Publications by authors named "Sung Sup Park"

257 Publications

Epidemiologic Trends of Thalassemia, 2006-2018: A Nationwide Population-Based Study.

J Clin Med 2022 Apr 20;11(9). Epub 2022 Apr 20.

Department of Laboratory Medicine, Hallym University Sacred Heart Hospital, Anyang 14068, Korea.

Thalassemia is the most common form of hereditary anemia. Here, we aimed to investigate the 13-year trend of the epidemiologic profiles and risk of comorbidities in thalassemia using a nationwide population-based registry in Korea. Diagnosis of thalassemia, the comorbidities and transfusion events in patients with thalassemia were identified in the Korean National Health Insurance database, which includes the entire population. The prevalence of thalassemia increased from 0.74/100,000 in 2006 to 2.76/100,000 in 2018. Notably, the incidence rate has nearly doubled in the last 2 years from 0.22/100,000 in 2016 to 0.41/100,000 in 2018. The annual transfusion rate gradually decreased from 34.7% in 2006 to 20.6% in 2018. Transfusion events in patients with thalassemia were significantly associated with the risk of comorbidities (diabetes: odds ratio [OR] = 3.68, 95% confidence interval [CI] = 2.59-5.22; hypertension: OR = 3.06, 95% CI = 2.35-4.00; dyslipidemia: OR = 1.72, 95% CI = 1.22-2.43; atrial fibrillation: OR = 3.52, 95% CI = 1.69-7.32; myocardial infarction: OR = 3.02, 95% CI = 1.09-8.38; stroke: OR = 3.32, 95% CI = 2.05-5.36; congestive heart failure: OR = 2.83, 95% CI = 1.62-4.97; end-stage renal disease: OR = 3.25, 95% CI = 1.96-5.37). Early detection of comorbidities and timely intervention are required for the management of thalassemia.
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http://dx.doi.org/10.3390/jcm11092289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9104717PMC
April 2022

Genetic mutation spectrum of pantothenate kinase-associated neurodegeneration expanded by breakpoint sequencing in pantothenate kinase 2 gene.

Orphanet J Rare Dis 2022 03 4;17(1):111. Epub 2022 Mar 4.

Department of Laboratory Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.

Background: Neurodegeneration with brain iron accumulation describes a group of rare heterogeneous progressive neurodegenerative disorders characterized by excessive iron accumulation in the basal ganglia region. Pantothenate kinase-associated neurodegeneration (PKAN) is a major form of this disease.

Results: A total of 7 unrelated patients were diagnosed with PKAN in a single tertiary center from August 2009 to February 2018. Ten variants in PANK2 including three novel sequence variants and one large exonic deletion were detected. Sequencing of the breakpoint was performed to predict the mechanism of large deletion and AluSx3 and AluSz6 were found with approximately 97.3% sequence homology.

Conclusion: The findings support the disease-causing role of PANK2 and indicate the possibility that exonic deletion of PANK2 found in PKAN is mediated through Alu-mediated homologous recombination.
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http://dx.doi.org/10.1186/s13023-022-02251-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8896100PMC
March 2022

Night-time gastric acid suppression by tegoprazan compared to vonoprazan or esomeprazole.

Br J Clin Pharmacol 2022 Jul 23;88(7):3288-3296. Epub 2022 Feb 23.

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.

Aims: Nocturnal acid breakthrough has been considered an unmet need of proton-pump inhibitors. Tegoprazan, a novel potassium-competitive acid blocker, is expected to show improved properties for this unmet need. This study was aimed to compare night-time acid suppression by tegoprazan with that by vonoprazan or esomeprazole, and to explore the effect of CYP2C19 phenotypes on acid-suppressive effects.

Methods: A randomized, open-label, 3-period, 6-sequence crossover study was conducted. A single oral dose of tegoprazan 50 mg, vonoprazan 20 mg or esomeprazole 40 mg was administered at night in each period. Continuous intragastric pH was monitored at baseline and after each dosing.

Results: Sixteen healthy subjects (6 CYP2C19 extensive metabolizers, 5 intermediate metabolizers, 5 poor metabolizers) completed the study. After a single dose of tegoprazan, intragastric pH increased more rapidly to over 4 at approximately 1 hour compared to the other treatments, and elevated intragastric pH was maintained stably at night. Tegoprazan exhibited night-time acid suppression for slightly but not significantly longer than vonoprazan, and greater than esomeprazole; % time at pH ≥ 4 at night was 66.0%, 60.5% and 36.1% for tegoprazan, vonoprazan and esomeprazole, respectively. Night-time acid suppression by tegoprazan and vonoprazan was not dependent on CYP2C19 phenotypes, while that by esomeprazole tended to be influenced by CYP2C19 phenotypes.

Conclusion: Tegoprazan produced more rapid, potent and well sustained night-time acid suppression vs. vonoprazan or esomeprazole when administered at night. Furthermore, tegoprazan showed no CYP2C19 phenotype dependency in acid suppression. It suggests the potential of tegoprazan, especially in preventing nocturnal acid breakthrough.
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http://dx.doi.org/10.1111/bcp.15268DOI Listing
July 2022

Variants in Pediatric Chronic Intestinal Pseudo-obstruction With Megacystis.

J Neurogastroenterol Motil 2022 Jan;28(1):104-110

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.

Background/aims: Chronic intestinal pseudo-obstruction (CIPO) is a clinically heterogeneous syndrome characterized by compromised peristalsis and intestinal obstruction. Variants of actin gamma 2 (), a protein crucial for correct enteric muscle contraction, have been found in CIPO patients. The aim of this study is to examine the clinical features and variants in Korean patients with CIPO.

Methods: From January 1995 to August 2020, 12 patients diagnosed with CIPO were included and genetic analysis testing of was performed.

Results: Heterozygous missense variants were found in 6 patients (50.0%). The p.Arg257Cys variant was found in 3 patients, and p.Arg63Gln and p.Arg178His variants were found in 1 patient each. A novel variant, p.Ile193Phe, was found in 1 patient. Three patients were diagnosed at birth, 2 at the age of 1 year, and 1 at 3 years of age. Abnormal prenatal genitourinary ultrasonographic findings were found in all 6 patients; microcolon was found in 4 patients (66.7%), and megacystis in all 6 patients. The pathology showed abnormal ganglion cells as well as myopathic findings. All patients are dependent on total parenteral nutrition and are to date alive.

Conclusions: variants are commonly found in Korean patients with CIPO. In CIPO patients with megacystis and abnormal prenatal ultrasonography, genetic testing of should be considered. Molecular diagnosis of CIPO is more important than pathologic diagnosis.
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http://dx.doi.org/10.5056/jnm20243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748860PMC
January 2022

Consistent count region-copy number variation (CCR-CNV): an expandable and robust tool for clinical diagnosis of copy number variation at the exon level using next-generation sequencing data.

Genet Med 2022 03 1;24(3):663-672. Epub 2021 Dec 1.

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea. Electronic address:

Purpose: Despite the importance of exonic copy number variations (CNVs) in human genetic diseases, reliable next-generation sequencing-based methods for detecting them are unavailable. We developed an expandable and robust exonic CNV detection tool called consistent count region (CCR)-CNV.

Methods: In total, about 1000 samples of the truth set were used for validating CCR-CNV. We compared CCR-CNV performance with 2 well-known CNV tools. Finally, to overcome the limitations of CCR-CNV, we devised a combined approach.

Results: The mean sensitivity and specificity of CCR-CNV alone were above 95%, which was superior to that of other CNV tools, such as DECoN and Atlas-CNV. However, low covered region and positive predictive value and high false discovery rate act as obstacles to its use in clinical settings. The combined approach showed much improved performance than CCR-CNV alone.

Conclusion: In this study, we present a novel diagnostic tool that allows the identification of exonic CNVs with high confidence using various reagents and clinical next-generation sequencing platforms. We validated this method using the largest multiple ligation-dependent probe amplification-confirmed data set, including sufficient copy normal control data. The approach, combined with existing CNV tools, allows the implementation of CCR-CNV in clinical settings.
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http://dx.doi.org/10.1016/j.gim.2021.10.025DOI Listing
March 2022

SnackNTM: An Open-Source Software for Sanger Sequencing-based Identification of Nontuberculous Mycobacterial Species.

Ann Lab Med 2022 Mar;42(2):213-248

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Background: Sequence-based identification is one of the most effective methods for species-level identification of nontuberculous mycobacteria (NTM). However, it is time-consuming because of the bioinformatics processes involved, including sequence trimming, consensus sequence generation, and public database searches. We developed a simple and fully automated software that enabled species-level identification of NTM from trace files, SnackNTM (https://github.com/Young-gonKim/SnackNTM).

Methods: JAVA programing language was used for software development. The SnackNTM diagnostic algorithm utilized 16S rRNA gene sequences, according to the Clinical & Laboratory Standards Institute guidelines, and an gene region was adjunctively utilized to narrow down the species. The software performance was validated using trace files of 234 clinical cases, comprising 217 consecutive cases and 17 additionally selected cases of unique species.

Results: SnackNTM could analyze multiple cases at once, and all the bioinformatics processes required for sequence-based NTM identification were automatically performed with a single mouse click. SnackNTM successfully identified 95.9% (208/217) of consecutive clinical cases, and the results showed 99.0% (206/208) agreement with manual classification results. SnackNTM successfully identified all 17 cases of unique species. In a processing time comparison test, the analysis and reporting of 30 cases, which took 150 minutes manually, took only 40 minutes with SnackNTM.

Conclusions: SnackNTM is expected to reduce the workload for NTM identification, especially in clinical laboratories that process large numbers of cases.
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http://dx.doi.org/10.3343/alm.2022.42.2.213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548243PMC
March 2022

Clinical Utility of Methylation-Specific Multiplex Ligation-Dependent Probe Amplification for the Diagnosis of Prader-Willi Syndrome and Angelman Syndrome.

Ann Lab Med 2022 Jan;42(1):79-88

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Background: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genomic imprinting disorders that are mainly caused by a deletion on 15q11-q13, the uniparental disomy of chromosome 15, or an imprinting defect. We evaluated the utility of methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a diagnostic tool and for demonstrating the relationship between molecular mechanisms and clinical presentation.

Methods: We performed MS-MLPA using DNA samples from 93 subjects (45 PWS, 24 AS, and 24 non-PWS/AS controls) who had previously undergone MS-PCR for the diagnosis of PWS/AS. We compared the results of both assays, and patients' clinical phenotypes were reviewed retrospectively.

Results: MS-MLPA showed a 100% concordance rate with MS-PCR. Among the 45 PWS patients, 26 (57.8%) had a deletion of 15q11-q13, and the others (42.2%) had uniparental disomy 15 or an imprinting defect. Among the 24 AS patients, 16 (66.7%) had a deletion of 15q11-q13, 7 AS patients (29.2%) had uniparental disomy 15 or an imprinting defect, and one AS patient (4.2%) showed an imprinting center deletion.

Conclusions: MS-MLPA has clinical utility for the diagnosis of PWS/AS, and it is superior to MS-PCR in that it can identify the molecular mechanism underlying the disease.
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http://dx.doi.org/10.3343/alm.2022.42.1.79DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368237PMC
January 2022

Intronic LINE-1 insertion in SLCO1B3 as a highly prevalent cause of rotor syndrome in East Asian population.

J Hum Genet 2022 Feb 5;67(2):71-77. Epub 2021 Aug 5.

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

Rotor syndrome is caused by digenic loss-of-function variants in SLCO1B1 and SLCO1B3 but only a few studies have reported co-occurring inactivating variants from both genes. A rotor syndrome-causing long interspersed element-1 (LINE-1) insertion in SLCO1B3 had been reported to be highly prevalent in the Japanese population but there has been no additional report. In spite of its known association with various human diseases, LINE-1 is hard to detect with current sequencing technologies. In this study, we aimed to devise a method to screen the LINE-1 insertion variant and investigate the frequency of this variant in various populations. A chimeric sequence, that was generated by concatenating the reference sequence at the junction and a part of inserted LINE-1 sequence, was searched from 725 raw sequencing data files. In cases containing the chimeric sequence, confirmatory long-range PCR and gap-PCR were performed. In total, 95 (13.1%) of 725 patients were positive for the chimeric sequence, and all were confirmed to have the SLCO1B3 LINE-1 insertion by PCR-based tests. The same chimeric sequence was searched from the 1000 Genomes Project data repository and the carrier frequency was remarkably high in the East Asian populations (10.1%), especially in Southern Han Chinese (18.5%), but almost absent in other populations. This SLCO1B3 LINE-1 insertion should be screened in a population-specific manner under suspicion of Rotor syndrome and the methods proposed in this study would enable this in a simple way.
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http://dx.doi.org/10.1038/s10038-021-00967-1DOI Listing
February 2022

Longitudinal proteomic profiling provides insights into host response and proteome dynamics in COVID-19 progression.

Proteomics 2021 06 14;21(11-12):e2000278. Epub 2021 May 14.

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.

In managing patients with coronavirus disease 2019 (COVID-19), early identification of those at high risk and real-time monitoring of disease progression to severe COVID-19 is a major challenge. We aimed to identify potential early prognostic protein markers and to expand understanding of proteome dynamics during clinical progression of the disease. We performed in-depth proteome profiling on 137 sera, longitudinally collected from 25 patients with COVID-19 (non-severe patients, n = 13; patients who progressed to severe COVID-19, n = 12). We identified 11 potential biomarkers, including the novel markers IGLV3-19 and BNC2, as early potential prognostic indicators of severe COVID-19. These potential biomarkers are mainly involved in biological processes associated with humoral immune response, interferon signalling, acute phase response, lipid metabolism, and platelet degranulation. We further revealed that the longitudinal changes of 40 proteins persistently increased or decreased as the disease progressed to severe COVID-19. These 40 potential biomarkers could effectively reflect the clinical progression of the disease. Our findings provide some new insights into host response to SARS-CoV-2 infection, which are valuable for understanding of COVID-19 disease progression. This study also identified potential biomarkers that could be further validated, which may support better predicting and monitoring progression to severe COVID-19.
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http://dx.doi.org/10.1002/pmic.202000278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206655PMC
June 2021

Molecular basis and diagnosis of thalassemia.

Blood Res 2021 Apr;56(S1):S39-S43

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Thalassemia is characterized by the impaired synthesis of globin chains due to disease-causing variants in α- or β-globin genes. In this review, we provide an overview of the molecular basis underlying α- and β-thalassemia, and of the current technologies used to characterize these disease-causing variants for the diagnosis of thalassemia. Understanding these molecular basis and technologies will prove to be beneficial for the accurate diagnosis of thalassemia.
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http://dx.doi.org/10.5045/br.2021.2020332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093999PMC
April 2021

Determination of Clinical Characteristics of -Derived Species by Reanalysis of Isolates Formerly Reported as .

Ann Lab Med 2021 Sep;41(5):463-468

Department of Laboratory Medicine, Seoul National University Hospital, Seoul, Korea.

Background: Seven genotypic subtypes of were recently demonstrated to represent distinct species based on phylogenomic analysis. sensu stricto (formerly known as subtype 1) is most frequently associated with human diseases; only a few studies have compared the diverse clinical characteristics of subtypes, including their drug susceptibilities. We determined the actual incidence of infections caused by each subtype of and identified their clinical characteristics.

Methods: We subtyped isolates identified as over the last 10 years at a tertiary care hospital. Percent identity score of stored sequencing data was calculated using curated reference sequences of all subtypes. Clinical characteristics were compared between those classified as subtype 1 and other subtypes. Student's -test, Wilcoxon rank-sum test, and Fisher's exact test were used for comparisons.

Results: Overall, 21.7% of the isolates were identified as species distinct from . The proportion of patients with subtype 1 infection who received treatment was significantly higher than that of patients with other subtype infections (55.3% vs. 7.7%, =0.003). Only patients with subtype 1 infection received surgical treatment. Non-subtype 1 isolates showed a higher frequency of resistance to ciprofloxacin and trimethoprim/sulfamethoxazole.

Conclusions: Non-subtype 1 isolates should be separately identified in routine clinical laboratory tests for appropriate treatment selection.
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http://dx.doi.org/10.3343/alm.2021.41.5.463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041593PMC
September 2021

FMS-like Tyrosine Kinase 3-Internal Tandem Duplication Allele Concentrations Should Be Determined in a Mutation-Type-Specific Manner.

Clin Chem 2021 03;67(4):691-693

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.1093/clinchem/hvab019DOI Listing
March 2021

Comparison of Respiratory Specimens for the Detection of SARS-CoV-2.

Ann Clin Lab Sci 2021 Jan;51(1):140-144

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

We compared SARS-CoV-2 detection rate of different respiratory specimens (nasopharyngeal swab [NPS], n=92; oropharyngeal swab [OPS], n=18; sputum, n=11). We also compared cycle threshold (Ct) values of paired specimen types obtained from the same patient on the same day. Then we characterized viral load kinetics of NPS (n=142), OPS (n=126), and sputum (n=75), during disease course. Sputum samples showed higher detection rate than NPS, and OPS exhibited the lowest detection rate. The median Ct values in NPS were significantly lower than in paired OPS, and higher than in paired sputum, respectively (<0.05). During the disease course, viral load was the lowest in OPS and the highest in sputum samples.
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January 2021

Accuracy and Performance Evaluation of Triplet Repeat Primed PCR as an Alternative to Conventional Diagnostic Methods for Fragile X Syndrome.

Ann Lab Med 2021 Jul;41(4):394-400

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Background: Conventional diagnosis of fragile X syndrome (FXS) is based on a combination of fragment analysis (FA) and Southern blotting (SB); however, this diagnostic approach is time- and labor-intensive and has pitfalls such as the possibility of missing large number alleles. Triplet repeat primed PCR (TP-PCR) is a current alternative used to overcome these limitations. We evaluated the diagnostic usefulness of TP-PCR compared with the conventional diagnostic protocol consisting of FA and/or SB in terms of allele categorization, repeat number correlation, and zygosity concordance in female genetic carriers.

Methods: From November 2013 to March 2018, 458 patients (326 males, 132 females) were simultaneously examined using FA and/or SB and TP-PCR by detecting CGG repeat numbers in gene and diagnosed as per American College of Medical Genetics guidelines.

Results: The TP-PCR results showed high concordance with the FA and/or SB results for all three aspects (allele categorization, repeat number correlation, and zygosity concordance in female genetic carriers). TP-PCR detected CGG expansions ≥200 in all full mutation (FM) allele cases in male patients, as well as both the normal allele (NL) and FM allele in female carriers. In premutation (PM) allele carriers, the TP-PCR results were consistent with the FA and/or SB results. In terms of zygosity concordance in female genetic carriers, 12 NL cases detected by TP-PCR showed a merged peak consisting of two close heterozygous peaks; however, this issue was resolved using a 10-fold dilution.

Conclusions: TP-PCR may serve as a reliable alternative method for FXS diagnosis.
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http://dx.doi.org/10.3343/alm.2021.41.4.394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884195PMC
July 2021

SLC20A2 mutation manifesting as very late-onset orofacial dyskinesia.

Neurol Sci 2021 06 16;42(6):2561-2564. Epub 2021 Jan 16.

Department of Neurology, Seoul National University Hospital, Seoul, South Korea.

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http://dx.doi.org/10.1007/s10072-020-04976-4DOI Listing
June 2021

Clinical and genetic profiling of nevoid basal cell carcinoma syndrome in Korean patients by whole-exome sequencing.

Sci Rep 2021 01 13;11(1):1163. Epub 2021 Jan 13.

Department of Dermatology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.

Nevoid basal cell carcinoma syndrome (NBCCS) is mainly characterised by multiple basal cell carcinomas (BCCs) caused by PTCH1, PTCH2, and SUFU. However, clinical and genetic data on Asian NBCCS patients are limited. We aimed to analyse the clinical phenotypes and genetic spectrum of Korean patients with NBCCS. Fifteen patients with NBCCS at Seoul National University Hospital were included, and their clinical data were analysed. Whole-exome sequencing and/or multiplex ligation-dependent probe amplification using peripheral blood were performed to identify genetic causes. Genetic analysis revealed that 73.3% (11/15) of the patients carried 9 pathogenic variants, only in the PTCH1 gene. Variants of uncertain significance (VUS) and likely benign were also detected in 2 (13.3%) and 2 (13.3%) patients, respectively. BCCs were found in the majority of the cases (93.3%) and the number of BCCs increased with age (ρ = 0.595, P = 0.019). This study revealed that PTCH1 pathogenic variants were the main cause of NBCCS in Korean patients. As BCCs are commonly detected, a periodic dermatologic examination is recommended. Finally, our results support the addition of genetic screening to the existing criteria for NBCCS diagnosis.
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http://dx.doi.org/10.1038/s41598-020-80867-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806620PMC
January 2021

Whole Exome Sequencing Identifies Novel Genetic Alterations in Patients with Pheochromocytoma/Paraganglioma.

Endocrinol Metab (Seoul) 2020 12 23;35(4):909-917. Epub 2020 Dec 23.

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Background: Pheochromocytoma and paragangliomas (PPGL) are known as tumors with the highest level of heritability, approximately 30% of all cases. Clinical practice guidelines of PPGL recommend genetic testing for germline variants in all patients. In this study, we used whole exome sequencing to identify novel causative variants associated with PPGL to improve the detection of rare genetic variants in our cohort.

Methods: Thirty-six tested negative for pathogenic variants in previous Sanger sequencing or targeted gene panel testing for PPGL underwent whole exome sequencing. Whole exome sequencing was performed using DNA samples enriched using TruSeq Custom Enrichment Kit and sequenced with MiSeq (Illumina Inc.). Sequencing alignment and variant calling were performed using SAMtools.

Results: Among previously mutation undetected 36 patients, two likely pathogenic variants and 13 variants of uncertain significance (VUS) were detected in 32 pheochromocytoma-related genes. SDHA c.778G>A (p.Gly260Arg) was detected in a patient with head and neck paraganglioma, and KIF1B c.2787-2A>C in a patient with a bladder paraganglioma. Additionally, a likely pathogenic variant in BRCA2, VUS in TP53, and VUS in NFU1 were detected.

Conclusion: Exome sequencing further identified genetic alterations by 5.6% in previously mutation undetected patients in PPGL. Implementation of targeted gene sequencing consisted of extended genes of PPGL in routine clinical screening can support the level of comprehensive patient assessment.
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http://dx.doi.org/10.3803/EnM.2020.756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803589PMC
December 2020

Two Cases of Facioscapulohumeral Muscular Dystrophy 2 in Korea.

Yonsei Med J 2021 Jan;62(1):95-98

Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disorder characterized by weakness of facial, shoulder, abdominal, hip girdle, humeral, and anterior distal leg muscles, with descending progression from the face to the legs in an asymmetric pattern. In about 5% of patients with FSHD, no D4Z4 repeat contraction on chromosome 4q35 is observed; this disease entity is called FSHD2. FSHD2 is characterized by DNA hypomethylation on the 4q-subtelomeric macrosatellite repeat array D4Z4. In Korea, there have been no previous reports of FSHD2. We report the first two cases of FSHD2 in Korea, carrying c.3801delG and c.1580C>T mutations in the gene, respectively. For rapid and accurate diagnosis of FSHD2, genetic analysis of the D4Z4 haplotype and methylation with next-generation sequencing are required.
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http://dx.doi.org/10.3349/ymj.2021.62.1.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820446PMC
January 2021

SnackVar: An Open-Source Software for Sanger Sequencing Analysis Optimized for Clinical Use.

J Mol Diagn 2021 02 24;23(2):140-148. Epub 2020 Nov 24.

Department of Laboratory Medicine, Seoul National University Hospital, Seoul, Republic of Korea. Electronic address:

Despite the wide application of next-generation sequencing, Sanger sequencing still plays a necessary role in clinical laboratories. However, recent developments in the field of bioinformatics have focused mostly on next-generation sequencing, while tools for Sanger sequencing have shown little progress. In this study, SnackVar (https://github.com/Young-gonKim/SnackVar, last accessed June 22, 2020), a novel graphical user interface-based software for Sanger sequencing, was developed. All types of variants, including heterozygous insertion/deletion variants, can be identified by SnackVar with minimal user effort. The featured reference sequences of all of the genes are prestored in SnackVar, allowing for detected variants to be precisely described based on coding DNA references according to the nomenclature of the Human Genome Variation Society. Among 88 previously reported variants from four insertion/deletion-rich genes (BRCA1, APC, CALR, and CEBPA), the result of SnackVar agreed with reported results in 87 variants [98.9% (93.0%; 99.9%)]. The cause of one incorrect variant calling was proven to be erroneous base callings from poor-quality trace files. Compared with commercial software, SnackVar required less than one-half of the time taken for the analysis of a selected set of test cases. We expect SnackVar to be a cost-effective option for clinical laboratories performing Sanger sequencing.
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http://dx.doi.org/10.1016/j.jmoldx.2020.11.001DOI Listing
February 2021

Noninvasive prenatal test of single-gene disorders by linked-read direct haplotyping: application in various diseases.

Eur J Hum Genet 2021 03 24;29(3):463-470. Epub 2020 Nov 24.

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

Direct haplotyping enables noninvasive prenatal testing (NIPT) without analyzing proband, which is a promising strategy for pregnancies at risk of an inherited single-gene disorder. Here, we aimed to expand the scope of single-gene disorders that NIPT using linked-read direct haplotyping would be applicable to. Three families at risk of myotonic dystrophy type 1, lipoid congenital adrenal hyperplasia, and Fukuyama congenital muscular dystrophy were recruited. All cases exhibited distinct characteristics that are often encountered as hurdles (i.e., repeat expansion, identical variants in both parents, and novel variants with retrotransposon insertion) in the universal clinical application of NIPT. Direct haplotyping of parental genomes was performed by linked-read sequencing, combined with allele-specific PCR, if necessary. Target DMPK, STAR, and FKTN genes in the maternal plasma DNA were sequenced. Posterior risk calculations and an Anderson-Darling test were performed to deduce the maternal and paternal inheritance, respectively. In all cases, we could predict the inheritance of maternal mutant allele with > 99.9% confidence, while paternal mutant alleles were not predicted to be inherited. Our study indicates that direct haplotyping and posterior risk calculation can be applied with subtle modifications to NIPT for the detection of an expanded range of diseases.
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http://dx.doi.org/10.1038/s41431-020-00759-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940412PMC
March 2021

Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection After Recovery from Mild Coronavirus Disease 2019.

Clin Infect Dis 2021 11;73(9):e3002-e3008

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.

Background: Positive results from real-time reverse-transcription polymerase chain reaction (rRT-PCR) in recovered patients raise concern that patients who recover from coronavirus disease 2019 (COVID-19) may be at risk of reinfection. Currently, however, evidence that supports reinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been reported.

Methods: We conducted whole-genome sequencing of the viral RNA from clinical specimens at the initial infection and at the positive retest from 6 patients who recovered from COVID-19 and retested positive for SARS-CoV-2 via rRT-PCR after recovery. A total of 13 viral RNAs from the patients' respiratory specimens were consecutively obtained, which enabled us to characterize the difference in viral genomes between initial infection and positive retest.

Results: At the time of the positive retest, we were able to acquire a complete genome sequence from patient 1, a 21-year-old previously healthy woman. In this patient, through the phylogenetic analysis, we confirmed that the viral RNA of positive retest was clustered into a subgroup distinct from that of the initial infection, suggesting that there was a reinfection of SARS-CoV-2 with a subtype that was different from that of the primary strain. The spike protein D614G substitution that defines the clade "G" emerged in reinfection, while mutations that characterize the clade "V" (ie, nsp6 L37F and ORF3a G251V) were present at initial infection.

Conclusions: Reinfection with a genetically distinct SARS-CoV-2 strain may occur in an immunocompetent patient shortly after recovery from mild COVID-19. SARS-CoV-2 infection may not confer immunity against a different SARS-CoV-2 strain.
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http://dx.doi.org/10.1093/cid/ciaa1421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890673PMC
November 2021

Characteristics of germline mutations in Korean patients with pheochromocytoma/paraganglioma.

J Med Genet 2022 01 20;59(1):56-64. Epub 2020 Nov 20.

Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea (the Republic of)

Background: Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing neuroendocrine tumours. PPGLs are a rare but important cause of secondary hypertension owing to their high morbidity and mortality. Patients with PPGL exhibit an increased prevalence of mutations in one of the PPGL susceptibility genes according to previous studies. We aimed to investigate the characteristics of germline mutations in the largest number of Korean patients with PPGL.

Methods: In this study, 161 patients with PPGL were evaluated. Phenotype data, including biochemical, pathological and anatomical imaging results, were collected. Germline mutations in 10 PPGL-related genes were tested by targeted next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification.

Results: Approximately 21% of apparently sporadic PPGLs harboured germline mutations of the PPGL-related genes. The mutation carriers were younger at the first diagnosis and had more bilateral (28.6% vs 4.0%, p<0.001) and multifocal (11.4% vs 1.6%, p=0.027) PPGLs, but showed no metastatic risk (17.1% vs 11.1%, p=0.504), than non-mutation carriers. Missense mutation of p.V111I was found in this cohort of Asian patients, which was associated with unilateral pheochromocytoma with dominantly epinephrine production.

Conclusion: This study covered the largest number of Korean patients with PPGL. To our knowledge, it is the first to compare results of targeted NGS panel with those of conventional sequencing methods in Asia. We demonstrated that the variant type, as well as the mutated gene, may determine the phenotype and prognosis of PPGLs.
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http://dx.doi.org/10.1136/jmedgenet-2020-107102DOI Listing
January 2022

Strabismus in chronic progressive external ophthalmoplegia.

Acta Ophthalmol 2021 Mar 15;99(2):e274-e280. Epub 2020 Nov 15.

Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.

Purpose: To elucidate the patterns of strabismus and ophthalmoplegia associated with chronic progressive external ophthalmoplegia (CPEO) confirmed by mitochondrial DNA (mtDNA) deletions in Asians.

Methods: A total of 10 patients confirmed to have mtDNA deletion associated with CPEO were included. Long-range PCR encompassing the entire mtDNA was carried out. In the cases with mtDNA deletion, the exact deletion ranges of mtDNA were identified by sequencing. A full ophthalmologic examination including prism and alternate cover test in the primary position, evaluation of ductions and versions, and binocularity was performed in 10 patients with confirmed mtDNA deletions associated with CPEO.

Results: All of the patients showed ophthalmoplegia as well as ptosis, even after eyelid surgeries. Ophthalmoplegia was symmetric between both eyes in nine patients (90%) while one patient (10%) showed asymmetric ophthalmoplegia with esotropia and left hypotropia. Among the nine patients with symmetric involvement, four patients (44%) showed exotropia, three (33%) had exotropia with vertical deviation, and the remaining two patients (22%) showed orthotropia. Five out of 10 patients (50%) complained of diplopia associated with strabismus, four of whom (80%) had vertical deviation. Three out of five patients (60%) without diplopia showed exotropia of 20 prism diopters (PD) to 50 PD.

Conclusions: Exotropia with/without vertical deviation is the most common form of strabismus in Asian patients with CPEO and only one of them showed a small angle of esotropia. Ophthalmoplegia could be asymmetric in 10% of CPEO patients.
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http://dx.doi.org/10.1111/aos.14558DOI Listing
March 2021

FABP3-mediated membrane lipid saturation alters fluidity and induces ER stress in skeletal muscle with aging.

Nat Commun 2020 11 9;11(1):5661. Epub 2020 Nov 9.

Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.

Sarcopenia is characterized by decreased skeletal muscle mass and function with age. Aged muscles have altered lipid compositions; however, the role and regulation of lipids are unknown. Here we report that FABP3 is upregulated in aged skeletal muscles, disrupting homeostasis via lipid remodeling. Lipidomic analyses reveal that FABP3 overexpression in young muscles alters the membrane lipid composition to that of aged muscle by decreasing polyunsaturated phospholipid acyl chains, while increasing sphingomyelin and lysophosphatidylcholine. FABP3-dependent membrane lipid remodeling causes ER stress via the PERK-eIF2α pathway and inhibits protein synthesis, limiting muscle recovery after immobilization. FABP3 knockdown induces a young-like lipid composition in aged muscles, reduces ER stress, and improves protein synthesis and muscle recovery. Further, FABP3 reduces membrane fluidity and knockdown increases fluidity in vitro, potentially causing ER stress. Therefore, FABP3 drives membrane lipid composition-mediated ER stress to regulate muscle homeostasis during aging and is a valuable target for sarcopenia.
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http://dx.doi.org/10.1038/s41467-020-19501-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653047PMC
November 2020

Establishment of Pediatric Reference Intervals for Routine Laboratory Tests in Korean Population: A Retrospective Multicenter Analysis.

Ann Lab Med 2021 Mar;41(2):155-170

Department of Laboratory Medicine, Seoul National University Hospital and College of Medicine, Seoul, Korea.

Background: Reference intervals defined for adults or children of other ethnicities cannot be applied in the evaluation of Korean pediatric patients. Pediatric reference intervals are difficult to establish because children are in their growing stage and their physiology changes continuously. We aimed to establish reference intervals for routine laboratory tests for Korean pediatric patients through retrospective multicenter data analysis.

Methods: Preoperative laboratory test results from 1,031 pediatric patients aged 0 month-18 years who underwent minor surgeries in four university hospitals were collected. Age- and sex-specific reference intervals for routine laboratory tests were defined based on the Clinical and Laboratory Standards Institute (CLSI) EP28-A3c guidelines.

Results: The pediatric reference intervals determined in this study were different from existing adult reference intervals and pediatric reference intervals for other ethnicities. Most tests required age-specific partitioning, and some of those required sex-specific partitioning for at least one age-partitioned subgroup. Erythrocyte sedimentation rate, monocyte percentage, basophil percentage, activated partial thromboplastin time, glucose, cholesterol, albumin, bilirubin, chloride, and C-reactive protein did not show any difference between age- or sex-partitioned subgroups.

Conclusions: We determined Korean pediatric reference intervals for hematology, coagulation, and chemistry tests by indirect sampling based on medical record data from multiple institutions. These reference intervals would be valuable for clinical evaluations in the Korean pediatric population.
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http://dx.doi.org/10.3343/alm.2021.41.2.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591287PMC
March 2021

Hereditary Fructose Intolerance Diagnosed in Adulthood.

Gut Liver 2021 01;15(1):142-145

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.

Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by a mutation in the aldolase B gene. HFI patients exhibit nausea, vomiting, abdominal pain, hypoglycemia, and elevated liver enzymes after dietary fructose exposure. Chronic exposure might lead to failure to thrive, liver failure, renal failure, and, eventually, death. HFI usually manifests in infants when they are being weaned off of breastmilk. Because HFI has an excellent prognosis when patients maintain a strict restrictive diet, some patients remain undiagnosed due to the voluntary avoidance of sweet foods. In the past, HFI was diagnosed using a fructose tolerance test, liver enzyme assays or intestinal biopsy specimens. Currently, HFI is diagnosed through the analysis of aldolase B mutations. Here, HFI was diagnosed in a 41-year-old woman who complained of sweating, nausea, and vomiting after consuming sweets. She had a compound heterozygous mutation in the aldolase B gene; gene analysis revealed pathogenic nonsense (c.178C>T, p.Arg60Ter) and frameshift (c.360_363delCAAA, p.Asn120LysfsTer32) variants. This is the first report of a Korean HFI patient diagnosed in adulthood.
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http://dx.doi.org/10.5009/gnl20189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817925PMC
January 2021

Optimization and validation of a fluorogenic dipeptidyl peptidase 4 enzymatic assay in human plasma.

Anal Biochem 2021 01 12;612:113952. Epub 2020 Sep 12.

Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea. Electronic address:

During the development of a specific dipeptidyl peptidase 4 (DPP4) inhibitor to treat type 2 diabetes, a fluorogenic kinetic analysis for DPP4 enzymatic activity using Gly-Pro-Aminomethylcoumarin (AMC) as a substrate was optimized and validated for recombinant DPP4 and human plasma samples. The sensitivity, calibration curve, detection range, accuracy, precision, recovery efficiency, Km constant, short/long-term stability, and stability after freezing-thawing cycles were analyzed. DPP4 enzymatic activity (mU/min) was measured as the initial velocity (Vo) of the enzymatic reaction over time. The sensitivity of the Vo value was 14,488 mU/min for recombinant DPP4 and 17,995 mU/min for human plasma samples. The dynamic ranges of the calibration curve were linear and reliable between 1.11 × 10-1.86 × 10 mU/min of the mean Vo value and in the DPP4 concentration range of 23.4-3,000 ng/mL. The assay's accuracy and precision met acceptance criteria for all samples. Plasma DPP4 was stable under various storage temperatures, even after three freeze-thaw cycles. Our optimized, validated bioanalytic method for measuring DPP4 activity in plasma samples was successfully employed to evaluate the effect of evogliptin (DA-1229) tartrate, which irreversibly and dose-dependently inhibits DPP4 enzymatic activity, without the dilution effect of human plasma samples and irrespective of the co-treated metformin.
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http://dx.doi.org/10.1016/j.ab.2020.113952DOI Listing
January 2021

Young-Onset Parkinson's Disease with Impulse Control Disorder Due to Novel Variants of F-Box Only Protein 7.

J Mov Disord 2020 Sep 9;13(3):225-228. Epub 2020 Sep 9.

Department of Neurology and Movement Disorder Center, Parkinson Study Group, Neuroscience Research Institute, College of Medicine, Seoul National University Hospital, Seoul, Korea.

F-box only protein 7 (FBXO7) is a rare monogenic cause of hereditary Parkinson's disease (PD) with an autosomal recessive mode of inheritance and a broad spectrum of clinical manifestations. Here, we report a de novo PD patient with onset at the age of 28 with novel compound heterozygous variants in the FBXO7 gene (c.1162C>T, p.Gln388X; c.80G>A, p.Arg27His). The clinical features of the patient were problematic impulse control disorder behaviors and pyromania, and pyramidal signs were negative. We describe the novel pathogenic variants of the FBXO7 gene with detailed clinical pictures to report the expanding genotypes and phenotypes of FBXO7-associated parkinsonism.
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http://dx.doi.org/10.14802/jmd.20026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502300PMC
September 2020
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