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BACKGROUND: Ectodermal dysplasia (ED) is a rare genetic disorder that affects structures derived from the ectodermal germ layer. RESULTS: In this study, we analyzed the genetic profiles of 27 Korean patients with ED. Whole exome sequencing (WES) was performed on 23 patients, and targeted panel sequencing was conducted on the remaining 4 patients. Among the patients in the cohort, 74.1% (20/27) tested positive for ED. Of these positive cases, EDA and EDAR mutations were found in 80% (16/20). Notably, 23.1% (3/13) of EDA-positive cases exhibited copy number variations. Among the 23 patients who underwent WES, we conducted a virtual panel analysis of eight well-known genes, resulting in diagnoses for 56.5% (13/23) of the cases. Additionally, further analysis of approximately 5,000 OMIM genes identified four more cases, increasing the overall positivity rate by approximately 17%. These findings underscore the potential of WES for improving the diagnostic yield of ED. Remarkably, 94.1% of the patients manifesting the complete triad of ED symptoms (hair/skin/dental) displayed detectable EDA/EDAR mutations. In contrast, none of the 7 patients without these three symptoms exhibited EDA/EDAR mutations. CONCLUSIONS: When conducting molecular diagnostics for ED, opting for targeted sequencing of EDA/EDAR mutations is advisable for cases with classical symptoms, while WES is deemed an effective strategy for cases in which these symptoms are absent.

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This study assessed the relationship between daily life changes and mental health in Korean adolescents during the COVID-19 pandemic. Data from middle and high school students who responded to the relevant survey items the 2021 Korea Youth Risk Behavior Survey were analyzed (n = 53,868). The survey assessed changes in economic status, physical activity, skipping breakfast, drinking, smoking, and mental health, including stress, depression, generalized anxiety disorder, and suicidal ideation, due to the COVID-19 pandemic. The overall prevalence of perceived stress, depression, generalized anxiety disorder, and suicidal ideation was 38.6%, 26.4%, 12.2%, and 12.4%. Adolescents whose economic status worsened due to COVID-19 had a higher risk of perceived stress, depression, generalized anxiety disorder, and suicidal ideation. Changes in physical activity and breakfast consumption due to the COVID-19 pandemic were significantly associated with increases in perceived stress, depression, generalized anxiety disorder, and suicidal ideation. Adolescents who increased their alcohol consumption had the highest risk of perceived stress, depression, generalized anxiety disorder, and suicidal ideation. Changes in economic status and health behaviors caused by the COVID-19 pandemic had a negative effect on the mental health of Korean adolescents. These results can be used to identify adolescents at high risk of developing mental health problems.

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Purpose: Considering the high disease burden and unique features of Asian patients with breast cancer (BC), it is essential to have a comprehensive view of genetic characteristics in this population. An institutional targeted sequencing platform was developed through the Korea Research-Driven Hospitals project and was incorporated into clinical practice. This study explores the use of targeted next-generation sequencing (NGS) and its outcomes in patients with advanced/metastatic BC in the real world. Materials and Methods: We reviewed the results of NGS tests administered to BC patients using a customized sequencing platform - FiRST Cancer Panel (FCP) - over seven years. We systematically described clinical translation of FCP for precise diagnostics, personalized therapeutic strategies, and unraveling disease pathogenesis. Results: NGS tests were conducted on 548 samples from 522 patients with BC. 97.6% of tested samples harbored at least one pathogenic alteration. The common alterations included mutations in TP53(56.2%), PIK3CA(31.2%), GATA3(13.8%), BRCA2(10.2%), and amplifications of CCND1(10.8%), FGF19(10.0%), and ERBB2(9.5%). NGS analysis of ERBB2 amplification correlated well with HER2 immunohistochemistry and in situ hybridization. RNA panel analyses found potentially actionable and prognostic fusion genes. FCP effectively screened for potentially germline pathogenic/likely pathogenic mutation. 10.3% of BC patients received matched therapy guided by NGS, resulting in a significant overall survival advantage (p=0.022), especially for metastatic BCs. . Conclusion: Clinical NGS provided multifaceted benefits, deepening our understanding of the disease, improving diagnostic precision, and paving the way for targeted therapies. The concrete advantages of FCP highlight the importance of multi-gene testing for BC, especially for metastatic conditions.

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Chimerism monitoring following allogeneic hematopoietic cell transplantation (HCT) plays a pivotal role in evaluating engraftment status and identifying early indicators of relapse. Recent advancements in next-generation sequencing (NGS) technology have introduced AlloSeq HCT as a more sensitive alternative to short tandem repeat (STR) analysis. This study aimed to compare AlloSeq HCT with STR, focusing on the prediction of early relapse post-allogeneic HCT. Chimerism levels in 29 HCT recipients were assessed using both STR and NGS, employing a total of 125 whole blood or bone marrow aspirate samples (68 post-HCT and 57 pre-HCT samples from recipients or donors). AlloSeq HCT exhibited high concordance with STR and demonstrated the potential for early detection of chimeric changes, particularly at extremely low levels. The combined advantages of high sensitivity and automated data analysis offered by AlloSeq HCT substantiate its clinical adoption for effective chimerism monitoring.

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Measurable residual disease (MRD) testing, a standard procedure in B-lymphoblastic leukemia (B-ALL) diagnostics, is assessed using multiparametric flow cytometry (MFC) and next-generation sequencing (NGS) analysis of immunoglobulin gene rearrangements. We evaluated the concordance between eight-color, two-tube MFC-MRD the LymphoTrack NGS-MRD assays using 139 follow-up samples from 54 pediatric patients with B-ALL. We also assessed the effect of hemodilution in MFC-MRD assays. The MRD-concordance rate was 79.9% (N=111), with 25 (18.0%) and 3 (2.2%) samples testing positive only by NGS-MRD (MFC-NGS+MRD) and MFC-MRD (MFC+NGS-MRD), respectively. We found a significant correlation in MRD values from total nucleated cells between the two methods (r=0.736 [0.647-0.806], P<0.001). The median MRD value of MFC-NGS+MRD samples was estimated to be 0.0012% (0.0001%-0.0263%) using the NGS-MRD assays. Notably, 14.3% of MFC-NGS+MRD samples showed NGS-MRD values below the limit of detection in the MFC-MRD assays. The percentages of hematogones detected in MFC-MRD assays significantly differed between the discordant and concordant cases (P<0.001). MFC and NGS-MRD assays showed relatively high concordance and correlation in MRD assessment, whereas the NGS-MRD assay detected MRD more frequently than the MFC-MRD assay in pediatric B-ALL. Evaluating the hematogone percentages can aid in assessing the impact of sample hemodilution.

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Circulating tumor DNA (ctDNA) has emerged as a promising tool for various clinical applications, including early diagnosis, therapeutic target identification, treatment response monitoring, prognosis evaluation, and minimal residual disease detection. Consequently, ctDNA assays have been incorporated into clinical practice. In this review, we offer an in-depth exploration of the clinical implementation of ctDNA assays. Notably, we examined existing evidence related to pre-analytical procedures, analytical components in current technologies, and result interpretation and reporting processes. The primary objective of this guidelines is to provide recommendations for the clinical utilization of ctDNA assays.

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BACKGROUND: Although the epidemiology of Huntington's disease (HD) in Korea differs notably from that in Western countries, the genetic disparities between these regions remain unclear. OBJECTIVE: To investigate the characteristics and clinical significance of cytosine-adenine-guanine (CAG) repeat size associated with HD in the Korean population. METHODS: We analyzed the CAG repeat lengths of the HTT gene in 941 healthy individuals (1,882 alleles) and 954 patients with chorea (1,908 alleles) from two referral hospitals in Korea. We presented normative CAG repeat length data for the Korean population and computed the reduced penetrance (36-39 CAG) and intermediate allele (27-35 CAG) frequencies in the two groups. Furthermore, we investigated the relationship between intermediate alleles and chorea development using logistic regression models in individuals aged ≥55 years. RESULTS: The mean (±standard deviation) CAG repeat length in healthy individuals was 17.5 ± 2.0, with a reduced penetrance allele frequency of 0.05 % (1/1882) and intermediate allele frequency of 0.69 % (13/1882). We identified 213 patients with genetically confirmed HD whose CAG repeat length ranged from 39 to 140, with a mean of 45.2 ± 7.9 in the longer allele. Compared with normal CAG repeat alleles, intermediate CAG repeat alleles were significantly related to a higher risk of developing chorea (age of onset range, 63-84 years) in individuals aged ≥55 years. CONCLUSIONS: This study provides insights into the specific characteristics of CAG repeat lengths in the HTT gene in the Korean population. The reduced penetrance and intermediate allele frequencies in the Korean general population seem to be lower than those reported in Western populations. The presence of intermediate alleles may increase the risk of chorea in the Korean elderly population, which requires further large-scale investigations.

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Peutz-Jeghers syndrome (PJS; MIM 175200) is an autosomal dominant multiple-organ cancer syndrome. It is characterized by brown macules distributed in the perioral skin, oral mucosa, hands and feet, and hamartomatous gastrointestinal polyps that can eventually lead to intestinal obstruction, abdominal pain, bleeding, and anemia. Patients with PJS are at a higher risk of ovarian, testicular, breast, lung, and pancreatic cancers. This predisposition is due to the pathogenic variant in serine/threonine kinase 11 (STK11) gene located on chromosome 19p13.3. Here, we present the dermoscopic findings, histopathologic features of acral pigmentation, and DNA sequencing results of the patient with PJS. We also report a successful removal of acral pigmentation using the Q-switched Nd:YAG laser (QSNYL) treatment. Our results suggest that QSNYL therapy could be a treatment option for acral pigmentation in patients with PJS.

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This study aims to assess whether the On-X aortic valved conduit better restores normal valvular and ascending aortic hemodynamics than other commonly used bileaflet mechanical valved conduit prostheses from St. Jude Medical and Carbomedics by using same-day transthoracic echocardiography (TTE) and 4D flow magnetic resonance imaging (MRI) examinations. TTE and 4D flow MRI were performed back-to-back in 10 patients with On-X, six patients with St. Jude (two) and Carbomedics (four) prostheses, and 36 healthy volunteers. TTE evaluated valvular hemodynamic parameters: transvalvular peak velocity (TPV), mean and peak transvalvular pressure gradient (TPG), and effective orifice area (EOA). 4D flow MRI evaluated the peak systolic 3D viscous energy loss rate (VELR) density and mean vorticity magnitude in the ascending aorta (AAo). While higher TPV and mean and peak TPG were recorded in all patients compared to healthy subjects, the values in On-X patients were closer to those in healthy subjects (TPV 1.9 ± 0.3 vs. 2.2 ± 0.3 vs. 1.2 ± 0.2 m/s, mean TPG 7.4 ± 1.9 vs. 9.2 ± 2.3 vs. 3.1 ± 0.9 mmHg, peak TPG 15.3 ± 5.2 vs. 18.9 ± 5.2 vs. 6.1 ± 1.8 mmHg, p < 0.001). Likewise, while higher VELR density and mean vorticity magnitude were recorded in all patients than in healthy subjects, the values in On-X patients were closer to those in healthy subjects (VELR: 50.6 ± 20.1 vs. 89.8 ± 35.2 vs. 21.4 ± 9.2 W/m3, p < 0.001) and vorticity (147.6 ± 30.0 vs. 191.2 ± 26.0 vs. 84.6 ± 20.5 s-1, p < 0.001). This study demonstrates that the On-X aortic valved conduit may produce less aberrant hemodynamics in the AAo while maintaining similar valvular hemodynamics to St. Jude Medical and Carbomedics alternatives.

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Research presented at conferences may increase context-specific evidence in low- and middle-income countries (LMICs), where global childhood disease burden is greatest and where massive relative deficits in research persist. Publication of studies presented at conferences is necessary for complete results dissemination. Our objective was to determine the frequency of publication of pediatric global health conference abstracts and to identify factors associated with publication. We conducted a cross-sectional study of abstracts that reported pediatric research conducted in at least one LMIC presented at seven major scientific conferences in 2017, 2018, and 2019. We used PubMed, EMBASE and Google Scholar to search for publications of the results presented as abstracts. We created a Kaplan-Meier curve to determine the cumulative incidence of publications and used predetermined abstract-level factors to create a multivariable Cox proportional hazard model to identify factors associated with time to publication. There were 8,105 abstracts reviewed and 1,433 (17.7%) reported pediatric research conducted in one or more LMICs. The probability of publication of pediatric global health abstracts was 33.6% (95% confidence interval [CI] 31.2-36.1%) at 24 months and 46.6% (95% CI 44.0-49.3%) at 48 months. Abstracts that reported research conducted in East Asia and Pacific (adjusted hazard ratio [aHR] 3.06, 95% CI 1.74-5.24), South Asia (aHR 2.25, 95% CI 1.30-3.91%), and upper-middle-income countries (1.50, 95% CI 1.12-2.02) were published sooner than those that reported research in LMICs in Europe and Central Asia and lower-middle-income countries, respectively. Fewer than half of pediatric global health abstracts were published in peer-reviewed journals up to four years after presentation at international conferences. Efforts are urgently needed to promote the widespread and long-lasting dissemination of pediatric research conducted in LMICs presented as abstracts to provide a more robust evidence base for both clinical care and policy related to child health.

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The Korean Genetic Diagnosis Program for Rare Disease (KGDP) enrolled 1890 patients with rare diseases between March 2017 and October 2022. Children and adolescents accounted for the majority of the patients, and systemic disease was the most common presenting symptom. The exome-based virtual disease-specific multigene panel was the most frequently used analytical method, with an overall diagnostic yield of 33.3%. A total of 629 positive cases were diagnosed, involving 297 genes. All 297 genes identified in these cases were confirmed to be known genes listed in the OMIM database. The nationwide KGDP network and its cooperation with the Korean Undiagnosed Diseases Program (KUDP) provide a more comprehensive genetic analysis of undiagnosed cases. The partnership between the KGDP and KUDP has the potential to improve the diagnosis and treatment options for patients. In conclusion, KGDP serves as the primary access point or gateway to KUDP.

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BACKGROUND: Left atrial (LA) volume is related to LA reservoir strain (LASR ), but the relationship is not fully resolved. We sought to model the relationship between LA end-diastolic and end-systolic volumes (LAEDV and LAESV) and LASR based on a geometrical approach to exploit the relationship between LASR and volume. METHODS: Modeling the LA as a hemisphere with radius r, LASR was recognized to vary linearly with r and LA volume with r3 . Expanding this cubic relation as a Taylor series resulted in a simple linear equation: LAESV/LAEDV = 1 + 3 × LASR . To validate this, 52 transthoracic echocardiograms were analyzed from 18 patients who underwent transcatheter edge-to-edge repair (TEER) with MitraClip with serial assessment pre-procedure, 1 month post-clip, and 12 months post-TEER. Linear regression was performed to compare the geometric equation to a statistical model created by a line of best fit to relate LAESV/LAEDV to LASR . RESULTS: The statistical and geometric model both resulted in a strong correlation (r = .8, p < .001, respectively). The slope of the line in the statistical model was 3.3, which was statistically indistinguishable from the expected slope of 3 based on the geometric model (Figure 2A). Using the geometric model to compare the measured versus calculated LAESV/LAEDV also resulted in a strong correlation (r = .8, p < .001)(Figure 2B). CONCLUSION: We describe the relationship between LA volume and strain mathematically by considering the geometry of the LA. This model enhances our understanding of the interaction between atrial strain and volume. Further research is necessary to validate this using 3D atrial volumes in a broader cohort of subjects.

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T-cell large granular lymphocyte leukemia (T-LGL) is often accompanied by pure red cell aplasia (PRCA). A high depth of next generation sequencing (NGS) was used for detection of the mutational profiles in T-LGL alone (n = 25) and T-LGL combined with PRCA (n = 16). Beside STAT3 mutation (41.5%), the frequently mutated genes included KMT2D (17.1%), TERT (12.2%), SUZ12 (9.8%), BCOR (7.3%), DNMT3A (7.3%), and RUNX1 (7.3%). Mutations of the TERT promoter showed a good response to treatment. 3 of 41 (7.3%) T-LGL patients with diverse gene mutations were revealed as T-LGL combined with myelodysplastic syndrome (MDS) after review of bone marrow slide. T-LGL combined with PRCA showed unique features (low VAF level of STAT3 mutation, low lymphocyte count, old age). Low ANC was detected in a STAT3 mutant with a low level of VAF, suggesting that even the low mutational burden of STAT3 is sufficient for reduction of ANC. In retrospective analysis of 591 patients without T-LGL, one MDS patient with STAT3 mutation was revealed to have subclinical T-LGL. T-LGL combined with PRCA may be classified as unique subtype of T-LGL. High depth NGS can enable sensitive detection of concomitant MDS in T-LGL. Mutation of the TERT promoter may indicate good response to treatment of T-LGL, thus, its addition to an NGS panel may be recommended.

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Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder affecting ciliary structure and function. PCD exhibiting dynein regulatory complex subunit 1 (DRC1) exon 1-4 deletion has been reported in several Japanese PCD patients; however, no large scale studies have been performed. Here, we aimed to determine the prevalence and founder effect of this variant in the Korean population. Using an in-house copy number variation tool, we screened for DRC1 exon 1-4 deletion in 20 patients with PCD and exome data of 1435 patients in the Seoul National University Hospital repository. In cases of suspected DRC1 deletion, confirmatory gap-PCR was performed. In a PCD cohort, three of 20 (15%) patients were positive for DRC1 exon 1-4 deletion (NM_145038.5(DRC1): c.1-3952_540 + 1331del27748-bp) while pathogenic variants were found in CCDC39 (N = 1), DNAAF6 (N = 1), DNAH9 (N = 1). In the 1,435-sample exome data, seven patients (0.49%) were confirmed to have DRC1 exon 1-4 deletion. A chimeric sequence including the junction was searched from the 1000 Genomes Project data repository. One Japanese patient (0.96%) was found to have the same DRC1 exon 1-4 deletion, which was absent in other populations. This study demonstrated that the DRC1 exon 1-4 deletion is a founder mutation based on haplotype analysis. In summary, the prevalence of PCD based on DRC1 exon 1-4 deletion is particularly high in Korean and Japanese populations, which is attributed to the founder effect. Genetic testing for DRC1 exon 1-4 deletion should be considered as an initial screening tool for Korean and Japanese patients with PCD.

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