas Nucleares/genética , Proteínas Tirosina Fosfatasas/genética , Pueblo Asiatico/genética , Simulación por Computador , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad , Humanos , Masculino , MutaciónRESUMEN
Studies have highlighted the critical role of GATA6 in conotruncal heart defects (CTDs). Nevertheless, relationship between GATA6 variants and different CTDs remains largely unknown. Here GATA6 gene was screened in 542 patients with CTDs using targeted sequencing. Variant frequency was 2.0% (11/542). Three novel variants: c.86C>A (p.A29E), c.296T>A (p.V99D) and c.1254delC (p.S418fs) were identified in patients with transposition of the great arteries, double outlet right ventricle and persistent truncus arteriosus, respectively, but in none of the 400 controls. Western blot revealed that A29E and V99D mutant protein had similar expression pattern with wild-type GATA6 protein, but S418fs mutant protein appeared as a truncated doublet. Reporter gene assay demonstrated that A29E and V99D mutant protein retained the ability to activate BNP and ANF promoter, whereas S418fs mutant protein failed to transactivate both of them, compared with wild-type. Subcellular localization of wild-type, A29E and V99D mutant protein were in the nucleus, while S418fs mutant protein was expressed both in the nucleus and cytoplasm. In conclusion, GATA6 variant frequency in sporadic CTDs patients was higher than that in other congenital heart diseases. Variant c.1254delC was a pathogenic variant associated with CTDs, especially PTA, whereas c.86C>A and c.296T>A should be considered as likely pathogenic variants.
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Factor de Transcripción GATA6/genética , Variación Genética/genética , Cardiopatías Congénitas/genética , Adolescente , Secuencia de Aminoácidos , Animales , Línea Celular , Núcleo Celular/genética , Niño , Preescolar , Citoplasma/genética , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Ratones , Proteínas Mutantes/genética , Regiones Promotoras Genéticas/genética , Activación Transcripcional/genéticaRESUMEN
Obesity is a clinical syndrome which is driven by interactions between multiple genetic and environmental factors. Monogenic obesity is a rare type of obesity which is caused by a mutation in a single gene. Patients with monogenic obesity may develop early onset of obesity and severe metabolic abnormalities. In this study, we screened mutations of LEP in a total of 135 Chinese individuals including 35 obese patients whose BMI ≥ 32 kg/m(2) and 100 controls with BMI < 25 kg/m(2). Moreover, detailed information and clinical measurements of the participants were also collected. Finally, we identified a novel nonsynonymous mutation H118L in exon 3 of LEP in one patient with BMI 46.0 kg/m(2). This mutation was not identified in the controls. We speculated that the mutation H118L in LEP might be associated with severe obesity in Chinese subjects. However, the substantial mechanism should be further investigated.