15,314 results match your criteria pathogenic variants


Symptom Prevalence and Genotype-Phenotype Correlations in Patients With TANGO2-Related Metabolic Encephalopathy and Arrhythmias (TRMEA).

Pediatr Neurol 2021 Mar 8;119:34-39. Epub 2021 Mar 8.

Department of Neurology and Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio. Electronic address:

Background: TANGO2-related metabolic encephalopathy and arrhythmias (TRMEA) is a rare, phenotypically heterogeneous, neurological disease affecting children.

Methods: We conducted a chart review of five children with molecularly confirmed TRMEA diagnosed at our institution and compiled pathogenic variant frequency and symptom prevalence from cases previously reported in the literature.

Results: Including those patients in our case series, 76 patients with TRMEA have been described. Read More

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Generation of pathogenic TPP1 mutations in human stem cells as a model for neuronal ceroid lipofuscinosis type 2 disease.

Stem Cell Res 2021 Apr 6;53:102323. Epub 2021 Apr 6.

Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island 02912, USA; Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science, Brown University, Providence, Rhode Island 02912, USA; Hassenfeld Child Health Innovation Institute, Brown University, Providence, Rhode Island 02912, USA. Electronic address:

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an autosomal recessive neurodegenerative disorder generally with onset at 2 to 4 years of age and characterized by seizures, loss of vision, progressive motor and mental decline, and premature death. CLN2 disease is caused by loss-of-function mutations in the tripeptidyl peptidase 1 (TPP1) gene leading to deficiency in TPP1 enzyme activity. Approximately 60% of patients have one of two pathogenic variants (c. Read More

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Comparison of The Carrier Frequency of Pathogenic Variants of DMD Gene in an Indian Cohort.

J Neuromuscul Dis 2021 Apr 2. Epub 2021 Apr 2.

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India.

Background: Duchenne muscular dystrophy (DMD) is an X-linked disorder caused due to large deletions, duplications,and small pathogenic variants. This article compares the carrier frequency of different pathogenic variants in the DMD gene for the first time in an Indian cohort.

Methods: Ninety-one mothers of genetically confirmed DMD probands are included in this study. Read More

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Neuromuscular Junction Abnormalities in Mitochondrial Disease: An Observational Cohort Study.

Neurol Clin Pract 2021 Apr;11(2):97-104

Department of Neurology (LPB), Centro Hospitalar Universitário de São João, Porto, Portugal; and Wellcome Centre for Mitochondrial Research (YSN, GSG, AMS, RM, RWT, DMT), Translational and Clinical Research Institute (RGW), Newcastle University, Newcastle upon Tyne, United Kingdom.

Objective: To determine the prevalence of neuromuscular junction (NMJ) abnormalities in patients with mitochondrial disease.

Methods: Eighty patients with genetically proven mitochondrial disease were recruited from a national center for mitochondrial disease in the United Kingdom. Participants underwent detailed clinical and neurophysiologic testing including single-fiber electromyography. Read More

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Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy.

Front Neurol 2021 25;12:602979. Epub 2021 Mar 25.

University Angers, MitoLab team, UMR CNRS 6015-INSERM U1083, Unité MitoVasc, SFR ICAT, Angers, France.

Advances in next-generation sequencing (NGS) facilitate the diagnosis of genetic disorders. To evaluate its use for the molecular diagnosis of inherited optic neuropathy (ION), a blinding disease caused by the degeneration of retinal ganglion cells, we performed genetic analysis using targeted NGS of 22 already known and candidate genes in a cohort of 1,102 affected individuals. The panel design, library preparation, and sequencing reactions were performed using the Ion AmpliSeq technology. Read More

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Comprehensive germline-genomic and clinical profiling in 160 unselected children and adolescents with cancer.

Eur J Hum Genet 2021 Apr 12. Epub 2021 Apr 12.

Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.

In childhood cancer, the frequency of cancer-associated germline variants and their inheritance patterns are not thoroughly investigated. Moreover, the identification of children carrying a genetic predisposition by clinical means remains challenging. In this single-center study, we performed trio whole-exome sequencing and comprehensive clinical evaluation of a prospectively enrolled cohort of 160 children with cancer and their parents. Read More

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Confirmation of COL4A6 variants in X-linked nonsyndromic hearing loss and its clinical implications.

Eur J Hum Genet 2021 Apr 12. Epub 2021 Apr 12.

Department of Pediatrics, Division of Genetics and Metabolism, UNC Chapel Hill, Chapel Hill, NC, USA.

Hearing loss (HL) is one of the most common sensory defects, of which X-linked nonsyndromic hearing loss (NSHL) accounts for only 1-2%. While a COL4A6 variant has been reported in a single Hungarian family with NSHL associated with inner ear malformation, causative role of COL4A6 variants and their phenotypic consequences in NSHL remain elusive. Here we report two families in which we identified a male member with X-linked HL. Read More

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Genomic profiling of multiple tissues in two patients with multiple endocrine neoplasia type 1.

Biomed Res 2021 ;42(2):89-94

Shizuoka Cancer Center.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor syndrome. This hereditary cancer is caused by germline variants in MEN1. Two patients with MEN1 were identified via whole exome sequencing and gene expression profile analysis, conducted for 5,063 patients with various types of cancers. Read More

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January 2021

A case of Carney triad complicated by renal cell carcinoma and a germline SDHA pathogenic variant.

Endocrinol Diabetes Metab Case Rep 2021 Mar 28;2021. Epub 2021 Mar 28.

Section on Endocrinology and Genetics, National Institutes of Health, Bethesda, Maryland, USA.

Summary: Succinate dehydrogenase deficiency has been associated with several neoplasias, including renal cell carcinoma (RCC) and those associated with hereditary paraganglioma (PGL)/ pheochromocytoma (PHEO) syndromes, Carney dyad, and Carney triad. Carney triad is a rare multitumoral syndrome characterized by co-existing PGL, gastrointestinal stromal tumor (GIST), and pulmonary chondroma (CHO). We report a case of a 57-year-old male who presented with para-aortic and gastroesophogeal masses, and a right renal superior pole lesion, which were classified as multiple PGLs, a GIST, and a clear cell renal carcinoma, respectively, on pathology following surgical resection. Read More

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Gene-Specific Variation in Colorectal Cancer Surveillance Strategies for Lynch Syndrome.

Gastroenterology 2021 Apr 8. Epub 2021 Apr 8.

Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York; Division of Digestive and Liver Diseases, Columbia University Irving Medical Cancer and the Vagelos College of Physicians and Surgeons, New York, New York; Division of General Medicine, Columbia University Irving Medical Cancer and the Vagelos College of Physicians and Surgeons, New York, New York.

Background & Aims: Lynch syndrome is associated with pathogenic variants in 4 mismatch repair (MMR) genes that increase lifetime risk of colorectal cancer (CRC). Guidelines recommend intensive CRC surveillance with colonoscopy every 1-2 years starting at 25 years for all carriers of Lynch syndrome-associated variants, regardless of gene product. We constructed a simulation model to analyze the effects of different ages of colonoscopy initiation and surveillance intervals for each MMR gene (MLH1, MSH2, MSH6, and PMS2) on CRC incidence and mortality, quality-adjusted life-years (QALYs), and cost. Read More

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Examination of ATM, BRCA1, and BRCA2 promoter methylation in patients with pancreatic cancer.

Pancreatology 2021 Mar 28. Epub 2021 Mar 28.

Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Pancreatic cancer is a lethal disease with a poor 5-year survival rate. Pathogenic germline variants in the coding regions of ATM, BRCA1, and BRCA2 are found in up to 4.8% of pancreatic cancer patients. Read More

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Clinical and Genetic Features of Autosomal Dominant Alport Syndrome: A Case Series.

Am J Kidney Dis 2021 Apr 1. Epub 2021 Apr 1.

Inherited Kidney Diseases, Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Medicine Department-Universitat Autónoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain. Electronic address:

Rationale & Objective: Alport syndrome (AS) is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic variants in COL4A3, COL4A4 or COL4A5 genes. The aim of this study was to evaluate the clinical and genetic spectrum of patients with autosomal dominant Alport syndrome (ADAS). Read More

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Immune cytopenias as a continuum in inborn errors of immunity: An in-depth clinical and immunological exploration.

Immun Inflamm Dis 2021 Apr 10. Epub 2021 Apr 10.

Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Background: Immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia (AIN) are disorders characterized by immune-mediated destruction of hematopoietic cell lineages. A link between pediatric immune cytopenias and inborn errors of immunity (IEI) was established in particular in the combined and chronic forms.

Objective: Aim of this study is to provide clinical-immunological parameters to hematologists useful for a prompt identification of children with immune cytopenias deserving a deeper immunological and genetic evaluation. Read More

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White-Sutton syndrome with hot water epilepsy and coexistence of SHOX gene variations.

Acta Neurol Belg 2021 Apr 10. Epub 2021 Apr 10.

Department of Medical Genetics, Duzce University Medical Faculty, Duzce, Turkey.

The purpose of this study is to reveal the effect on the clinical phenotype of variants detected at family examination of a case of combined pogo transposable element derived with zinc finger domain (POGZ) gene, tubulin folding cofactor E (TBCE) gene, and short stature homeobox (SHOX) gene variation. A Turkish non-consanguineous family consisting of five members was investigated. Whole exome sequence analysis and chromosomal microarray analysis (CMA) were performed for a 2-year-old male patient (the proband) with global developmental delay, hypotonia, dysmorphia, and hot water epilepsy. Read More

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Zinc transporter mutations linked to acrodermatitis enteropathica disrupt function and cause mistrafficking.

J Biol Chem 2021 Jan 8;296:100269. Epub 2021 Jan 8.

Department of Chemistry, Michigan State University, East Lansing, Michigan, USA; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, USA. Electronic address:

ZIP4 is a representative member of the Zrt-/Irt-like protein (ZIP) transporter family and responsible for zinc uptake from diet. Loss-of-function mutations of human ZIP4 (hZIP4) drastically reduce zinc absorption, causing a life-threatening autosomal recessive disorder, acrodermatitis enteropathica (AE). These mutations occur not only in the conserved transmembrane zinc transport machinery, but also in the extracellular domain (ECD) of hZIP4, which is only present in a fraction of mammalian ZIPs. Read More

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January 2021

Impact of national guidelines on use of BRCA1/2 germline testing, risk management advice given to women with pathogenic BRCA1/2 variants and uptake of advice.

Hered Cancer Clin Pract 2021 Apr 9;19(1):24. Epub 2021 Apr 9.

Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.

Background: This nationwide study assessed the impact of nationally agreed cancer genetics guidelines on use of BRCA1/2 germline testing, risk management advice given by health professionals to women with pathogenic BRCA1/2 variants and uptake of such advice by patients.

Methods: Clinic files of 883 women who had initial proband screens for BRCA1/2 pathogenic variants at 12 familial cancer clinics between July 2008-July 2009 (i.e. Read More

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Carrier frequency and incidence estimation of Smith-Lemli-Opitz syndrome in East Asian populations by Genome Aggregation Database (gnomAD) based analysis.

Orphanet J Rare Dis 2021 Apr 9;16(1):166. Epub 2021 Apr 9.

Green Cross Genome, 107, Ihyeon-ro 30beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do, 16924, Republic of Korea.

Background: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal, recessively inherited congenital malformation syndrome characterized by multiple congenital anomalies such as microcephaly with mental defects, distinctive facial features, genital abnormalities, and 2-3 syndactyly of the toes. SLOS is caused by defective 7-dehydrocholesterol reductase, which is encoded by the DHCR7 gene. This study aimed to analyze the carrier frequency and expected incidence of SLOS in East Asians and Koreans using exome data from the Genome Aggregation Database (gnomAD) through the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology guideline (2015 ACMG-AMP guideline). Read More

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Ataxia telangiectasia mutated germline pathogenic variant in adrenocortical carcinoma.

Cancer Genet 2021 Mar 24;256-257:21-25. Epub 2021 Mar 24.

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States. Electronic address:

Background: Adrenocortical carcinoma (ACC) is a rare malignancy arising from the adrenal cortex. ACC carries a dismal prognosis and surgery offers the only chance for a cure. Germline pathogenic variants among certain oncogenes have been implicated in ACC. Read More

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Ablation of Mto1 in zebrafish exhibited hypertrophic cardiomyopathy manifested by mitochondrion RNA maturation deficiency.

Nucleic Acids Res 2021 Apr 9. Epub 2021 Apr 9.

Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310058, China.

Deficient maturations of mitochondrial transcripts are linked to clinical abnormalities but their pathophysiology remains elusive. Previous investigations showed that pathogenic variants in MTO1 for the biosynthesis of τm5U of tRNAGlu, tRNAGln, tRNALys, tRNATrp and tRNALeu(UUR) were associated with hypertrophic cardiomyopathy (HCM). Using mto1 knock-out(KO) zebrafish generated by CRISPR/Cas9 system, we demonstrated the pleiotropic effects of Mto1 deficiency on mitochondrial RNA maturations. Read More

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The benefits and challenges of family genetic testing in rare genetic diseases-lessons from Fabry disease.

Mol Genet Genomic Med 2021 Apr 9:e1666. Epub 2021 Apr 9.

Research Centre for Medical Genetics, Moscow, Russia.

Background: Family genetic testing of patients newly diagnosed with a rare genetic disease can improve early diagnosis of family members, allowing patients to receive disease-specific therapies when available. Fabry disease, an X-linked lysosomal storage disorder caused by pathogenic variants in GLA, can lead to end-stage renal disease, cardiac arrhythmias, and stroke. Diagnostic delays are common due to the rarity of the disease and non-specificity of early symptoms. Read More

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Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer's disease.

Hum Mol Genet 2021 Apr 9. Epub 2021 Apr 9.

Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China.

To identify novel risk genes and better understand the molecular pathway underlying Alzheimer's disease (ad), whole-exome sequencing (WES) was performed in 215 early-onset ad (EOAD) patients and 255 unrelated healthy controls of Han Chinese ethnicity. Subsequent validation, computational annotation and in vitro functional studies were performed to evaluate the role of candidate variants in EOAD. We identified two rare missense variants in the phosphodiesterase 11A (PDE11A) gene in individuals with EOad. Read More

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[Analysis of clinical features and genetic variants in a Chinese pedigree affected with tuberous sclerosis].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2021 Apr;38(4):363-365

Department of Nephrology, Nanhua Hospital Affiliated to South China University, Hengyang, Hunan 421002, China.

Objective: To analyze the clinical features of a Chinese pedigree affected with tuberculosis sclerosis and explore its molecular pathogenesis.

Methods: Clinical data of the proband and members of his pedigree were collected. Whole exome sequencing was carried out to detect variants of the TSC1 and TSC2 genes. Read More

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[Frontometaphyseal dysplasia 1 caused by variant of FLNA gene in a case].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2021 Apr;38(4):355-358

Shanghai Chindren's Medical Center Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.

Objective: To explore the clinical and genetic characteristics of a child with frontometaphyseal dysplasia 1 (FMD1) due to variant of FLNA gene.

Methods: Clinical phenotype of the patient was analyzed. Whole exome sequencing (WES) was carried out to detect pathogenic genetic variants. Read More

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[Genetic analysis of three patients with Kleefstra syndrome].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2021 Apr;38(4):347-350

Xianning Central Hospital (the First Affiliated Hospital of Hubei University of Science and Technology), Xianning, Hubei 437100, China.

Objective: To analyze the clinical and genetic features of three patient diagnosed with Kleefstra syndrome.

Methods: Whole exome sequencing (WES) was carried out for the probands and their parents. Suspected variants were validated by Sanger sequencing. Read More

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ActiveDriverDB: Interpreting Genetic Variation in Human and Cancer Genomes Using Post-translational Modification Sites and Signaling Networks (2021 Update).

Front Cell Dev Biol 2021 23;9:626821. Epub 2021 Mar 23.

Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.

Deciphering the functional impact of genetic variation is required to understand phenotypic diversity and the molecular mechanisms of inherited disease and cancer. While millions of genetic variants are now mapped in genome sequencing projects, distinguishing functional variants remains a major challenge. Protein-coding variation can be interpreted using post-translational modification (PTM) sites that are core components of cellular signaling networks controlling molecular processes and pathways. Read More

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EYS mutations and implementation of minigene assay for variant classification in EYS-associated retinitis pigmentosa in northern Sweden.

Sci Rep 2021 Apr 8;11(1):7696. Epub 2021 Apr 8.

Medical Biosciences/Medical and Clinical Genetics, University of Umeå, 901 87, Umeå, Sweden.

Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of inherited retinal degenerations. The ortholog of Drosophila eyes shut/spacemaker, EYS on chromosome 6q12 is a major genetic cause of recessive RP worldwide, with prevalence of 5 to 30%. In this study, by using targeted NGS, MLPA and Sanger sequencing we uncovered the EYS gene as one of the most common genetic cause of autosomal recessive RP in northern Sweden accounting for at least 16%. Read More

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Low-level variant calling for non-matched samples using a position-based and nucleotide-specific approach.

BMC Bioinformatics 2021 Apr 8;22(1):181. Epub 2021 Apr 8.

National Human Genome Research Institute, National Institutes of Health, 50 South Drive Room 5140, Bethesda, MD, 20892, USA.

Background: The widespread use of next-generation sequencing has identified an important role for somatic mosaicism in many diseases. However, detecting low-level mosaic variants from next-generation sequencing data remains challenging.

Results: Here, we present a method for Position-Based Variant Identification (PBVI) that uses empirically-derived distributions of alternate nucleotides from a control dataset. Read More

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Tay-Sachs Disease: Two Novel Rare HEXA Mutations from Pakistan and Morocco.

Klin Padiatr 2021 Apr 8. Epub 2021 Apr 8.

Institute of Biochemistry and Biotechnology, Pir Mehar Ali Shah Arid Agriculture University, Rawalpindi, Pakistan.

Background: Tay-Sachs disease (TSD) is a rare autosomalrecessive genetic disorder characterized by progressive destruction of nerve cells in the brain and spinal cord. It is caused by genetic variations in the HEXA gene leading to a deficiency of β hexosaminidase A (HEXA) isoenzyme activity. This study aimed to identify causative gene variants in 3 unrelated consanguineous families presented with TSD from Pakistan and Morocco. Read More

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An International Evidence Based Reappraisal of Genes Associated with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) using the ClinGen Framework.

Circ Genom Precis Med 2021 Apr 8. Epub 2021 Apr 8.

Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam & Department of Genetics, University of Utrecht, University Medical Center Utrecht, Utrecht, the Netherlands.

- Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by ventricular arrhythmias and progressive ventricular dysfunction. Genetic testing is recommended and a pathogenic variant in an ARVC-associated gene is a major criterion for diagnosis according to the 2010 Task Force Criteria (TFC). As incorrect attribution of a gene to ARVC can contribute to misdiagnosis, we assembled an international multidisciplinary ARVC ClinGen Gene Curation Expert Panel to reappraise all reported ARVC genes. Read More

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