• Journal of Genetic Medicine
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• v.10 no.2
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• pp.94-98
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• 2013

Dystrophinopathy, caused by mutations in the DMD gene, presents with variable clinical phenotypes ranging from the severe Duchenne muscular dystrophy (DMD) to the milder Becker muscular dystrophy(BMD) forms. DMD is a recessive X-linked form of muscular dystrophy. Two-thirds of mothers of affected males are thought to be DMD carriers. Approximately 2.5-7.8% of female DMD carriers have muscle weakness and are categorized as manifesting DMD carriers. The symptoms of female carriers of DMD range from mild muscle weakness to severe gait problems. The most commonly presented symptom is mild proximal muscle weakness, which is often asymmetric and progressive, but shows variable clinical spectrum with BMD of more severe DMD-like phenotype. Atypical presentations in manifesting carriers are myalgia or cramps without limb weakness, isolated cardiomyopathy and camptocormia. Multiplex PCR and MLPA analysis are common techniques to identify mutations in the DMD gene. Relationship between X-chromosome inactivation and clinical severity is not clear. Female carriers of DMD are not less common, and they have an important role of birth of a male DMD.

• Journal of Genetic Medicine
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• v.10 no.2
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• pp.88-93
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• 2013

Alexander disease (ALXD) is a rare demyelinating disease of the white matter of the brain that is caused by a mutation in the glial fibrillary acidic protein (GFAP) gene. The overexpression of GFAP in astrocytes induces a failure in the developmental growth of the myelin sheath. The neurodegenerative destruction of the myelin sheath of the white matter is accompanied by an accumulation of abnormal deposits of Rosenthal fibers in astrocytes, which is the hallmark of ALXD. The disease can be divided into four groups based on the onset age of the patients: neonatal, infantile, juvenile, or adult. Early-onset disease is more severe, progresses rapidly, and results in a shorter life span than late-onset cases. Magnetic resonance imaging and genetic tests are mostly used for diagnostic purposes. Pathological tests of brain tissue for Rosenthal fibers are definitive diagnostic methods. Therapeutic strategies are being investigated. Ceftriaxone, which is an enhancer of glial glutamate transporter (GLT-1) expression, is currently in clinical trials for the treatment of patients with ALXD. To date, there are no clinically available treatments. The cause, pathology, pathophysiology, inheritance, clinical features, diagnosis, and treatment of ALXD will be reviewed comprehensively.

• Molecules and Cells
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• v.39 no.2
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• pp.77-86
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• 2016

Cancer is a heterogeneous disease caused by diverse genomic alterations in oncogenes and tumor suppressor genes. Despite recent advances in high-throughput sequencing technologies and development of targeted therapies, novel cancer drug development is limited due to the high attrition rate from clinical studies. Patient-derived xenografts (PDX), which are established by the transfer of patient tumors into immunodeficient mice, serve as a platform for co-clinical trials by enabling the integration of clinical data, genomic profiles, and drug responsiveness data to determine precisely targeted therapies. PDX models retain many of the key characteristics of patients' tumors including histology, genomic signature, cellular heterogeneity, and drug responsiveness. These models can also be applied to the development of biomarkers for drug responsiveness and personalized drug selection. This review summarizes our current knowledge of this field, including methodologic aspects, applications in drug development, challenges and limitations, and utilization for precision cancer medicine.

• Journal of Genetic Medicine
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• v.16 no.1
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• pp.1-9
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• 2019

Noonan syndrome (NS) and NS-related disorders (cardio-facio-cutaneous syndrome, Costello syndrome, NS with multiple lentigines, or LEOPARD [lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensory neural deafness] syndrome) are collectively named as RASopathies. Clinical presentations are similar, featured with typical facial features, short stature, intellectual disability, ectodermal abnormalities, congenital heart diseases, chest & skeletal deformity and delayed puberty. During past decades, molecular etiologies of RASopathies have been growingly discovered. The functional perturbations of the RAS-mitogen-activated protein kinase pathway are resulted from the mutation of more than 20 genes (PTPN11, SOS1, RAF1, SHOC2, BRAF, KRAS, NRAS, HRAS, MEK1, MEK2, CBL, SOS2, RIT, RRAS, RASA2, SPRY1, LZTR1, MAP3K8, MYST4, A2ML1, RRAS2). The PTPN11 (40-50%), SOS1 (10-20%), RAF1 (3-17%), and RIT1 (5-9%) mutations are common in NS patients. In this review, the constellation of overlapping clinical features of RASopathies will be described based on genotype as well as their differential diagnostic points and management.

• Journal of Genetic Medicine
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• v.17 no.2
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• pp.83-88
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• 2020

Silver-Russell syndrome (SRS) is a rare genetic disorder characterized by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, a triangular face, body asymmetry, and feeding difficulties. It is primarily diagnosed according to a clinical scoring system; however, the clinical diagnosis is confirmed with molecular testing, and the disease is stratified into the specific molecular subtypes. SRS is a genetically heterogeneous condition. The major molecular changes are hypomethylation of imprinting control region 1 in 11p15.5 and maternal uniparental disomy of chromosome 7 (UPD(7)mat). Therefore, first-line molecular testing should include methylation-specific approaches for these regions. Here, we report an extremely low birth weight (ELBW) infant with intrauterine growth retardation, postnatal growth retardation, and dysmorphic facial appearance-characteristics consistent with the clinical diagnostic criteria of SRS. Methylation-specific molecular genetic analysis revealed UPD(7)mat, while the loss of heterozygosity was not detected on chromosomal microarray analysis. We present a case of SRS with suspected uniparental heterodisomy of chromosome 7 in an ELBW infant.

• Genomics & Informatics
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• v.19 no.3
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• pp.22.1-22.5
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• 2021

Automatic document classification for highly interrelated classes is a demanding task that becomes more challenging when there is little labeled data for training. Such is the case of the coronavirus disease 2019 (COVID-19) clinical repository-a repository of classified and translated academic articles related to COVID-19 and relevant to the clinical practice-where a 3-way classification scheme is being applied to COVID-19 literature. During the 7th Biomedical Linked Annotation Hackathon (BLAH7) hackathon, we performed experiments to explore the use of named-entity-recognition (NER) to improve the classification. We processed the literature with OntoGene's Biomedical Entity Recogniser (OGER) and used the resulting identified Named Entities (NE) and their links to major biological databases as extra input features for the classifier. We compared the results with a baseline model without the OGER extracted features. In these proof-of-concept experiments, we observed a clear gain on COVID-19 literature classification. In particular, NE's origin was useful to classify document types and NE's type for clinical specialties. Due to the limitations of the small dataset, we can only conclude that our results suggests that NER would benefit this classification task. In order to accurately estimate this benefit, further experiments with a larger dataset would be needed.

• Genomics & Informatics
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• v.21 no.3
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• pp.31.1-31.8
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• 2023

Multiple myeloma (MM) is a hematological malignancy. It is widely believed that genetic factors play a significant role in the development of MM, as investigated in numerous studies. However, the application of genomic information for clinical purposes, including diagnostic and prognostic biomarkers, remains largely confined to research. In this study, we utilized genetic information from the Genomic-Driven Clinical Implementation for Multiple Myeloma database, which is dedicated to clinical trial studies on MM. This genetic information was sourced from the genome-wide association studies catalog database. We prioritized genes with the potential to cause MM based on established annotations, as well as biological risk genes for MM, as potential drug target candidates. The DrugBank database was employed to identify drug candidates targeting these genes. Our research led to the discovery of 14 MM biological risk genes and the identification of 10 drugs that target three of these genes. Notably, only one of these 10 drugs, panobinostat, has been approved for use in MM. The two most promising genes, calcium signal-modulating cyclophilin ligand (CAMLG) and histone deacetylase 2 (HDAC2), were targeted by four drugs (cyclosporine, belinostat, vorinostat, and romidepsin), all of which have clinical evidence supporting their use in the treatment of MM. Interestingly, five of the 10 drugs have been approved for other indications than MM, but they may also be effective in treating MM. Therefore, this study aimed to clarify the genomic variants involved in the pathogenesis of MM and highlight the potential benefits of these genomic variants in drug discovery.

• Genomics & Informatics
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• v.7 no.3
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• pp.163-167
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• 2009

Since its first release in 2007, the National Institute of Food and Drug Safety Evaluation (NIFDS) has provided pharmacogenomic and comparative information specific to Koreans to allow regulatory reviewers and researchers to adapt their working practices to pharmacogenomics. The highlights of this year's additions include "Drug Information", "Gene Information" and "Pharmacogenomic information in the drug labels" sections. These new additions provide information on 737 genes, 719 drugs and pharmacogenomic data of the labels or relabels of 253 approved drugs as of November 2008. The latest version of the Korean Pharmacogenomic Database (KPD, release 2.0) has expanded significantly since its previous release. More SNP and haplotype information has been added to the database with the latest version of the KPD containing approximately four times as many SNPs and haplotypes than the previous version (719 vs. 152, and 30 vs. 7 respectively). Through the "SNP" and "Haplotype" sections, the KPD provides unique Korean SNP and haplotype information as well as comparative information of other populations (Japanese, Chinese, European, African) to offer a range of pharmacogenomic data that can help reviewers and the public understand pharmacogenomic information. The quality and quantity of information in the KPD has also been improved considerably. This data can be found at: http://www.nitr.go.kr/nitr/contents/m134700/view.do/.

• Journal of Genetic Medicine
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• v.12 no.2
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• pp.100-108
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• 2015

Purpose: Conventional methods for the prenatal detection of fetal RhD status involve invasive procedures such as fetal blood sampling and amniocentesis. The identification of cell-free fetal DNA (cffDNA) in maternal plasma creates the possibility of determining fetal RhD status by analyzing maternal plasma DNA. However, some technical problems still exist, especially the lack of a positive control marker for the presence of fetal DNA. Therefore, we assessed the feasibility and accuracy of fetal RHD genotyping incorporating the RASSF1A epigenetic fetal DNA marker from cffDNA in the maternal plasma of RhD-negative pregnant women in Korea. Materials and Methods: We analyzed maternal plasma from 41 pregnant women identified as RhD-negative by serological testing. Multiplex real-time PCR was performed by amplifying RHD exons 5 and 7 and the SRY gene, with RASSF1A being used as a gender-independent fetal epigenetic marker. The results were compared with those obtained by postnatal serological analysis of cord blood and gender identification. Results: Among the 41 fetuses, 37 were RhD-positive and 4 were RhD-negative according to the serological analysis of cord blood. There was 100% concordance between fetal RHD genotyping and serological cord blood results. Detection of the RASSF1A gene verified the presence of cffDNA, and the fetal SRY status was correctly detected in all 41 cases. Conclusion: Noninvasive fetal RHD genotyping with cffDNA incorporating RASSF1A is a feasible, reliable, and accurate method of determining fetal RhD status. It is an alternative to amniocentesis for the management of RhD-negative women and reduces the need for unnecessary RhIG prophylaxis.

• Journal of Genetic Medicine
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• v.12 no.2
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• pp.79-84
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• 2015

Purpose: We developed and validated a fetal trisomy detection method for use as a noninvasive prenatal test (NIPT) including a Clinical Laboratory Improvement Amendments (CLIA)-certified bioinformatics pipeline on a cloud-based computing system using both Illumina and Life Technology sequencing platforms for 221 Korean clinical samples. We determined the necessary proportions of the fetal fraction in the cell-free DNA (cfDNA) sample for NIPT of trisomies 13, 18, and 21 through a limit of quantification (LOQ) test. Materials and Methods: Next-generation sequencing libraries from 221 clinical samples and three positive controls were generated using Illumina and Life Technology chemistries. Sequencing results were uploaded to a cloud and mapped on the human reference genome (GRCh37/hg19) using bioinformatics tools. Based on Z-scores calculated by normalization of the mapped read counts, final aneuploidy reports were automatically generated for fetal aneuploidy determination. Results: We identified in total 29 aneuploid samples, and additional analytical methods performed to confirm the results showed that one of these was a false-positive. The LOQ test showed that the proportion of fetal fraction in the cfDNA sample would affect the interpretation of the aneuploidy results. Conclusion: Noninvasive chromosome examination (NICE), a CLIA-certified NIPT with a cloud-based bioinformatics platform, showed unambiguous success in fetus aneuploidy detection.