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  • 1
    Online Resource
    Online Resource
    The Korean undiagnosed diseases program phase I: expansion of the nationwide network and the development of long-term infrastructure
    Springer Science and Business Media LLC ; 2022
    In:  Orphanet Journal of Rare Diseases Vol. 17, No. 1 ( 2022-10-08)
    Details
    In: Orphanet Journal of Rare Diseases, Springer Science and Business Media LLC, Vol. 17, No. 1 ( 2022-10-08)
    Abstract: Phase I of the Korean Undiagnosed Diseases Program (KUDP), performed for 3 years, has been completed. The Phase I program aimed to solve the problem of undiagnosed patients throughout the country and develop infrastructure, including a data management system and functional core laboratory, for long-term translational research. Herein, we share the clinical experiences of the Phase I program and introduce the activities of the functional core laboratory and data management system. Results During the program (2018–2020), 458 patients were enrolled and classified into 3 groups according to the following criteria: (I) those with a specific clinical assessment which can be verified by direct testing (32 patients); (II) those with a disease group with genetic and phenotypic heterogeneity (353 patients); and (III) those with atypical presentations or diseases unknown to date (73 patients). All patients underwent individualized diagnostic processes based on the decision of an expert consortium. Confirmative diagnoses were obtained for 242 patients (52.8%). The diagnostic yield was different for each group: 81.3% for Group I, 53.3% for Group II, and 38.4% for Group III. Diagnoses were made by next-generation sequencing for 204 patients (84.3%) and other genetic testing for 35 patients (14.5%). Three patients (1.2%) were diagnosed with nongenetic disorders. The KUDP functional core laboratory, with a group of experts, organized a streamlined research pipeline covering various resources, including animal models, stem cells, structural modeling and metabolic and biochemical approaches. Regular data review was performed to screen for candidate genes among undiagnosed patients, and six different genes were identified for functional research. We also developed a web-based database system that supports clinical cohort management and provides a matchmaker exchange protocol based on a matchbox, likely to reinforce the nationwide clinical network and further international collaboration. Conclusions The KUDP evaluated the unmet needs of undiagnosed patients and established infrastructure for a data-sharing system and future functional research. The advancement of the KUDP may lead to sustainable bench-to-bedside research in Korea and contribute to ongoing international collaboration.
    Type of Medium: Online Resource
    ISSN: 1750-1172
    URL: Article
    DOI: 10.1186/s13023-022-02520-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2225857-7
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  • 2
    Online Resource
    Online Resource
    Identifying Pathogenic Variants of Monogenic Diabetes Using Targeted Exome Sequencing
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Background: Targeted exome sequencing is widely used for genetic diagnosis of rare disease and it is replacing Sanger sequencing. In this study we investigated pathogenic variants of monogenic diabetes genes in Korean early onset diabetes patients using targeted exome sequencing. Method: The main eligible criteria for this study was: non-type 1 diabetes patients with age of onset & lt; 30 years old and body mass index (BMI) & lt; 30 kg/m2. Among the 2353 patients screened from the diabetes registry of Seoul National University Hospital Diabetes Clinic, a total of 93 participants were eligible. We analyzed 30 monogenic diabetes genes using targeted exome sequencing. Identified genetic variants were evaluated by ACMG-AMP guideline for their pathogenicity. Result: Among the 93 index patients, a total of 83 rare (minor allele frequency & lt; 0.5%), non-silent variants were found and evaluated for its pathogenicity according to the ACMG-AMP guideline. These variants were classified as likely benign (N=8), uncertain significance (N=59), likely pathogenic (N=13), and pathogenic (N=5). Three causative mutations were identified in HNF4A (p.R136W, p.M1I, p.R89Q), four mutations in five patients were identified in HNF1A (c.G-124C, p.Y166N, p.L26Q, p.R278Q), four mutations were found in GCK (p.G410S, p.N231S, p.L164F, p.H156fs) and one mutation was identified in HNF1B (p.L168P). Other causative mutations were identified in WFS1 (p.R629W), INS (c.C-60G), ABCC8 (p.R933Q) and FOXP3 (p.Q200R). Mitochondria 3243 A & gt;G variant was identified in two patients. Patients with pathogenic variants had higher MODY probability score and lower BMI than those without causative gene variants (p=0.015, p=0.039, respectively). Conclusions: In this study, a total of 19 (20.4%) participants were identified to have monogenic cause of diabetes among 93 early onset diabetes patients. Further research is required to validate the clinical utility of targeted exome sequencing in early onset diabetes patients. Disclosure S. Park: None. S. Jang: None. Y. Lee: None. Y. Cho: None. H. Jang: None. K. Park: None. S. Kwak: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-267-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1501252-9
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  • 3
    Online Resource
    Online Resource
    MicroRNA Expression Profiles in Gastric Carcinogenesis
    Springer Science and Business Media LLC ; 2018
    In:  Scientific Reports Vol. 8, No. 1 ( 2018-09-26)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-09-26)
    Abstract: Intestinal-type gastric carcinoma exhibits a multistep carcinogenic sequence from adenoma to carcinoma with a gradual increase in genomic alterations. But the roles of microRNAs (miRNA) in this multistage cascade are not fully explored. To identify differentially expressed miRNA (DEM) during early gastric carcinogenesis, we performed miRNA microarray profiling with 24 gastric cancers and precursor lesions (7 early gastric cancer [EGC], 3 adenomas with high-grade dysplasia, 4 adenomas with low-grade dysplasia, and 10 adjacent normal tissues). Alterations in the expression of 132 miRNA were detected; these were categorized into three groups based on their expression patterns. Of these, 42 miRNAs were aberrantly expressed in EGC. Five miRNA (miR-26a, miR-375, miR-574-3p, miR-145, and miR-15b) showed decreased expression since adenoma. Expression of two miRNA, miR-200C and miR-29a, was down-regulated in EGCs compared to normal mucosa or adenomas. Six miRNA (miR-601, miR-107, miR-18a, miR-370, miR-300, and miR-96) showed increased expression in gastric cancer compared to normal or adenoma samples. Five representative miRNAs were further validated with RT-qPCR in independent 77 samples. Taken together, these results suggest that the dysregulated miRNA show alterations at the early stages of gastric tumorigenesis and may be used as a candidate biomarker.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-018-32782-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2615211-3
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  • 4
    Online Resource
    Online Resource
    Identifying Pathogenic Variants of Monogenic Diabetes Using Targeted Panel Sequencing in an East Asian Population
    The Endocrine Society ; 2019
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 104, No. 9 ( 2019-09-01), p. 4188-4198
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 104, No. 9 ( 2019-09-01), p. 4188-4198
    Abstract: Monogenic diabetes is a specific type of diabetes in which precision medicine could be applied. In this study, we used targeted panel sequencing to investigate pathogenic variants in Korean patients with clinically suspected monogenic diabetes. Methods The eligibility criteria for inclusion were patients with nontype 1 diabetes with age at onset ≤30 years and body mass index (BMI) ≤30 kg/m2. Among the 2090 patients with nontype 1 diabetes, 109 had suspected monogenic diabetes and underwent genetic testing. We analyzed 30 monogenic diabetes genes using targeted panel sequencing. The pathogenicity of the genetic variants was evaluated according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines. Results Among the 109 patients with suspected monogenic diabetes, 23 patients (21.1%) harbored pathogenic/likely pathogenic variants. A total of 14 pathogenic/likely pathogenic variants of common maturity-onset diabetes of the young (MODY) genes were identified in GCK, HNF1A, HNF4A, and HNF1B. Other pathogenic/likely pathogenic variants were identified in WFS1, INS, ABCC8, and FOXP3. The mitochondrial DNA 3243A 〉 G variant was identified in five participants. Patients with pathogenic/likely pathogenic variants had a significantly higher MODY probability, a lower BMI, and a lower C-peptide level than those without pathogenic/likely pathogenic variants (P = 0.007, P = 0.001, and P = 0.012, respectively). Conclusions Using targeted panel sequencing followed by pathogenicity evaluation, we were able to make molecular genetic diagnoses for 23 patients (21.1%) with suspected monogenic diabetes. Lower BMI, higher MODY probability, and lower C-peptide level were characteristics of these participants.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2018-02397
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2019
    detail.hit.zdb_id: 2026217-6
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  • 5
    Online Resource
    Online Resource
    Sequencing Cell-free Fetal DNA in Pregnant Women With GCK -MODY
    The Endocrine Society ; 2021
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 106, No. 9 ( 2021-08-18), p. 2678-2689
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 106, No. 9 ( 2021-08-18), p. 2678-2689
    Abstract: Individuals with monogenic diabetes due to inactivating glucokinase (GCK) variants typically do not require treatment, except potentially during pregnancy. In pregnancy, fetal GCK genotype determines whether treatment is indicated, but noninvasive methods are not clinically available. Objective This work aims to develop a method to determine fetal GCK genotype noninvasively using maternal cell-free fetal DNA. Methods This was a proof-of-concept study involving 3 pregnant women with a causal GCK variant that used information from 1) massive parallel sequencing of maternal plasma cell-free DNA, 2) direct haplotype sequences of maternal genomic DNA, and 3) the paternal genotypes to estimate relative haplotype dosage of the pathogenic variant-linked haplotype. Statistical testing of variant inheritance was performed using a sequential probability ratio test (SPRT). Results In each of the 3 cases, plasma cell-free DNA was extracted once between gestational weeks 24 and 36. The fetal fraction of cell-free DNA ranged from 21.8% to 23.0%. Paternal homozygous alleles that were identical to the maternal GCK variant-linked allele were not overrepresented in the cell-free DNA. Paternal homozygous alleles that were identical to the maternal wild-type–linked allele were significantly overrepresented. Based on the SPRT, we predicted that all 3 cases did not inherit the GCK variant. Postnatal infant genotyping confirmed our prediction in each case. Conclusion We have successfully implemented a noninvasive method to predict fetal GCK genotype using cell-free DNA in 3 pregnant women carrying an inactivating GCK variant. This method could guide tailoring of hyperglycemia treatment in pregnancies of women with GCK monogenic diabetes.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgab265
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2021
    detail.hit.zdb_id: 2026217-6
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  • 6
    Online Resource
    Online Resource
    1387-P: Genotyping Cell-Free Fetal DNA to Decide whether to Treat Hyperglycemia during Pregnancy in Women with GCK Monogenic Diabetes—A Case Study
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Patients with inactivating glucokinase (GCK) mutation usually do not require treatment except for during pregnancy. The decision to treat hyperglycemia during pregnancy would depend on the fetal GCK genotype. However, it has not been able to noninvasively investigate the fetal genotype antenatally. In this study, we developed a method to determine cell-free fetal genotype of GCK and applied it in a case of pregnant woman with GCK mutation. A 40 years old woman in her second pregnancy presented with hyperglycemia. She was diagnosed with GCK p.Gly411Ser (chr7:44185121C & gt;T; NM_000162 c.G1228A) mutation prior to her second pregnancy. We used targeted linked-read deep sequencing to resolve the haplotypes of GCK for both the women and her husband. Cell-free DNA was extracted from maternal plasma at week 24 of gestation and were subjected to massively parallel sequencing. The allelic fraction of the heterozygous variants that were in maternal mutant-linked haplotype were analyzed. The fetal fraction of the maternal plasma cell-free DNA was 21.8%. In maternal plasma cell-free DNA, a total of 12 heterozygous variants, that were homozygous in paternal genomic DNA, were identified within 40 kb of the disease-causing mutation. The average allelic fraction of the 12 variants in the mutant-linked haplotype and the wild type-linked haplotype in the cell-free DNA was 44.1% and 55.9%, respectively. This significant difference in allelic fraction of the haplotypes suggested that the fetus did not inherit the GCK mutant-linked haplotype (P 0.0081). The inferred fetal genotype was available at week 30 of gestation and the patient was treated with basal-bolus insulin therapy until term at 38 weeks. The fetal birth weight was 2,980 g (25th percentile). The fetal genotype of GCK was confirmed by Sanger sequencing postnatally. This was the first study to use cell-free DNA to determine fetal genotype to guide treatment of hyperglycemia in pregnant women with GCK mutation. Disclosure S. Kwak: None. S. Jang: None. S. Kang: None. H. Jang: None. S. Lee: None. J. Chae: None. K. Park: None. Funding Korean Ministry of Health and Welfare (HI15C3131, HI13C1468)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-1387-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
    detail.hit.zdb_id: 1501252-9
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  • 7
    Online Resource
    Online Resource
    Importance of early diagnosis in LMNA ‐related muscular dystrophy for cardiac surveillance
    Wiley ; 2019
    In:  Muscle & Nerve Vol. 60, No. 6 ( 2019-12), p. 668-672
    Details
    In: Muscle & Nerve, Wiley, Vol. 60, No. 6 ( 2019-12), p. 668-672
    Abstract: The identification of LMNA ‐related muscular dystrophy is important because it poses life‐threatening cardiac complications. However, diagnosis of LMNA ‐related muscular dystrophy based on clinical features is challenging. Methods We reviewed the clinical phenotypes of 14 children with LMNA variants, focusing on the cardiac function and genotypes. Results Most patients presented with motor developmental delay or gait abnormalities. Eight (57%) patients had prominent neck extensor weakness or contractures. All patients showed ankle contractures at an early stage. Regular cardiac surveillance allowed for the detection of dysrhythmias in 57% of patients at a mean age of 14 years (range, 5–26). All patients had missense variants; however, there were no clear phenotype–genotype correlations. Discussion Early diagnosis of LMNA ‐related muscular dystrophy provides an opportunity for cardiac surveillance, potentially leading to the prevention of cardiac mortality in children.
    Type of Medium: Online Resource
    ISSN: 0148-639X , 1097-4598
    URL: Issue
    URL: Article
    DOI: 10.1002/mus.v60.6
    DOI: 10.1002/mus.26700
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 1476641-3
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis
    Wiley ; 2016
    In:  The Journal of Pathology Vol. 240, No. 3 ( 2016-11), p. 304-314
    Details
    In: The Journal of Pathology, Wiley, Vol. 240, No. 3 ( 2016-11), p. 304-314
    Abstract: Several recurrent mutations and epigenetic changes have been identified in advanced gastric cancer, but the genetic alterations associated with early gastric carcinogenesis and malignant transformation remain unclear. We investigated the genomic and transcriptomic landscape of adenomas with low‐grade dysplasia ( LGD ) and high‐grade dysplasia ( HGD ), and intestinal‐type early gastric cancer ( EGC ). The results were validated in an independent cohort that included EGCs directly adjacent to adenoma ( EGC ‐adenomas) that were in the process of malignant transformation, and de novo EGCs that do not seem to have been derived from adenoma. The expression patterns clearly divided into normal, LGD , and EGC , whereas those of HGD overlapped with LGD or EGC . These results suggest that HGD is the critical stage determining malignant transformation. We found that genes related to focal adhesion and extracellular matrix receptor interaction pathways were upregulated as LGD progressed to EGC , whereas canonical Wnt signalling and peroxisome proliferator‐activated receptor ( PPAR ) signalling pathway genes were downregulated in EGC . Genomic alterations such as somatic mutation, gene fusion and copy number variation increased gradually from LGD to EGC . APC mutations were present in 67% of LGDs , 58% of HGDs , and 18% of EGCs . RNF43 mutations were present only in HGD and EGC , and TP53 mutations were present only in EGC . In a validation cohort, RNF43 mutations were present in 35.2% of EGC ‐adenomas, but in only 8.6% of de novo EGCs . This is the first study to investigate the genomic and transcriptomic landscape of multistep gastric carcinogenesis. We investigated important alterations and their related pathways in each step as tumours progressed from LGD to HGD and eventually to EGC . We suggest that mutations and downregulation of RNF43 may play a critical role in the transition from adenoma to carcinoma. Given these findings and Wnt dependency in tumours with RNF43 mutation, intestinal‐type gastric cancer or adenoma with RNF43 mutation might represent a promising indication for Wnt‐targeted agents. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.2016.240.issue-3
    DOI: 10.1002/path.4777
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 1475280-3
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  • 9
    Online Resource
    Online Resource
    Targeted linked-read sequencing for direct haplotype phasing of maternal DMD alleles: a practical and reliable method for noninvasive prenatal diagnosis
    Springer Science and Business Media LLC ; 2018
    In:  Scientific Reports Vol. 8, No. 1 ( 2018-06-06)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-06-06)
    Abstract: For the noninvasive prenatal diagnosis (NIPD) of X-linked recessive diseases such as Duchenne muscular dystrophy (DMD), maternal haplotype phasing is a critical step for dosage analysis of the inherited allele. Until recently, the proband-based indirect haplotyping method has been preferred despite its limitations for use in clinical practice. Here, we describe a method for directly determining the maternal haplotype without requiring the proband’s DNA in DMD families. We used targeted linked-read deep sequencing (mean coverage of 692×) of gDNA from 5 mothers to resolve their haplotypes and predict the mutation status of the fetus. The haplotype of DMD alleles in the carrier mother was successfully phased through a targeted linked-read sequencing platform. Compared with the proband-based phasing method, linked-read sequencing was more accurate in differentiating whether the recombination events occurred in the proband or in the fetus. The predicted inheritance of the DMD mutation was diagnosed correctly in all 5 families in which the mutation had been confirmed using amniocentesis or chorionic villus sampling. Direct haplotyping by this targeted linked-read sequencing method could be used as a phasing method for the NIPD of DMD, especially when the genomic DNA of the proband is unavailable.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-018-26941-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2615211-3
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  • 10
    Online Resource
    Online Resource
    Findings of a 1303 Korean whole-exome sequencing study
    Springer Science and Business Media LLC ; 2017
    In:  Experimental & Molecular Medicine Vol. 49, No. 7 ( 2017-7), p. e356-e356
    Details
    In: Experimental & Molecular Medicine, Springer Science and Business Media LLC, Vol. 49, No. 7 ( 2017-7), p. e356-e356
    Type of Medium: Online Resource
    ISSN: 1226-3613 , 2092-6413
    URL: Article
    DOI: 10.1038/emm.2017.142
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2084833-X
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