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The ARX mutations encompass a nearly continuous spectrum of neurodevelopmental disorders (NDDs), ranging from lissencephaly to Proud syndrome, as well as infantile spasms without brain malformations, and including both syndromic and non-syndromic intellectual disabilities (IDs). We describe worsening neuropsychiatric symptoms in the offspring of a Korean family with ID/developmental delay (DD) caused by a novel ARX p.Lys385Ter variant. Sequential genetic testing was performed to investigate the ID, DD, agenesis of the corpus callosum (ACC), and developmental epileptic encephalopathy (DEE) observed in the proband. A comprehensive trio clinical exome sequencing approach using a Celemics G-Mendeliome Clinical Exome Sequencing Panel was employed. Given the clinical manifestations observed in the proband, gene panel sequencing identified a heterozygous ARX variant, c.1153A>T/p.Lys385Ter (Reference transcript ID: NM_139058.3), as the most likely cause of ID, DD, ACC, and DEE in the proband. Sanger sequencing confirmed the segregation of the ARX variant, c.1153A>T/p.Lys385Ter, with the phenotype and established the maternally inherited dominant status of the heterozygous variant in the patient, as well as in her grandmother, mother, and aunt. Our case report adds to the understanding of the female phenotype in ARX -related disorders caused by loss-of-function variants in the ARX gene. Genetic counseling for ARX families should proceed with caution, as female carriers can exhibit a wide range of phenotypes, from normal cognitive development to ID/DD, ACC, and DEE.

Inhalable airborne microplastics (MPs) presented in indoor and outdoor environments, can deeply penetrate the lungs, potentially triggering inflammation and respiratory illnesses. The present study aims to evaluate human health risks from respirable particulate matter (PM)-bound trace metals and MPs in indoor (SW- subway and IRH- indoor residential houses) and outdoor (OD) environments. This research provides an initial approach to human respiratory tract (HRT) mass depositions of PM10-bound total MPs and nine specific MP types to predict potential human health threats from inhalation exposure. Results indicate that PM-bound trace metals and MPs were around 4 times higher in SW microenvironments compared to OD locations. In IRH, cancer risk (CR) levels were estimated 9 and 4 times higher for PM10 and PM2.5, respectively. Additionally, MP particle depositions per gram of lung cell weight were highest in IRH (23.77), followed by OD and SW. Whereas, lifetime alveoli depositions of MPs were estimated at 13.73 MP/g, which exceeds previously reported respiratory disease fatality cases by 10 to 5 times. Prolonged exposure duration at IRH emerged as a key factor contributing to increased CR and MP lung deposition levels. This research highlights severe lung risks from inhaling PM-bound MPs and metals, offering valuable health insights., Competing Interests: Declaration of Competing Interest This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. We have read and understood your journal’s policies, and we believe that neither the manuscript nor the study violates any of these. There are no conflicts of interest to declare. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Maturity-onset diabetes of the young (MODY; OMIM # 606391) comprises a cluster of inherited disorders within non-autoimmune diabetes mellitus (DM), typically emerging during adolescence or young adulthood. We report a novel in-frame deletion of HNF1B in a family with renal cysts and MODY, furthering our understanding of HNF1B -related phenotypes. We conducted sequential genetic testing to investigate the glucose intolerance, renal cysts, hepatic cysts, and agenesis of the dorsal pancreas observed in the proband. A comprehensive clinical exome sequencing approach using a Celemics G-Mendeliome Clinical Exome Sequencing Panel was employed. Considering the clinical manifestations observed in the proband, gene panel sequencing identified a heterozygous HNF1B variant, c.36_38delCCT/p.(Leu13del) (reference transcript ID: NM_000458.4), as the most likely cause of MODY in the proband. The patient's clinical presentation was consistent with MODY caused by the HNF1B variant, showing signs of glucose intolerance, renal cysts, hepatic cysts, and agenesis of the dorsal pancreas. Sanger sequencing confirmed the same HNF1B variant and established the paternally inherited autosomal dominant status of the heterozygous variant in the patient, as well as in his father and sister. The presence of early-onset diabetes, renal cysts, a family history of the condition, and nephropathy appearing before or after the diagnosis of diabetes mellitus (DM) suggests a diagnosis of HNF1B -MODY5. Early diagnosis is crucial for preventing complications of DM, enabling family screening, providing pre-conceptional genetic counseling, and monitoring kidney function decline.

16p11.2 copy number variations (CNVs) are increasingly recognized as one of the most frequent genomic disorders, and the 16p11.2 microdeletion exhibits broad phenotypic variability and a diverse clinical phenotype. We describe the neurodevelopmental course and discordant clinical phenotypes observed within and between individuals with identical 16p11.2 microdeletions. An analysis with the CytoScan Dx Assay was conducted on a GeneChip System 3000Dx, and the sample signals were then compared to a reference set using the Chromosome Analysis Suite software version 3.1. Ten patients from six separate families were identified with 16p11.2 microdeletions. Nine breakpoints (BPs) 4-5 and one BP2-5 of the 16p11.2 microdeletion were identified. All patients with 16p11.2 microdeletions exhibited developmental delay and/or intellectual disability. Sixty percent of patients presented with neonatal hypotonia, but muscle weakness improved with age. Benign infantile epilepsy manifested between the ages of 7-10 months (a median of 8 months) in six patients (60%). Vertebral dysplasia was observed in two patients (20%), and mild scoliosis was noted in three patients. Sixty percent of patients were overweight. We present six unrelated Korean families, among which identical 16p11.2 microdeletions resulted in diverse developmental trajectories and discordant phenotypes. The clinical variability and incomplete penetrance observed in individuals with 16p11.2 microdeletions remain unclear, posing challenges to accurate clinical interpretation and diagnosis.

Background: Humoral immune responses and infection risk after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) vaccination during the Omicron BA.5 and BN.1 variants predominant period remains unexplored in pediatric population., Methods: We examined anti-spike (anti-S) immunoglobulin G (IgG) responses in a total of 986 children aged 4-18 years who visited outpatient clinics between June 2022 and January 2023, with a history of SARS-CoV-2 infection alone, completed two doses of COVID-19 vaccination alone, vaccine-breakthrough infection (i.e., infection after the single dose of vaccination), and no antigenic exposure. Furthermore, to determine SARS-CoV-2 infection risk, the incidence of newly developed SARS-CoV-2 infection was investigated up to March 2023., Results: The anti-S IgG levels in the 'vaccine-breakthrough infection' group exceeded those in the 'infection alone' and 'vaccination alone' groups (both P < 0.01). Furthermore, the 'vaccination alone' group experienced more rapid anti-S IgG waning than the 'infection alone' and 'vaccine-breakthrough infection' groups (both P < 0.01). We could not identify newly developed SARS-CoV-2 infection in the 'vaccine-breakthrough infection' group., Conclusion: Our findings suggest that hybrid immunity, acquired from SARS-CoV-2 infection and COVID-19 vaccination, was a potentially higher and longer-lasting humoral immune response and protected against SARS-CoV-2 infection in pediatric population during Omicron BA.5 and BN.1 variants predominant., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Choi, Achangwa, Park, Lee, Lee, Jeon, Choi, Do, Nam, Lee, Kim, Ryu and Kee.)

This study aimed to assess the impact of Asian dust (AD) on the human health and the environment. Particulate matter (PM) and PM-bound trace elements and bacteria were examined to determine the chemical and biological hazards associated with AD days and compared with non-AD days in Seoul. On AD days, the mean PM10 concentration was ∼3.5 times higher than that on non-AD days. Elements generated from the Earth's crust (Al, Fe, and Ca) and anthropogenic sources (Pb, Ni, and Cd) were identified as major contributors to coarse and fine particles, respectively. During AD days, the study area was recognized as "severe" for pollution index and pollution load index levels, and "moderately to heavily polluted" for geoaccumulation index levels. The potential cancer risk (CR) and non-CR were estimated for the dust generated during AD events. On AD days, total CR levels were significant (in 1.08 × 10 -5 -2.22 × 10 -5 ), which were associated with PM-bound As, Cd, and Ni. In addition, inhalation CR was found to be similar to the incremental lifetime CR levels estimated using the human respiratory tract mass deposition model. In a short exposure duration (14 days), high PM and bacterial mass deposition, significant non-CR levels, and a high presence of potential respiratory infection-causing pathogens (Rothia mucilaginosa) were observed during AD days. Significant non-CR levels were observed for bacterial exposure, despite insignificant levels of PM10-bound elements. Therefore, the substantial ecological risk, CR, and non-CR levels for inhalation exposure to PM-bound bacteria, and the presence of potential respiratory pathogens, indicate that AD events pose a significant risk to both human lung health and the environment. This study provides the first comprehensive examination of significant non-CR levels for bacteria and carcinogenicity of PM-bound metals during AD events., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Mutations in ITM2B have been reported to be associated with several familial dementias, such as Familial British dementia and familial Danish dementia. These are autosomal dominant disorders characterized by progressive dementia with an onset at around the fifth decade of life. We describe a family with cognitive impairment caused by a novel ITM2B p.*267Serext*11 mutation. The probands presented with cognitive impairment and cerebral infarction. MRI revealed diffuse white matter hyperintensity and microbleeds. Amyloid deposition was not observed on amyloid positron emission tomography. Our case suggests that the BRI2 mutation impacts cognition regardless of amyloid-β accumulation.

Myotonic dystrophy type 1 (DM1) is the most common autosomal-dominant disorder caused by the CTG repeat expansion of the DMPK , and it has been categorized into three phenotypes: mild, classic, and congenital DM1. Here, we reviewed the intergenerational influence of gender and phenotype of the transmitting parent on the occurrence of Korean DM1. A total of 44 parent-child pairs matched for the gender of the transmitting parent and the affected child and 29 parent-child pairs matched for the gender and DM1 phenotype of the transmitting parent were reviewed. The CTG repeat size of the DMPK in the affected child was found to be significantly greater when transmitted by a female parent to a female child (DM1-FF) (median, 1309 repeats; range, 400-2083) than when transmitted by a male parent to a male child (650; 160-1030; p = 0.038 and 0.048 using the Tukey HSD and the Bonferroni test) or by a male parent to a female child (480; 94-1140; p = 0.003). The difference in the CTG repeat size of the DMPK between the transmitting parent and the affected child was also lower when transmitted from a male parent with classic DM1 (-235; -280 to 0) compared to when it was transmitted from a female parent with mild DM1 (866; 612-905; p = 0.015 and 0.019) or from a female parent with classic DM1 (DM1-FC) (605; 10-1393; p = 0.005). This study highlights that gender and the DM1 phenotype of the transmitting parent had an impact on the CTG repeat size of the DMPK in the affected child, with greater increases being inherited from the DM1-FF or DM1-FC situations in Korean DM1.

Secondary hyperparathyroidism (SHPT) is characterized by excessive serum parathyroid hormone levels in response to decreasing kidney function, and tertiary hyperparathyroidism (THPT) is often the result of a long-standing SHPT. To date, several genes have been associated with the pathogenesis of primary hyperparathyroidism (PHPT). However, the molecular genetic mechanisms of uremic hyperparathyroidism (HPT) remain uncharacterized. To elucidate the differences in genetic alterations between PHPT and SHPT/THPT, the targeted next-generation sequencing of genes associated with HPT was performed using DNA extracted from parathyroid tissues. As a result, 26 variants in 19 PHPT or SHPT/THPT appeared as candidate pathogenic mutations, which corresponded to 9 (35%) nonsense, 8 (31%) frameshift, 6 (23%) missense, and 3 (11%) splice site mutations. The MEN1 (23%, 6/26), ASXL3 (15%, 4/26), EZH2 (12%, 3/26), and MTOR (8%, 2/26) genes were frequently mutated. Sixteen of 25 patients with PHPT (64%) had one or more mutations, whereas 3 (21%) of 21 patients with SHPT/THPT had only 1 mutation (p = 0.001). Sixteen of 28 patients (57%) with parathyroid adenoma (PA) had one or more mutations, whereas 3 of 18 patients (17%) with parathyroid hyperplasia (PH) had just one mutation (p = 0.003). Known driver mutations associated with parathyroid tumorigenesis such as CCND1/PRAD1, CDC73/HRPT2, and MEN1 were identified only in PA (44%, 7/16 with mutations). Our results suggest that molecular genetic abnormalities in SHPT/THPT are distinct from those in PHPT. These findings may help in analyzing the molecular pathogenesis underlying uremic HPT development., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this study, the feasibility of the membrane distillation (MD) process as a wastewater reclamation system for portable reuse was investigated. The flux was stably maintained at about 20 L/m 2 h (LMH) at ΔT 30 °C, compared to higher flux at ΔT 50 °C, which showed a rapid decrease in the flux due to severe fouling. MD produced excellent quality of potable water satisfied the drinking water standards of Korea from effluent of sewage treatment plant (ESTP). The fractions of the hydrophobic OC (HOC) and chromatographic DOC (CDOC) from LC-OCD analysis was firstly suggested to understand different organic transport during the MD process. The transport of organic matters across the MD membrane mitigated at low operation temperature and the transported organics in all the tested waters were mostly volatile low molecular weight organics, aromatic amino acids. All of thirteen selected pharmaceuticals were completely removed by MD, regardless of their properties. In order to retard the membrane fouling of the MD process, coagulation and filtration pre-treatments were applied. The pre-treatment process coupled MD process could successfully remove impurities including NH 4 -N without severe membrane fouling. Moreover, coagulation pretreatment reduced transport of ammonia due to decrease in pH., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Respiratory syncytial virus (RSV) is a major pathogen causing respiratory tract infections in infants and young children. The aim of this study was to confirm the genetic evolution of RSV causing respiratory infections in children at Daejeon in Korea, through G gene analysis of RSV-A and RSV-B strains that were prevalent from 2017 to 2019., Methods: Pediatric patients admitted for lower respiratory tract infections at The Catholic University of Korea Daejeon St. Mary's Hospital in the 2017 and 2018/2019 RSV seasonal epidemics, who had RSV detected via multiplex polymerase chain reaction (PCR) were included. The nucleic acid containing RSV-RNA isolated from each of the patients' nasal discharge during standard multiplex PCR testing was stored. The G gene was sequenced and phylogenetic analysis was performed using MEGA X program and the genotype was confirmed., Results: A total of 155 specimens including 49 specimens from 2017 and 106 specimens from 2018-2019 were tested. The genotype was confirmed in 18 specimens (RSV-A:RSV-B = 4:14) from 2017 and 8 specimens (RSV-A:RSV-B = 7:1) from 2018/2019. In the phylogenetic analysis, all RSV-A type showed ON1 genotype and RSV-B showed BA9 genotype., Conclusion: RSV-B belonging to BA9 in 2017, and RSV-A belonging to ON1 genotype in 2018/2019 was the most prevalent circulating genotypes during the two RSV seasons in Daejeon, Korea., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2020 The Korean Academy of Medical Sciences.)

Objectives: Hereditary elliptocytosis (HE) is inherited in an autosomal dominant fashion, and the majority of HE-associated defects occur due to qualitative and quantitative defects in the RBC membrane skeleton proteins α-spectrin, β-spectrin, or protein 4.1R. The complex EPB41 gene encodes a diverse family of protein 4.1R isoforms which are key components of the erythroid membrane skeleton that regulates red cell morphology and mechanical stability. The purpose of this study was to investigate the genome of a Korean patient with HE to discover the causative gene mutation using gene panel sequencing. Methods: An 89-year-old female presented to the Emergency Department and was diagnosed with pancreatitis and gallstones. A peripheral blood smear revealed that approximately 60% of the RBCs were abnormally shaped and appeared oval or elongated, from slightly egg-shaped to rod or pencil forms (elliptocytes). Targeted gene panel sequencing consisting of 33 genes related to inherited RBC disorders and Sanger sequencing were performed. Results: A heterozygous c.2112G > A of the EPB41 gene leading to premature termination codon (NM&#95;001166005.1:c.2112G > A, p.Trp704*) was identified. This variant, which had not been previously reported to be related to HE, was confirmed by Sanger sequencing. Thus, the patient's diagnosis of HE-1 was genetically confirmed. Conclusion: The present study confirmed a novel mutation of the EPB41 gene that plays an important role in expanding the mutational distribution in HE-1. It could also be helpful for understanding the correlation between the genotype and phenotype in HE.

Antibiotic resistance genes (ARGs) are emerging contaminants that pose a potential threat to human health worldwide. Urban wastewater treatment plants (WWTPs) are a main source of both antibiotic-resistant bacteria and ARGs released into the environment. Nevertheless, the propagation of ARGs and their underlying mechanisms and the dynamics of mobile genetic elements (MGEs) in WWTPs have rarely been investigated in South Korea. In this study, shotgun metagenomic analysis was used to identify comprehensive ARGs and their mechanisms, bacterial communities, and MGEs from 4 configurations with 2 activated sludge (AS) and 2 anaerobic digestion sludge (ADS) samples. A total of 181 ARG subtypes belonging to 22 ARG types were broadly detected, and the ARG abundances in the AS samples were 1.3-2.0 orders of magnitude higher than in the ADS samples. Multidrug and bacitracin resistance genes were the predominant ARG types in AS samples, followed by ARGs against sulfonamide, tetracycline, and β-lactam. However, the composition of ARG types in ADS samples was significantly changed. The abundance of multidrug and β-lactam resistance genes was drastically reduced in the ADS samples. The resistance genes of MLS were the predominant, followed by ARGs against sulfonamide and tetracycline in the ADS samples. In addition, plasmids were the dominant MGEs in the AS samples, while integrons (intI1) were the dominant MGEs in the ADS samples. These results provide valuable information regarding the prevalence of ARG types and MGEs and the difference patterns between the AS and ADS systems.

Bacterial communities in wastewater treatment plants (WWTPs) affect plant functionality through their role in the removal of pollutants from wastewater. Bacterial communities vary extensively based on plant operating conditions and influent characteristics. The capacity of WWTPs can also affect the bacterial community via variations in the organic or nutrient composition of the influent. Despite the importance considering capacity, the characteristics that control bacterial community assembly are largely unknown. In this study, we discovered that bacterial communities in WWTPs in Korea and Vietnam, which differ remarkably in capacity, exhibit unique structures and interactions that are governed mainly by the capacity of WWTPs. Bacterial communities were analysed using 16S rRNA gene sequencing and exhibited clear differences between the two regions, with these differences being most pronounced in activated sludge. We found that capacity contributed the most to bacterial interactions and community structure, whereas other factors had less impact. Co-occurrence network analysis showed that microorganisms from high-capacity WWTPs are more interrelated than those from low-capacity WWTPs, which corresponds to the tighter clustering of bacterial communities in Korea. These results will contribute to the understanding of bacterial community assembly in activated sludge processing.

Background: Variable disease phenotypes can be influenced by several factors such as allelic variation, environmental factors, genetic modifiers, and genotype-environment interaction. Herein to the best of our knowledge, this is the first report of the coexistence of DMD and RNF213 gene mutations in a Korean family with differing disease phenotypes of Duchenne muscular dystrophy (DMD) and Moyamoya disease (MMD) in each female sibling., Methods: Deletion or duplication of the exon in DMD was screened using multiplex ligation-dependent probe amplification (MLPA). Subsequently, single exon deletion or duplication identified by MLPA was confirmed by Sanger sequencing. On the other hand, a common missense mutation [NM&#95;001256071.2:c.14429G>A (p.Arg4810Lys)] related to MMD in exon 60 of RNF213 was also identified by Sanger sequencing., Results: Three female family members carried the same disease-causing mutations, c.9953&#95;9954delAG of DMD and c.14429G>A of RNF213. Two (II-2 and II-3) of these siblings suffer from the disease but exhibited different DMD or MMD symptoms, while the mother (I-2) seemed almost unaffected., Conclusion: This report illustrates the difficulty that might be encountered in the interpretation of complex clinical manifestations when different genetic defects affecting neuromuscular and vascular diseases coexist., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Background: To validate the clinical application of chromosomal microarray analysis (CMA) as a first-tier clinical diagnostic test and to determine the impact of CMA results on patient clinical management, we conducted a multicenter prospective study in Korean patients diagnosed as having developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA)., Methods: We performed both CMA and G-banding cytogenetics as the first-tier tests in 617 patients. To determine whether the CMA results directly influenced treatment recommendations, the referring clinicians were asked to complete a 39-item questionnaire for each patient separately after receiving the CMA results., Results: A total of 122 patients (19.8%) had abnormal CMA results, with either pathogenic variants (N=65) or variants of possible significance (VPS, N=57). Thirty-five well-known diseases were detected: 16p11.2 microdeletion syndrome was the most common, followed by Prader-Willi syndrome, 15q11-q13 duplication, Down syndrome, and Duchenne muscular dystrophy. Variants of unknown significance (VUS) were discovered in 51 patients (8.3%). VUS of genes putatively associated with developmental disorders were found in five patients: IMMP2L deletion, PTCH1 duplication, and ATRNL1 deletion. CMA results influenced clinical management, such as imaging studies, specialist referral, and laboratory testing in 71.4% of patients overall, and in 86.0%, 83.3%, 75.0%, and 67.3% of patients with VPS, pathogenic variants, VUS, and benign variants, respectively., Conclusions: Clinical application of CMA as a first-tier test improves diagnostic yields and the quality of clinical management in patients with DD/ID, ASD, and MCA., Competing Interests: The authors declare that they have no competing interests., (© The Korean Society for Laboratory Medicine.)

In studies of the molecular basis of gastric cancer (GC), microsatellite instability (MSI) is one of the key factors. Somatic mutations found in GC are expected to contribute to MSI-high (H) tumorigenesis. We estimated somatic mutation distribution according to MSI status in 52 matched pair GC samples using the Ion Torrent Ion S5 XL with the AmpliSeq Cancer Hotspot panel.Seventy-five (9.8%) somatic variants consisting of 34 hotspot mutations and 41 other likely pathogenic variants were identified in 34 GC samples. The TP53 mutations was most common (35%, 26/75), followed by EGFR (8%, 6/75), HNF1A (8%, 6/75), PIK3CA (8%, 6/75), and ERBB2 (5%, 4/75). To determine MSI status, 52 matched pair samples were estimated using 15 MSI markers. Thirty-nine MS stable (S), 5 MSI-low (L), and 8 MSI-H were classified. GCs with MSI-H tended to have more variants significantly compared with GCs with MS stable (MSS) and MSI-L (standardized J-T statistic  =  3.161 for number of variants; P  =  .002). The mean number of all variants and hotspot mutations per tumor samples only in GCs with MSI-H were 3.9 (range, 1-6) and 1.1 (range, 0-3), respectively. Whereas, the mean number of all variants and hotspot mutations per tumor samples only in GCs with MSS/MSI-L were 1 (0-5)/0.8 (0-1) and 0.5 (0-3)/0.8 (0-1), respectively.In conclusion, GC with MSI-H harbored more mutations in genes that act as a tumor suppressor or oncogene compared to GC with MSS/MSI-L. This finding suggests that the accumulation of MSIs contributes to the genetic diversity and complexities of GC. In addition, targeted NGS approach allows for detection of common and also rare clinically actionable mutations and profiles of comutations in multiple patients simultaneously. Because GC shows distinctive patterns related to ethnics, further studies pertaining to different racial/ethnic groups or cancer types may reinforce our investigations.

Background: While the majority of germline inactivating mutations in BRCA1/2 are small-scale mutations, large genomic rearrangements (LGRs) are also detected in a variable proportion of patients. However, routine genetic methods are incapable of detecting LGRs, and comprehensive genetic testing algorithm is necessary., Methods: We performed multiplex ligation-dependent probe amplification assay for small-scale mutation negative patients at high-risk for LGR, based on previously published LGR risk criteria. The inclusion criteria for the high-risk subgroup were personal history of 1) early-onset breast cancer (diagnosed at ≤36 years); 2) two breast primaries; 3) breast cancer diagnosed at any age, with ≥1 close blood relatives (includes first-, second-, or third-degree) with breast and/or epithelial ovarian cancer; 4) both breast and epithelial ovarian cancer diagnosed at any age; and 5) epithelial ovarian cancer with ≥1 close blood relatives with breast and/or epithelial ovarian cancer., Results: Two LGRs were identified. One was a heterozygous deletion of exon 19 and the other was a heterozygous duplication of exon 4-6. The prevalence of LGRs was 7% among Sanger-negative, high-risk patients, and accounted for 13% of all BRCA1 mutations and 2% of all patients. Moreover, LGRs reported in Korean patients, including our 2 newly identified cases, were found exclusively in families with at least one high-risk feature., Conclusions: Our result suggests that selective LGR screening for Sanger-negative, high-risk patients is necessary for Korean patients.

Background: We describe the genetic profiles of Korean patients with glucose-6-phosphate dehydrogenase (G6PD) deficiencies and the effects of G6PD mutations on protein stability and enzyme activity on the basis of in silico analysis., Methods: In parallel with a genetic analysis, the pathogenicity of G6PD mutations detected in Korean patients was predicted in silico. The simulated effects of G6PD mutations were compared to the WHO classes based on G6PD enzyme activity. Four previously reported mutations and three newly diagnosed patients with missense mutations were estimated., Results: One novel mutation (p.Cys385Gly, labeled G6PD Kangnam) and two known mutations [p.Ile220Met (G6PD São Paulo) and p.Glu416Lys (G6PD Tokyo)] were identified in this study. G6PD mutations identified in Koreans were also found in Brazil (G6PD São Paulo), Poland (G6PD Seoul), United States of America (G6PD Riley), Mexico (G6PD Guadalajara), and Japan (G6PD Tokyo). Several mutations occurred at the same nucleotide, but resulted in different amino acid residue changes in different ethnic populations (p.Ile380 variant, G6PD Calvo Mackenna; p.Cys385 variants, Tomah, Madrid, Lynwood; p.Arg387 variant, Beverly Hills; p.Pro396 variant, Bari; and p.Pro396Ala in India). On the basis of the in silico analysis, Class I or II mutations were predicted to be highly deleterious, and the effects of one Class IV mutation were equivocal., Conclusions: The genetic profiles of Korean individuals with G6PD mutations indicated that the same mutations may have arisen by independent mutational events, and were not derived from shared ancestral mutations. The in silico analysis provided insight into the role of G6PD mutations in enzyme function and stability., Competing Interests: Authors' Disclosures of Potential Conflicts of Interest: No potential conflicts of interest relevant to this article were reported.

To investigate the underlying genetic influences of primary glaucoma in Korea, molecular analysis was performed in 112 sporadic cases, and results compared with healthy controls. The myocilin (MYOC) and optineurin (OPTN) genes were directly sequenced in 112 unrelated patients, including 17 with primary open‑angle glaucoma, 19 with juvenile open‑angle glaucoma, and 76 with normal tension glaucoma. Healthy unrelated Korean individuals (n=100) were used as the non‑selected population control. A total of three MYOC and four OPTN variants potentially associated with primary glaucoma were identified in 4 and 18 patients, respectively. A novel variant of MYOC, p.Leu255Pro, was predicted to be potentially pathogenic by in silico analysis. Another, p.Thr353Ile, has been previously reported. These two missense variants were detected in patients with a family history of glaucoma. Combined heterozygous variants p.[Thr123=;Ile288=] were identified in 2 of 112 (2%) patients but not in healthy controls. Among OPTN variants, a novel variant p.Arg271Cys was identified. Homozygous p.[Thr34=;Thr34=] (4/112, 4%), homozygous p.[Met98Lys;Met98Lys] (4/112, 4%), or combined heterozygous p.[Thr34=;Arg545Gln] (9/112, 8%) was significantly associated with the development of primary glaucoma [odds ratio (OR)=8.768, 95% confidence interval (CI)=1.972‑38.988; relative risk=1.818, 95% CI=1.473‑2.244; P=0.001]. The present study provides insight into the genetic or haplotype variants of MYOC and OPTN genes contributing to primary glaucoma. Haplotype variants identified in the present study may be regarded as potential contributing factors of primary glaucoma in Korea. Further studies, including those on additional genes, are required to elucidate the underlying pathogenic mechanism using a larger cohort to provide additional statistical power.

Background: In this study, we evaluated the analytic performance of two POCT devices and compared the results with a central laboratory method., Methods: A total of 100 patients were enrolled in this study. LipidPro (Infopia, USA) and LandMark (Infopia, Korea), were used for measuring total cholesterol (TC), triglyceride (TG), and high density lipoprotein cholesterol (HDL-C). Imprecision and linearity were assessed and the results of two POCT analyzers were compared with a central laboratory method., Results: Imprecision of LipidPro met the National Cholesterol Education Program (NCEP) criteria (mean % CV: TC 2.8%, TG 3.9%, and HDL-C 4.0%). LandMark met the National Cholesterol Education Program (NCEP) imprecision criteria for TC and TG, but not HDL-C (mean % CV: 2.7%, 3.5%, and 4.7%, respectively). Both analyzers showed excellent linearity for TC, TG, and HDL-C in test ranges. Total errors of TC, TG, and HDL-C measured by LipidPro were 6.1%, 8.7%, and 8.1%, respectively, and met the NCEP goals. The total errors of TG and HDL-C measured by LandMark met the NCEP goals; however, the total error of TC analysis did not meet the NCEP goals (total error; TC 11.1%, TG 11.2%, and HDL-C 9.6%)., Conclusions: LipidPro and LandMark are simple and rapid tests that provide a reliable alternative to conventional laboratory methods. The LipidPro device showed a slightly better analytical performance than LandMark based on the NCEP goals.

We report the first Far Eastern case of a Korean child with familial hemophagocytic lymphohistiocytosis (HLH) caused by a novel syntaxin 11 (STX11) mutation. A 33-month-old boy born to non-consanguineous Korean parents was admitted for intermittent fever lasting one week, pancytopenia, hepatosplenomegaly, and HLH in the bone marrow. Under the impression of HLH, genetic study revealed a novel homozygous missense mutation of STX11: c.650T>C, p.Leu217Pro. Although no large deletion or allele drop was identified, genotype analysis demonstrated that the homozygous c.650T>C may have resulted from the duplication of a maternal (unimaternal) chromosomal region and concurrent loss of the other paternal allele, likely caused by meiotic errors such as two crossover events. A cumulative study of such novel mutations and their effects on specific protein interactions may deepen the understanding of how abnormal STX1 expression results in deficient cytotoxic function.

A common ancestral haplotype is strongly suggested in the Korean and Japanese patients with Fanconi anemia (FA), because common mutations have been frequently found: c.2546delC and c.3720&#95;3724delAAACA of FANCA; c.307+1G>C, c.1066C>T, and c.1589&#95;1591delATA of FANCG. Our aim in this study was to investigate the origin of these common mutations of FANCA and FANCG. We genotyped 13 FA patients consisting of five FA-A patients and eight FA-G patients from the Korean FA population. Microsatellite markers used for haplotype analysis included four CA repeat markers which are closely linked with FANCA and eight CA repeat markers which are contiguous with FANCG. As a result, Korean FA-A patients carrying c.2546delC or c.3720&#95;3724delAAACA did not share the same haplotypes. However, three unique haplotypes carrying c.307+1G>C, c.1066C > T, or c.1589&#95;1591delATA, that consisted of eight polymorphic loci covering a flanking region were strongly associated with Korean FA-G, consistent with founder haplotypes reported previously in the Japanese FA-G population. Our finding confirmed the common ancestral haplotypes on the origins of the East Asian FA-G patients, which will improve our understanding of the molecular population genetics of FA-G. To the best of our knowledge, this is the first report on the association between disease-linked mutations and common ancestral haplotypes in the Korean FA population., (© 2015 John Wiley & Sons Ltd/University College London.)

Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by hypoproliferative anemia, associated physical malformations and a predisposition to cancer. DBA has been associated with mutations and deletions in the large and small ribosomal protein genes, and genetic aberrations have been detected in ∼50-60% of patients. In this study, nine Korean DBA patients were screened for mutations in eight known DBA genes (RPS19, RPS24, RPS17, RPS10, RPS26, RPL35A, RPL5 and RPL11) using the direct sequencing method. Mutations in RPS19, RPS26 and RPS17 were detected in four, two and one patient, respectively. Among the mutations detected in RPS19, two mutations were novel (c.26T>A, c.357-2A>G). For the mutation-negative cases, array-CGH analysis was performed to identify copy-number variations, and no deletions involving the known DBA gene regions were identified. The relative mRNA expression of RPS19 estimated using real-time quantitative PCR analysis revealed two- to fourfold reductions in RPS19 mRNA expression in three patients with RPS19 mutations, and p53 protein expression analysis by immunohistochemistry showed variable but significant nuclear staining in the DBA patients. In conclusion, heterozygous mutations in the known DBA genes RPS19, RPS26 and RPS17 were detected in seven out of nine Korean DBA patients. Among these patients, RPS19 was the most frequently mutated gene. In addition, decreased RPS19 mRNA expression and p53 overexpression were observed in the Korean DBA patients, which supports the hypothesis that haploinsufficiency and p53 hyperactivation represent a central pathway underlying the pathogenesis of DBA.

The aim of the present study was to analyze chromosome abnormalities in Korean patients with T-cell acute lymphoblastic leukemia (T-ALL). A total of 65 patients with newly diagnosed T-ALL were enrolled in the study from December 2004 to December 2011. Chromosome analysis was performed at diagnosis on short-term cultures of bone marrow specimens. Of these 65 patients, abnormal karyotypes were found in 50 (77 %). Numerical and structural chromosome abnormalities were identified in 16 (25 %) and 47 (72 %) patients, respectively. Deletion was the most common structural abnormality (48 %), followed by translocation (29 %). Overall survival (OS) and relapse-free survival (RFS) outcome were unaffected by the number and/or type of chromosome abnormalities in both childhood and adult T-ALL; however, the OS interval was longer for childhood patients than for adult patients in the entire cohort (P = 0.0003). Similarly, patients with first complete remission (CR) showed a better OS than those who failed to achieve first CR (P < 0.0001). There was a negative clinical impact in adult patients and patients without first CR according to multivariate analysis. This study helps to fill the gap regarding chromosome findings in T-ALL and may lead to identification of the molecular background behind phenotypic differences.

A Gram-reaction-positive, non-spore-forming, aerobic actinobacterial strain (2C6-41(T)) was isolated from the activated sludge from an industrial wastewater treatment plant in Daegu, South Korea. Its taxonomic position was investigated by using a polyphasic approach. On the basis of 16S rRNA gene sequence similarity, closest phylogenetic relatives to strain 2C6-41(T) were Brevibacterium pityocampae DSM 21720(T) (97.2 %), Brevibacterium salitolerans KCTC 19616(T) (96.7 %), Brevibacterium album KCTC 19173(T) (96.2 %) and Brevibacterium samyangense KCCM 42316(T) (96.2 %). The DNA G+C content of strain 2C6-41(T) was 66.4 mol%. Chemotaxonomic data, which included MK-8(H(2)) as the major menaquinone; meso-diaminopimelic acid, glutamic acid and alanine as cell-wall amino acids; ribose, mannose and glucose as major cell-wall sugars; and anteiso-C(15 : 0), anteiso-C(17 : 0), C(16 : 0) and iso-C(15 : 0) as major fatty acids, supported the affiliation of strain 2C6-41(T) to the genus Brevibacterium. The aromatic ring cleavage enzyme catechol 1,2-dioxygenase was not detected in strain 2C6-41(T), but catechol 2,3-dioxygenase was detected. The results of physiological and biochemical tests, and the low level of DNA-DNA relatedness to the closest phylogenetic relative enabled strain 2C6-41(T) to be differentiated genotypically and phenotypically from recognized species of the genus Brevibacterium. The isolate is therefore considered to represent a novel species in the genus Brevibacterium, for which the name Brevibacterium daeguense sp. nov. is proposed. The type strain is 2C6-41(T) (=KCTC 19800(T) = JCM 17458(T)).

For groundwater conservation and management, it is important to accurately assess groundwater pollution vulnerability. This study proposed an integrated model using ridge regression and a genetic algorithm (GA) to effectively select the major hydro-geological parameters influencing groundwater pollution vulnerability in an aquifer. The GA-Ridge regression method determined that depth to water, net recharge, topography, and the impact of vadose zone media were the hydro-geological parameters that influenced trichloroethene pollution vulnerability in a Korean aquifer. When using these selected hydro-geological parameters, the accuracy was improved for various statistical nonlinear and artificial intelligence (AI) techniques, such as multinomial logistic regression, decision trees, artificial neural networks, and case-based reasoning. These results provide a proof of concept that the GA-Ridge regression is effective at determining influential hydro-geological parameters for the pollution vulnerability of an aquifer, and in turn, improves the AI performance in assessing groundwater pollution vulnerability.

Spondyloepiphyseal dysplasia (SED) comprises a heterogeneous group of skeletal dysplasias that primarily affect the epiphyses and vertebral bodies. Patients affected by SED usually exhibit short stature and experience early development of degenerative osteoarthritis. SED is subdivided into congenita and tarda forms according to the age at onset and clinical severity, and further subdivided into genetically different forms according to the mode of inheritance and the gene involved. We report a 14-yr-old Korean male who presented with a disproportionately short stature and a short trunk. A pedigree analysis of 3 generations with 6 affected persons revealed an X-linked recessive mode of inheritance. Mutation analysis of the TRAPPC2 (previously called SEDL) gene, the only gene associated with X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT; MIM 313400), was performed, and a splice-donor site mutation in intron 3 of the TRAPPC2 gene (c.93+5G>A) was identified in the proband and in his unaffected mother (a heterozygote). This mutation is one of the 2 most frequent mutations reported in the medical literature, and is known to result in exon 3 skipping. This is the first report of a genetically confirmed X-linked SEDT case in Korea and highlights the importance of recognizing the mode of inheritance in the diagnosis of X-linked SEDT.

A Gram-reaction-negative, non-spore-forming, rod-shaped, aerobic bacterial strain, designated MJ11(T), was isolated from sludge of a leachate treatment plant in Daejeon, South Korea, and was characterized taxonomically by using a polyphasic approach. Comparative 16S rRNA gene sequence analysis showed that strain MJ11(T) belonged to the family Brucellaceae, class Alphaproteobacteria, and was most closely related to Ochrobactrum ciceri Ca-34(T) (97.9 % sequence similarity) and Ochrobactrum pituitosum CCUG 50899(T) (96.4 %). Comparative sequence analyses of the additional phylogenetic marker genes dnaK, groEL and gyrB confirmed the affiliation of strain MJ11(T) to the genus Ochrobactrum. The G+C content of the genomic DNA of strain MJ11(T) was 59.3 mol%. The detection of a quinone system with ubiquinone Q-10 as the predominant respiratory lipoquinone, a fatty acid profile with C(18 : 1)ω7c (62.6 %) and C(19 : 0) cyclo ω8c (14.2 %) as the major components, a polar lipid profile with phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phosphatidylmonomethylethanolamine, diphosphatidylglycerol and unknown aminolipids AL1 and AL2 as major polar lipids and spermidine and putrescine as the predominant polyamines also supported the affiliation of strain MJ11(T) to the genus Ochrobactrum. The DNA-DNA relatedness between strain MJ11(T) and Ochrobactrum ciceri DSM 22292(T) was 29 ± 7 %, clearly showing that the isolate constitutes a new genospecies. Strain MJ11(T) could be clearly differentiated from its closest neighbours on the basis of its phenotypic, genotypic and chemotaxonomic features. Therefore, strain MJ11(T) represents a novel species of the genus Ochrobactrum, for which the name Ochrobactrum daejeonense sp. nov. is proposed. The type strain is MJ11(T) ( = KCTC 22458(T) = JCM 16234(T)).

Gene-targeted FLX titanium pyrosequencing integrated with stable isotope probing (SIP) using [(13)C]biphenyl substrate revealed that tidal mudflat sediments harbor novel aromatic ring hydroxylating dioxygenases (ARHD). More than 80% of the detected ARHD genes comprise four clades (0.5 distance) with 49 to 70% amino acid identity to sequences in public databases. The 16S rRNA sequences enriched in the (13)C fraction were from the Betaproteobacteria, bacilli (primarily Paenibacillus-like), and unclassified phyla.

Diamond-Blackfan anemia (DBA) is a rare congenital erythroid hypoplastic anemia that usually presents early in infancy and is inherited in up to 45% of cases. It is characterized by red cell aplasia, congenital anomalies, and a predisposition to cancer. Corticosteroids and red blood cell transfusions are the mainstays of therapy. We describe a case of 3-month-old infant who presented with severe anemia, elevated levels of HbF and adenosine deaminase and bilateral hydronephrosis, who was later confirmed as DBA by mutation analysis using the direct sequencing method. Direct sequencing analysis of RPS19 gene was performed with both cDNA and genomic DNA extracted from peripheral blood and a c.3G>A point mutation of exon 2 resulting in p.Met1Ile was identified in this patient. The patient showed an inadequate response to steroid therapy and a partial response to RBC transfusion with a follow-up Hb level of 8.3 g/dL on her last visit to the outpatient clinic. DBA is a genetically and phenotypically heterogeneous disease, and we have reviewed the clinical characteristics of 25 Korean patients thus far reported in the literature. To our knowledge, this is the first case of DBA confirmed by mutation analysis in Korea, and mutation identification using molecular method is recommended for confirmation of this genetically and phenotypically heterogeneous disease.