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1.
Front Cardiovasc Med ; 9: 942808, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911562

RESUMO

A 46-year-old woman was admitted to the cardiovascular department because of a 3-month history of palpitations and exertional dyspnea. She had a history of a successful pregnancy at a very young age. The chest radiograph presented a "calabash" configuration. Echocardiogram discovered a large atrial septal defect with a suspected pulmonary vein abnormality. Cardiac CT revealed supracardiac total anomalous pulmonary venous return, whereby, all the pulmonary veins drain into a vertical vein and, finally, to the superior vena cava. Cardiac catheterization was consistent with anomalous pulmonary venous drainage without pulmonary hypertension. Finally, she underwent a successful surgical repair and appeared asymptomatic before her discharge.

2.
Nat Commun ; 13(1): 4012, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35817779

RESUMO

Human skin comprises stratified squamous epithelium and dermis with various stromal cells and the extracellular matrix (ECM). The basement membrane (BM), a thin layer at the top of the dermis, serves as a unique niche for determining the fate of epidermal stem cells (EpSCs) by transmitting physical and biochemical signals to establish epidermal cell polarity and maintain the hierarchical structure and function of skin tissue. However, how stem cell niches maintain tissue homeostasis and control wound healing by regulating the behavior of EpSCs is still not completely understood. In this study, a hierarchical skin proteome map is constructed using spatial quantitative proteomics combined with decellularization, laser capture microdissection, and mass spectrometry. The specific functions of different structures of normal native skin tissues or tissues with a dermatologic disease are analyzed in situ. Transforming growth factor-beta (TGFß)-induced protein ig-h3 (TGFBI), an ECM glycoprotein, in the BM is identified that could enhance the growth and function of EpSCs and promote wound healing. Our results provide insights into the way in which ECM proteins facilitate the growth and function of EpSCs as part of an important niche. The results may benefit the clinical treatment of skin ulcers or diseases with refractory lesions that involve epidermal cell dysfunction and re-epithelialization block in the future.


Assuntos
Epiderme , Proteômica , Células Epidérmicas , Epiderme/metabolismo , Matriz Extracelular , Humanos , Pele/patologia
3.
Mater Today Bio ; 15: 100319, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35757032

RESUMO

Graft healing after anterior cruciate ligament reconstruction (ACLR) involves slow biological processes, and various types of biological modulations have been explored to promote tendon-to-bone integration. Exosomes have been extensively studied as a promising new cell-free strategy for tissue regeneration, but few studies have reported their potential in tendon-to-bone healing. In this study, a novel type of exosome derived from magnetically actuated (iron oxide nanoparticles (IONPs) combined with a magnetic field) bone mesenchymal stem cells (BMSCs) (IONP-Exos) was developed, and the primary purpose of this study was to determine whether IONP-Exos exert more significant effects on tendon-to-bone healing than normal BMSC-derived exosomes (BMSC-Exos). Here, we isolated and characterized the two types of exosomes, conducted in vitro experiments to measure their effects on fibroblasts (NIH3T3), and performed in vivo experiments to compare the effects on tendon-to-bone integration. Moreover, functional exploration of exosomal miRNAs was further performed by utilizing a series of gain- and loss-of-function experiments. Experimental results showed that both BMSC-Exos and IONP-Exos could be shuttled intercellularly into NIH3T3 fibroblasts and enhanced fibroblast activity, including proliferation, migration, and fibrogenesis. In vivo, we found that IONP-Exos significantly prevented peri-tunnel bone loss, promoted more osseous ingrowth into the tendon graft, increased fibrocartilage formation at the tendon-bone tunnel interface, and induced a higher maximum load to failure than BMSC-Exos. Furthermore, overexpression of miR-21-5p remarkably enhanced fibrogenesis in vitro, and SMAD7 was shown to be involved in the promotive effect of IONP-Exos on tendon-to-bone healing. Our findings may provide new insights into the regulatory roles of IONPs in IONP-Exos communication via stimulating exosomal miR-21-5p secretion and the SMAD7 signaling pathway in the fibrogenic process of tendon-to-bone integration. This work could provide a new strategy to promote tendon-to-bone healing for tissue engineering in the future.

4.
Cell Rep ; 39(11): 110955, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35679865

RESUMO

Direct myocardial and vascular injuries due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-driven inflammation is the leading cause of acute cardiac injury associated with coronavirus disease 2019 (COVID-19). However, in-depth knowledge of the injury characteristics of the heart affected by inflammation is lacking. In this study, using a quantitative spatial proteomics strategy that combines comparative anatomy, laser-capture microdissection, and histological examination, we establish a region-resolved proteome map of the myocardia and microvessels with obvious inflammatory cells from hearts of patients with COVID-19. A series of molecular dysfunctions of myocardia and microvessels is observed in different cardiac regions. The myocardia and microvessels of the left atrial are the most susceptible to virus infection and inflammatory storm, suggesting more attention should be paid to the lesion and treatment of these two parts. These results can guide in improving clinical treatments for cardiovascular diseases associated with COVID-19.


Assuntos
COVID-19 , Traumatismos Cardíacos , COVID-19/complicações , Humanos , Inflamação , Proteoma , SARS-CoV-2
5.
Orphanet J Rare Dis ; 17(1): 209, 2022 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-35606856

RESUMO

BACKGROUND: Hypospadias is a congenital anomaly of the male urogenital system. Genetics factors play an important role in its pathogenesis. To search for potential causal genes/variants for hypospadias, we performed exome sequencing in a pedigree with three patients across two generations and a cohort of 49 sporadic patients with hypospadias. RESULTS: A novel BRAF variant (NM_004333.6: c.362C > A) was found to co-segregate with the hypospadias phenotype in the disease pedigree. In cells overexpressing the BRAF mutant, the phosphorylation level of p38 MAPK was significantly increased as compared with the cells overexpressing the wild-type BRAF or RASopathy-related BRAF mutant. This variant further led to a reduced transcription level of the SRY gene, which is essential for the normal development of the male reproductive system. In the cohort of sporadic patients, we identified two additional variants in p38 MAPK signaling-related genes (TRIM67 and DAB2IP) potentially associated with hypospadias. CONCLUSION: Our study expands the phenotypic spectrum of variants affecting p38 MAPK signaling toward the involvement of hypospadias.


Assuntos
Hipospadia , Proteínas Proto-Oncogênicas B-raf , Humanos , Hipospadia/genética , Sistema de Sinalização das MAP Quinases/genética , Masculino , Fenótipo , Fosforilação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Ativadoras de ras GTPase/genética
6.
Global Spine J ; : 21925682221098672, 2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35622711

RESUMO

STUDY DESIGN: Comparative study. OBJECTIVE: To compare manual and deep learning-based automated measurement of Cobb angle in adolescent idiopathic scoliosis. METHODS: We proposed a fully automated framework to measure the Cobb angle of AIS patients. Whole-spine images of 500 AIS individuals were collected. 200 digital radiographic (DR) images were labeled manually as training set, and the remaining 300 images were used to validate by mean absolute error (MAE), Pearson or spearman correlation coefficients, and intra/interclass correlation coefficients (ICCs). The relationship between accuracy of vertebral boundary identification and the subjective image quality score was evaluated. RESULTS: The PT, MT, and TL/L Cobb angles were measured by the automated framework within 300 milliseconds. Remarkable 2.92° MAE, .967 ICC, and high correlation coefficient (r = .972) were obtained for the major curve. The MAEs of PT, MT, and TL/L were 3.04°, 2.72°, and 2.53°, respectively. The ICCs of these 3 curves were .936, .977, and .964, respectively. 88.7% (266/300) of cases had a difference range of ±5°, with 84.3% (253/300) for PT, 89.7% (269/300) for MT, and 93.0% (279/300) for TL/L. The decreased bone/soft tissue contrast (2.94 vs 3.26; P=.039) and bone sharpness (2.97 vs 3.35; P=.029) were identified in the images with MAE exceeding 5°. CONCLUSION: The fully automated framework not only identifies the vertebral boundaries, vertebral sequences, the upper/lower end vertebras and apical vertebra, but also calculates the Cobb angle of PT, MT, and TL/L curves sequentially. The framework would shed new light on the assessment of AIS curvature.

7.
Ann Noninvasive Electrocardiol ; : e12964, 2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35612270

RESUMO

A 37-year-old man was admitted to our hospital with paroxysmal palpitation for half year. A previous electrogram showed a narrow complex tachycardia. Electrophysiologic study (EPS) found a concealed left-sided free wall pathway accessory. In addition, a transseptal approach was used for radiofrequency ablation. After successful ablation, EPS induced a wide complex tachycardia and a narrow complex tachycardia. The wide complex tachycardia was diagnosed as a right-sided Mahaim fiber atriofascicular accessory pathway, and the narrow complex tachycardia was diagnosed as atypical atrioventricular nodal reentrant tachycardia (AVNRT). Then, the right-sided Mahaim fiber atriofascicular accessory pathway and atypical AVNRT were successfully ablated. Herein, we report a rare case of a concealed left-sided accessory pathway combined with a right atriofascicular Mahaim fiber and atypical AVNRT.

8.
Sensors (Basel) ; 22(9)2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35591049

RESUMO

Multi-Target tracking is a central aspect of modeling the environment of autonomous vehicles. A mono camera is a necessary component in the autonomous driving system. One of the biggest advantages of the mono camera is it can give out the type of vehicle and cameras are the only sensors able to interpret 2D information such as road signs or lane markings. Besides this, it has the advantage of estimating the lateral velocity of the moving object. The mono camera is now being used by companies all over the world to build autonomous vehicles. In the expressway scenario, the forward-looking camera can generate a raw picture to extract information from and finally achieve tracking multiple vehicles at the same time. A multi-object tracking system, which is composed of a convolution neural network module, depth estimation module, kinematic state estimation module, data association module, and track management module, is needed. This paper applies the YOLO detection algorithm combined with the depth estimation algorithm, Extend Kalman Filter, and Nearest Neighbor algorithm with a gating trick to build the tracking system. Finally, the tracking system is tested on the vehicle equipped with a forward mono camera, and the results show that the lateral and longitudinal position and velocity can satisfy the need for Adaptive Cruise Control (ACC), Navigation On Pilot (NOP), Auto Emergency Braking (AEB), and other applications.


Assuntos
Condução de Veículo , Algoritmos , Redes Neurais de Computação
9.
Mol Hum Reprod ; 28(5)2022 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-35536241

RESUMO

Human cytotrophoblast (CTB) differentiation into syncytiotrophoblast (STB) is essential for placental formation and function. Understanding the molecular mechanisms involved in trophoblast differentiation is necessary as it would help in the development of novel therapeutic agents to treat placentation-mediated pregnancy complications. In this study, we found a common upregulated gene, ADAM-like Decysin-1 (ADAMDEC1), from five published microarray and RNA-sequencing datasets. Interference to ADAMDEC1 impaired forskolin-induced BeWo cells differentiation, while ADAMDEC1 overexpression promoted BeWo cells and 3D JEG-3 spheroids differentiation. Interestingly, ADAMDEC1 may inhibit Thrombospondin 1 rather than E-cadherin to trigger the activation of the cAMP signal pathway during CTB differentiation into STB. More importantly, a decreasing in ADAMDEC1 might be involved in the development of preeclampsia. Therefore, ADAMDEC1 is expected to become a new target for prediction of and intervention in placenta-derived pregnancy diseases.


Assuntos
Pré-Eclâmpsia , Trofoblastos , Diferenciação Celular/genética , Linhagem Celular Tumoral , Feminino , Humanos , Placenta , Placentação/genética , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Gravidez , Trofoblastos/metabolismo
11.
Ann Noninvasive Electrocardiol ; 27(4): e12949, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35460160

RESUMO

A 54-year-old man had a dual-chamber pacemaker implantation 9 years ago because of sick sinus syndrome at a different facility. The patient did not undergo any evaluation of his pacemaker for a long time with cardiologist. The patient was admitted to another hospital manifesting dyspnea and palpitation with atrial fibrillation for 1 month, and he was diagnosed with ventricular lead perforation. For further treatment, he was referred to our hospital, and an elective replacement indicator (ERI) of the battery state and a malpositioned ventricular lead into the middle cardiac vein were found. Finally, the pacing lead was left in the primary place and the pacemaker was replaced.


Assuntos
Fibrilação Atrial , Seio Coronário , Marca-Passo Artificial , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Estimulação Cardíaca Artificial , Seio Coronário/diagnóstico por imagem , Erros de Diagnóstico , Eletrocardiografia/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Marca-Passo Artificial/efeitos adversos
12.
Artigo em Inglês | MEDLINE | ID: mdl-35488101

RESUMO

microRNA (miRNA) is a type of endogenous short-chain non-coding RNA with regulatory function found in eukaryotes, which is involved in the regulation of a variety of cellular and biological processes. However, the research on the development of cashmere goat secondary hair follicles is still relatively scarce. In this study, small RNA libraries and mRNA libraries of 45 days, 55 days, 65 days, and 75 days of fetal skin of cashmere goats were constructed, and the constructed libraries were sequenced using Illumina Hiseq4000, and the expression profiles of miRNA and mRNA in cashmere goat fetal skin were obtained. The differentially expressed miRNAs and mRNAs in six control groups were identified and the qRT-PCR experiment shows that the sequencing results are accurate. Sixty-six miRNAs related to secondary hair follicle development were screened, and used TargetScan and miRanda to predict 33 highly expressed miRNA target genes. At the same time, 664 mRNAs related to the development of secondary hair follicles were screened, and GO enrichment and KEGG pathway analysis were performed. It was found that some miRNA target genes were consistent with the screening results of mRNAs related to secondary hair follicle development and were enriched in Notch signaling pathway, TGF-ß signaling pathway. Therefore, miR-145-5p-DLL4, miR-27b-3p-DLL4, miR-30e-5p-DLL4, miR-193b-3p-TGF-ß1, miR-181b-5p-NOTCH2, and miR-103-3p-NOTCH2 regulatory network related to the development of secondary hair follicles were constructed and the results of dual-luciferase reporter gene assay indicated that there is a targeted relationship between chi-miR-30e-5p and DLL4, which will provide a basis for molecular mechanism of miRNA-mRNA in the development of the hair follicles in cashmere goats.

13.
Front Genet ; 13: 804202, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35360850

RESUMO

Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant disorder of connective tissue characterized by crumpled ears, arachnodactyly, camptodactyly, large joint contracture, and kyphoscoliosis. The nature course of CCA has not been well-described. We aim to decipher the genetic and phenotypic spectrum of CCA. The cohort was enrolled in Beijing Jishuitan Hospital and Peking Union Medical College Hospital, Beijing, China, based on Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study (http://www.discostudy.org/). Exome sequencing was performed on patients' blood DNA. A recent published CCA scoring system was validated in our cohort. Seven novel variants and three previously reported FBN2 variants were identified through exome sequencing. Two variants outside of the neonatal region of FBN2 gene were found. The phenotypes were comparable between patients in our cohort and previous literature, with arachnodactyly, camptodactyly and large joints contractures found in almost all patients. All patients eligible for analysis were successfully classified into likely CCA based on the CCA scoring system. Furthermore, we found a double disease-causing heterozygous variant of FBN2 and ANKRD11 in a patient with blended phenotypes consisting of CCA and KBG syndrome. The identification of seven novel variants broadens the mutational and phenotypic spectrum of CCA and may provide implications for genetic counseling and clinical management.

14.
World J Surg Oncol ; 20(1): 106, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35365171

RESUMO

BACKGROUND: The presence of central lymph node metastases (CLNM) has been suggested as a risk factor for poorer prognosis and recurrence in papillary thyroid microcarcinoma (PTMC). However, the clinicopathologic factors for CLNM in clinical node-negative (CN0) PTMC were not well defined. This study aimed to perform a systematic review and meta-analysis to investigate the significant clinicopathologic predictors of CLNM in CN0 PTMC. METHODS: A systematic literature search was performed in PubMed, Embase, Cochrane Library, and Web of Science. Case-control studies on the association of clinicopathologic risk factors with CLNM in CN0 PTMC were included. RESULTS: Thirteen eligible studies involving 6068 patients with CN0 PTMC were included. From the pooled analyses, male (odds ratio [OR]: 2.07, 95% CI: 1.49-2.87, P < 0.001), multifocality (OR: 1.88, 95% CI: 1.54-2.29, P < 0.001), tumor size > 5 mm (OR: 1.84, 95% CI: 1.55-2.18, P < 0.001), and extrathyroidal extension (OR: 1.96, 95% CI: 1.30-2.95, P = 0.001) are significantly associated with increased risk of CLNM in CN0 PTMC. A sample size with a cutoff point of 200 was identified as the source of heterogeneity for sex according to meta-regression (t = 3.18, P = 0.033). Then, the subgroup analysis of male was performed, which illustrated that male increased the risk of CLNM in the small sample group (SG) and the large sample group (LG) by 6.11-folds and 2.01-folds, respectively (SG: OR, 6.11, 95% CI, 3.16-11.81, P < 0.001; LG: OR, 2.01, 95% CI, 1.65-2.46, P < 0.001). CONCLUSIONS: Male, multifocality, tumor size > 5 mm, and extrathyroidal extension may be reliable clinical predictors of CLNM in CN0 PTMC. Moreover, prophylactic central lymph node dissection should be considered in surgical decision-making for CN0 PTMC patients, who are male, multifocal, with tumor size > 5 mm, and with extrathyroidal extension. TRIAL REGISTRATION: CRD42021242211 (PROSPERO).


Assuntos
Carcinoma Papilar , Neoplasias da Glândula Tireoide , Carcinoma Papilar/patologia , Humanos , Metástase Linfática , Masculino , Esvaziamento Cervical , Neoplasias da Glândula Tireoide/patologia
15.
Orphanet J Rare Dis ; 17(1): 139, 2022 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-35346302

RESUMO

BACKGROUND: Skeletal deformity is characterized by an abnormal anatomical structure of bone and cartilage. In our previous studies, we have found that a substantial proportion of patients with skeletal deformity could be explained by monogenic disorders. More recently, complex phenotypes caused by more than one genetic defect (i.e., dual molecular diagnosis) have also been reported in skeletal deformities and may complicate the diagnostic odyssey of patients. In this study, we report the molecular and phenotypic characteristics of patients with dual molecular diagnosis and variable skeletal deformities. RESULTS: From 1108 patients who underwent exome sequencing, we identified eight probands with dual molecular diagnosis and variable skeletal deformities. All eight patients had dual diagnosis consisting of two autosomal dominant diseases. A total of 16 variants in 12 genes were identified, 5 of which were of de novo origin. Patients with dual molecular diagnosis presented blended phenotypes of two genetic diseases. Mendelian disorders occurred more than once include Osteogenesis Imperfecta Type I (COL1A1, MIM:166200), Neurofibromatosis, Type I (NF1, MIM:162200) and Marfan Syndrome (FBN1, MIM:154700). CONCLUSIONS: This study demonstrated the complicated skeletal phenotypes associated with dual molecular diagnosis. Exome sequencing represents a powerful tool to detect such complex conditions.


Assuntos
Neurofibromatose 1 , Osteogênese Imperfeita , Diagnóstico Duplo (Psiquiatria) , Humanos , Osteogênese Imperfeita/genética , Fenótipo , Sequenciamento Completo do Exoma
16.
Adv Sci (Weinh) ; 9(16): e2106075, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35315234

RESUMO

Localized scleroderma (LoS) is a rare chronic disease with extensive tissue fibrosis, inflammatory infiltration, microvascular alterations, and epidermal appendage lesions. However, a deeper understanding of the pathogenesis and treatment strategies of LoS is currently limited. In the present work, a proteome map of LoS skin is established, and the pathological features of LoS skin are characterized. Most importantly, a human-induced pluripotent stem cell-derived epithelial and mesenchymal (EM) organoids model in a 3D culture system for LoS therapy is established. According to the findings, the application of EM organoids on scleroderma skin can significantly reduce the degree of skin fibrosis. In particular, EM organoids enhance the activity of epidermal stem cells in the LoS skin and promotes the regeneration of sweat glands and blood vessels. These results highlight the potential application of organoids for promoting the recovery of scleroderma associated phenotypes and skin-associated functions. Furthermore, it can provide a new therapeutic alternative for patients suffering from disfigurement and skin function defects caused by LoS.


Assuntos
Células-Tronco Pluripotentes Induzidas , Esclerodermia Localizada , Diferenciação Celular , Fibrose , Humanos , Organoides
17.
Liver Int ; 42(5): 1097-1108, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35257483

RESUMO

BACKGROUND & AIMS: Genetic factors underlie a substantial proportion of paediatric liver diseases. Hereditary liver diseases have considerable genetic heterogeneity and variable clinical manifestations, which bring great challenges to clinical and molecular diagnoses. In this study, we investigated a group of paediatric patients with varying degrees of liver dysfunction using a hierarchical genetic testing strategy. METHODS: We first applied a panel encompassing 166 known causal genes of liver disease. We then used exome sequencing (ES) in those patients whose cases remained undiagnosed to identify the genetic aetiology of their symptoms. RESULTS: In total, we enrolled 131 unrelated paediatric patients with liver disease of Chinese Han ethnicity. We first applied targeted gene sequencing of 166 genes to all patients and yielded a diagnostic rate of 35.9% (47 of 131). Eighty-four patients who remained undiagnosed after target gene sequencing were subjected to ES. As a result, eight (8/84, 9.5%) of them obtained molecular diagnoses, including four patients suspected of abnormal bilirubin metabolism and four idiopathic cases. Non-typical genetic findings, including digenic inheritance and dual molecular diagnosis, were also identified. Through a comprehensive assessment of novel candidate variants of uncertain disease association, 11 patients of the remaining undiagnosed patients were able to obtain likely molecular diagnoses. CONCLUSIONS: Our study presents evidence for the diagnostic utility of sequential genetic testing in a cohort of patients with paediatric liver disease. Our findings expand the understanding of the phenotypic and mutational spectrum underlying this heterogeneous group of diseases.


Assuntos
Exoma , Hepatopatias , Criança , Testes Genéticos , Humanos , Hepatopatias/diagnóstico , Hepatopatias/genética , Mutação , Sequenciamento Completo do Exoma
18.
Neurology ; 98(16): e1670-e1678, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35228337

RESUMO

BACKGROUND AND OBJECTIVES: Brain arteriovenous malformation (bAVM) is a congenital disorder and a leading cause of hemorrhagic stroke. Germline genetic variants play an essential role in the pathogenesis of bAVM. However, the biological relevance of disease-associated genes identified in previous studies is elusive. In this study, we aim to systematically investigate the contribution of germline variants to bAVM and explore the critical molecular pathways underlying the pathogenesis of bAVM. METHODS: Probands with sporadic bAVM were consecutively recruited into this study from November 2015 to November 2018 and underwent exome sequencing. The controls were aggregated from individuals who were not known to have vascular malformation and underwent exome sequencing for clinical or research purposes. The retained control dataset included 4,609 individuals, including 251 individuals with parental samples sequenced. We first analyzed de novo variants in cases and controls and performed a pathway enrichment analysis. A gene-based rare variant association analysis was then performed to identify genes whose variants were significantly enriched in cases. RESULTS: We collected an exome-sequenced bAVM cohort consisting of 152 trios and 40 singletons. By first focusing on de novo variants, we observed a significant mutational burden of likely gene-disrupting variants in cases vs controls. By performing a pathway enrichment analysis of all nonsynonymous de novo variants identified in cases, we found the angiopoietin-like protein 8 (ANGPTL8) regulatory pathway to be significantly enriched in patients with bAVM. Through an exome-wide rare variant association analysis utilizing 4,394 in-house exome data as controls, we identified SLC19A3 as a disease-associated gene for bAVM. In addition, we found that the SLC19A3 variants in cases are preferably located at the N' side of the SLC19A3 protein. These findings implicate a phenotypic expansion of SLC19A3-related disorders with a domain-specific effect. DISCUSSION: This study provides insights into the biological basis of bAVM by identifying novel molecular pathways and candidate genes.


Assuntos
Malformações Arteriovenosas Intracranianas , Malformações do Sistema Nervoso , Hormônios Peptídicos , Proteínas Semelhantes a Angiopoietina/genética , Encéfalo/patologia , Exoma/genética , Predisposição Genética para Doença/genética , Humanos , Malformações Arteriovenosas Intracranianas/genética , Malformações Arteriovenosas Intracranianas/patologia , Proteínas de Membrana Transportadoras/genética , Mutação , Hormônios Peptídicos/genética , Sequenciamento Completo do Exoma
19.
Mol Genet Genomics ; 297(2): 387-396, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35122151

RESUMO

Segmental overgrowth of the skeletal muscles with bone involvement in body extremities, predominantly affecting the upper limb, is an extremely rare condition with only 40-50 affected children described clinically. The molecular pathogenesis of this disorder remains largely unclear except for the identification of a somatic PIK3CA mutation in each of the six patients genetically tested, all restricted to upper limbs in the literature. This study aimed to further characterize the molecular defects for patients affected with segmental overgrowth of the skeletal muscles by analyzing a 9-gene panel selected from the PI3K/AKT/mTOR pathway and genes associated with other related conditions. Nineteen unrelated patients were chosen for this study, comprising ten upper limb (nine unilateral and one bilateral) and nine lower limb (eight unilateral and one bilateral) cases with variable bone involvement. In each case, an activating PIK3CA mutation (p.E110del, p.N345K, p.E542K, p.E545K, p.H1047R, or p.H1047L) was identified in the affected muscle tissue with variant allele frequencies ranging from 13.88 to 30.43%, while no mutation was detected in the paired peripheral blood sample, indicating somatic mosaicism. All detected mutations were limited to PIK3CA and were previously reported in other overgrowth syndromes currently categorized under the PIK3CA-Related Overgrowth Spectrum (PROS). Our study provides strong molecular evidence that isolated segmental overgrowth of the skeletal muscle with bone involvement is a subtype of PROS. Our findings expand the PROS clinical presentations with a newly molecularly classified condition and can provide guidance in clinical and molecular diagnosis and treatment for patients with this condition.


Assuntos
Desenvolvimento Ósseo , Classe I de Fosfatidilinositol 3-Quinases , Transtornos do Crescimento , Músculo Esquelético , Fosfatidilinositol 3-Quinases , Desenvolvimento Ósseo/genética , Criança , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Extremidades , Transtornos do Crescimento/genética , Humanos , Músculo Esquelético/crescimento & desenvolvimento , Mutação , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo
20.
Genome Med ; 14(1): 21, 2022 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-35209950

RESUMO

BACKGROUND: Identifying breast cancer patients with DNA repair pathway-related germline pathogenic variants (GPVs) is important for effectively employing systemic treatment strategies and risk-reducing interventions. However, current criteria and risk prediction models for prioritizing genetic testing among breast cancer patients do not meet the demands of clinical practice due to insufficient accuracy. METHODS: The study population comprised 3041 breast cancer patients enrolled from seven hospitals between October 2017 and 11 August 2019, who underwent germline genetic testing of 50 cancer predisposition genes (CPGs). Associations among GPVs in different CPGs and endophenotypes were evaluated using a case-control analysis. A phenotype-based GPV risk prediction model named DNA-repair Associated Breast Cancer (DrABC) was developed based on hierarchical neural network architecture and validated in an independent multicenter cohort. The predictive performance of DrABC was compared with currently used models including BRCAPRO, BOADICEA, Myriad, PENN II, and the NCCN criteria. RESULTS: In total, 332 (11.3%) patients harbored GPVs in CPGs, including 134 (4.6%) in BRCA2, 131 (4.5%) in BRCA1, 33 (1.1%) in PALB2, and 37 (1.3%) in other CPGs. GPVs in CPGs were associated with distinct endophenotypes including the age at diagnosis, cancer history, family cancer history, and pathological characteristics. We developed a DrABC model to predict the risk of GPV carrier status in BRCA1/2 and other important CPGs. In predicting GPVs in BRCA1/2, the performance of DrABC (AUC = 0.79 [95% CI, 0.74-0.85], sensitivity = 82.1%, specificity = 63.1% in the independent validation cohort) was better than that of previous models (AUC range = 0.57-0.70). In predicting GPVs in any CPG, DrABC (AUC = 0.74 [95% CI, 0.69-0.79], sensitivity = 83.8%, specificity = 51.3% in the independent validation cohort) was also superior to previous models in their current versions (AUC range = 0.55-0.65). After training these previous models with the Chinese-specific dataset, DrABC still outperformed all other methods except for BOADICEA, which was the only previous model with the inclusion of pathological features. The DrABC model also showed higher sensitivity and specificity than the NCCN criteria in the multi-center validation cohort (83.8% and 51.3% vs. 78.8% and 31.2%, respectively, in predicting GPVs in any CPG). The DrABC model implementation is available online at http://gifts.bio-data.cn/ . CONCLUSIONS: By considering the distinct endophenotypes associated with different CPGs in breast cancer patients, a phenotype-driven prediction model based on hierarchical neural network architecture was created for identification of hereditary breast cancer. The model achieved superior performance in identifying GPV carriers among Chinese breast cancer patients.


Assuntos
Neoplasias da Mama , Aprendizado Profundo , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Reparo do DNA , Feminino , Predisposição Genética para Doença , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Mutação , Fenótipo
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