Fitness costs of Tn1546-type transposons harboring the vanA operon by plasmid type and structural diversity in Enterococcus faecium.

BACKGROUND: This study analyzed the genetic traits and fitness costs of vancomycin-resistant Enterococcus faecium (VREfm) blood isolates carrying Tn1546-type transposons harboring the vanA operon. METHODS: All E. faecium blood isolates were collected from eight general hospitals in South Korea during one-year study period. Antimicrobial susceptibility testing and vanA and vanB PCR were performed. Growth rates of E. faecium isolates were determined. The vanA-positive isolates were subjected to whole genome sequencing and conjugation experiments. RESULTS: Among 308 E. faecium isolates, 132 (42.9%) were positive for vanA. All Tn1546-type transposons harboring the vanA operon located on the plasmids, but on the chromosome in seven isolates. The plasmids harboring the vanA operon were grouped into four types; two types of circular, nonconjugative plasmids (Type A, n = 50; Type B, n = 46), and two types of putative linear, conjugative plasmids (Type C, n = 16; Type D, n = 5). Growth rates of vanA-positive E. faecium isolates were significantly lower than those of vanA-negative isolates (P < 0.001), and reduction in growth rate under vancomycin pressure was significantly larger in isolates harboring putative linear plasmids than in those harboring circular plasmids (P = 0.020). CONCLUSIONS: The possession of vanA operon was costly to bacterial hosts in antimicrobial-free environment, which provide evidence for the importance of reducing vancomycin pressure for prevention of VREfm dissemination. Fitness burden to bacterial hosts was varied by type and size of the vanA operon-harboring plasmid.

Shifting trends in bloodstream infection-causing microorganisms and their clinical impact in patients with haematologic malignancies in South Korea: A propensity score-matched study.

BACKGROUND: This study aimed to identify recent trends in the epidemiology of bloodstream infection (BSI)-causing microorganisms among patients with haematologic malignancies (HMs) between 2011 and 2021, and to determine their impact on patient outcomes. METHODS: This retrospective study included 6792 patients with HMs, of whom 1308 (19.3%) developed BSI within 1 y of diagnosis. The incidence of BSI-causing microorganisms was determined, and a propensity score-matched study was performed to identify risk factors for 28-d all-cause mortality in patients with HM. RESULTS: A total of 6792 patients with HMs were enrolled. The cumulative incidence of BSI and neutropenia was significantly higher in the acute myeloid leukaemia and acute lymphoblastic leukaemia groups compared to other groups, and neutropenia and type of HMs were risk factors for the development of BSI. The annual incidence of coagulase-negative staphylococci (CoNS)-BSI decreased significantly (P < 0.001), whereas Klebsiella pneumoniae-BSI increased (P = 0.01). Carbapenem nonsusceptibility rates in K. pneumoniae isolates increased from 0.0% to 76.5% (P < 0.001). BSI caused by K. pneumoniae (adjusted odds ratio 2.17; 95% confidence interval 1.12-4.21) was associated with higher 28-d all-cause mortality compared to that caused by CoNS (adjusted odds ratio 0.86; 95% confidence interval 0.48-1.55). CONCLUSION: The pathogenic spectrum of BSI-causing bacteria in patients with HMs gradually shifted from Gram-positive to Gram-negative, especially from CoNS to K. pneumoniae. Considering that K. pneumoniae-BSI had a significantly higher 28-d mortality rate than CoNS-BSI, this evolving trend could adversely impact the clinical outcomes of patients with HMs.

Development and validation of artificial intelligence models to predict urinary tract infections and secondary bloodstream infections in adult patients.

BACKGROUND: Traditional culture methods are time-consuming, making it difficult to utilize the results in the early stage of urinary tract infection (UTI) management, and automated urinalyses alone show insufficient performance for diagnosing UTIs. Several models have been proposed to predict urine culture positivity based on urinalysis. However, most of them have not been externally validated or consisted solely of urinalysis data obtained using one specific commercial analyzer. METHODS: A total of 259,187 patients were enrolled to develop artificial intelligence (AI) models. AI models were developed and validated for the diagnosis of UTI and urinary tract related-bloodstream infection (UT-BSI). The predictive performance of conventional urinalysis and AI algorithms were assessed by the areas under the receiver operating characteristic curve (AUROC). We also visualized feature importance rankings as Shapley additive explanation bar plots. RESULTS: In the two cohorts, the positive rates of urine culture tests were 25.2% and 30.4%, and the proportions of cases classified as UT-BSI were 1.8% and 1.6%. As a result of predicting UTI from the automated urinalysis, the AUROC were 0.745 (0.743-0.746) and 0.740 (0.737-0.743), and most AI algorithms presented excellent discriminant performance (AUROC > 0.9). In the external validation dataset, the XGBoost model achieved the best values in predicting both UTI (AUROC 0.967 [0.966-0.968]) and UT-BSI (AUROC 0.955 [0.951-0.959]). A reduced model using ten parameters was also derived. CONCLUSIONS: We found that AI models can improve the early prediction of urine culture positivity and UT-BSI by combining automated urinalysis with other clinical information. Clinical utilization of the model can reduce the risk of delayed antimicrobial therapy in patients with nonspecific symptoms of UTI and classify patients with UT-BSI who require further treatment and close monitoring.

Shift in risk factors for mortality by period of the bloodstream infection timeline.

BACKGROUND: This study was designed to determine changes in risk factors on the prognosis of patients during each period of the bloodstream infection (BSI) timeline. METHODS: Through an integrated study of multivariable regressions with machine learning techniques, the risk factors for mortality during each period of BSI were analyzed. RESULTS: A total of 302,303 inpatients who underwent blood cultures during 2011-2021 were enrolled. More than 8 % of BSI cases progressed to subsequent BSI, and risk factors were identified as gut colonization with vancomycin-resistant enterococci (aOR 1.82; 95 % CI 1.47-2.24), intensive care unit admission (aOR 3.37; 95 % CI 3.35-4.28), and current cancer chemotherapy (aOR 1.54; 95 % CI 1.36-1.74). The mean SOFA score of the deceased patients during the first 7 days was 10.6 (SD 4.3), which was significantly higher than those on days 8-30 (7.0 ± 4.2) and after Day 30 (4.0 ± 3.5). BSIs caused by Acinetobacter baumannii and Candida albicans were more likely to result in deaths of patients for all time periods (all, P < 0.001). BSIs caused by Enterococcus faecalis and Enterococcus faecium were associated with a poor outcome in the period after Day 30 (both, P < 0.001). Nonsusceptible phenotypes to ß-lactam/ß-lactamase inhibitors of Escherichia coli and Klebsiella pneumoniae influenced the prognoses of patients with BSI in terms of high mortality rates during both days 8-30 and after Day 30. CONCLUSION: Influence of microbiological factors on mortality, including BSI-causative microorganisms and their major antimicrobial resistance, was emphasized in both periods of days 8-30 and after Day 30.

Virulence Traits and Azole Resistance in Korean Candida auris Isolates.

We analyzed the virulence traits and azole resistance mechanisms of 104 Candida auris isolates collected from 13 Korean hospitals from 1996 to 2022. Of these 104 isolates, 96 (5 blood and 91 ear isolates) belonged to clade II, and 8 (6 blood and 2 other isolates) belonged to clade I. Fluconazole resistance (minimum inhibitory concentration ≥32 mg/L) was observed in 68.8% of clade II and 25.0% of clade I isolates. All 104 isolates were susceptible to amphotericin B and three echinocandins. In 2022, six clade I isolates indicated the first nosocomial C. auris cluster in Korea. Clade II C. auris isolates exhibited reduced thermotolerance at 42 °C, with diminished in vitro competitive growth and lower virulence in the Galleria mellonella model compared to non-clade II isolates. Of the 66 fluconazole-resistant clade II isolates, several amino acid substitutions were identified: Erg11p in 14 (21.2%), Tac1Ap in 2 (3.0%), Tac1Bp in 62 (93.9%), and Tac1Bp F214S in 33 (50.0%). Although there were a limited number of non-clade II isolates studied, our results suggest that clade II C. auris isolates from Korean hospitals might display lower virulence traits than non-clade II isolates, and their primary fluconazole resistance mechanism is linked to Tac1Bp mutations.

Differences of clinical characteristics and outcome in proven invasive Trichosporon infections caused by asahii and non-asahii species.

BACKGROUND: Trichosporon is an emerging yeast that causes invasive infections in immunocompromised patients experiencing prolonged hospitalisation, indwelling venous catheters and neutropenia. METHODS: This retrospective observational cohort study analysed invasive Trichosporon infections (ITIs) occurring between January 2005 and December 2022 at three tertiary hospitals and compared the clinical characteristics and prognostic factors of ITIs caused by Trichosporon asahii and non-T. asahii spp. After evaluating 1067 clinical isolates, we identified 46 patients with proven ITIs, defined as cases in which Trichosporon was isolated from blood, cerebrospinal fluid, or sterile tissues. RESULTS: The patients were separated into T. asahii and non-T. asahii groups containing 25 and 21 patients, respectively, all of which except one were immunocompromised. During this period, both the number of clinical isolates and patients with ITIs (mainly T. asahii) increased; whereas, cases involving non-T. asahii spp. decreased. Compared with the non-T. asahii group, the T. asahii group had more patients with multiple catheters (84% vs. 33%, p = .001) and those receiving renal replacement therapy (48% vs. 14%, p = .005). The all-cause 28-day mortality rate after ITI in the T. asahii group (44%) was significantly higher than in the non-T. asahii group (10%, Log-rank p = .014). The multivariate Cox regression model revealed that T. asahii (reference, non-T. asahii spp.; aHR = 4.3; 95% CI = 1.2-15.2, p = .024) and neutropenia for 5 days or more (aHR = 2.2, 95% CI = 1.5-3.6, p = .035) were independent factors in the 28-day mortality after ITI. CONCLUSION: The proven ITIs due to T. asahii produced more unfavourable outcomes compared with ITIs caused by non-T. asahii spp.

Changes in the prevalence of pathogens causing hospital-acquired bacterial pneumonia and the impact of their antimicrobial resistance patterns on clinical outcomes: A propensity-score-matched study.

BACKGROUND: This study aimed to evaluate changes in the prevalence of pathogens causing hospital-acquired bacterial pneumonia (HABP) and their antimicrobial resistance patterns in recent years, and to identify risk factors for 28-day all-cause mortality (ACM) in patients with HABP. METHODS: A propensity-score-matched study was performed by randomly allocating patients with ventilator-associated and non-ventilator-associated bacterial pneumonia admitted to two university hospitals between 2011 and 2021. RESULTS: In total, 17,250 patients with HABP were enrolled. The annual incidence of Staphylococcus aureus HABP decreased during the study period, while that of Klebsiella pneumoniae HABP increased significantly each year. Over the same period, the resistance rate of S. aureus to methicillin decreased from 88.4% to 64.4%, while the non-susceptibility rate of K. pneumoniae to carbapenems increased from 0% to 38%. HABP caused by A. baumannii [adjusted odds ratio (aOR) 1.50, 95% confidence interval (CI) 1.25-1.79], K. pneumoniae (aOR 1.28, 95% CI 1.16-1.40) and Stenotrophomonas maltophilia (aOR 1.32, 95% CI 1.05-1.66) was a risk factor for 28-day ACM. Patients with HABP caused by methicillin-resistant S. aureus and carbapenem-non-susceptible A. baumannii or K. pneumoniae had a significantly lower probability of survival. HABP with preceding coronavirus disease 2019 (COVID-19) was associated with high 28-day ACM (aOR 5.40, 955 CI 3.03-9.64) and high incidence of bacteraemic pneumonia (aOR 40.55, 95% CI 5.26-312.79). CONCLUSIONS: This study showed shifting trends in HABP-causing pathogens in terms of annual incidence and resistance rates to major therapeutic antimicrobial agents. HABP-causing bacterial pathogens, their antimicrobial resistance phenotypes, and preceding COVID-19 were significantly associated with progression of HABP to bloodstream infection and 28-day ACM in infected patients.

Feasible Detoxification Coating Material for Chemical Warfare Agents Using Poly(methyl methacrylate)-Branched Poly(ethyleneimine) Copolymer and Metal-Organic Framework Composites.

Defense against chemical warfare agents (CWAs) is regarded as a top priority for the protection of humanity, but it still depends on physical protection with severe limitations such as residual toxicity and post-treatment requirement. In this study, a strategically designed functional polymeric substrate was composited with a metal-organic framework catalyst to remove toxicity immediately. A series of PMMA-BPEI copolymers exhibited high processability as a coating and accelerated the catalytic activity of Zr(IV)-based metal-organic framework catalysts (UiO-66). Among them, PMB12_40 composite coating on a cotton fabric, containing a PMMA-BPEI copolymer (PMMA/BPEI = 1/2) and 40% of UiO-66 catalyst, can efficiently decompose nerve agent simulants (methyl-paraoxon) under both liquid phase (t1/2 = 0.14 h) and humidified (t1/2 = 4.8 h) conditions. Moreover, a real agent, GD, was decomposed 100% by PMB12_40 in 4 h at 25 °C and 65% relative humidity. On the basis of superior catalytic activity, the PMB composites are anticipated to be a potential material for active chemical protection coating.

Impact of urinary tract infection-causative microorganisms on the progression to bloodstream infection: A propensity score-matched analysis.

OBJECTIVES: We aimed to determine the risk factors for the progression of urinary tract infection (UTI) to bloodstream infection (BSI) and to evaluate the mortality-associated factors in patients with urinary tract-related BSI (UT-BSI). METHODS: A propensity score-matched study was conducted using clinical data from all adult patients with UTIs in two South Korean hospitals. RESULTS: A total of 84,406 patients with UTIs were enrolled. The relative incidence of UTIs caused by Escherichia coli decreased along with an increase in the incidence of Candida species infections during the study period. UTI caused by E. coli, Klebsiella pneumoniae, Staphylococcus aureus, and Candida species had a relatively high rate of progression to BSI. UT-BSI caused by Candida species (adjusted odd ratio 5.67; 95% confidence interval 3.97-8.11; p < 0.001) was significantly associated with high 30-day mortality. CONCLUSIONS: UTI-causative microorganisms were associated with both progression to UT-BSI and 30-day mortality in patients with UT-BSI. Considering the trend of increasing age of patients and more frequent use of indwelling urologic devices, UT-BSIs caused by other microorganisms than E. coli could be a more serious medical burden in the future.

Risk Factors of Severe Clostridioides difficile Infection; Sequential Organ Failure Assessment Score, Antibiotics, and Ribotypes.

We aimed to determine whether the Sequential Organ Failure Assessment (SOFA) score predicts the prognosis of patients with Clostridioides difficile infection (CDI). In addition, the association between the type of antibiotic used and PCR ribotypes was analyzed. We conducted a propensity score (PS)-matched study and machine learning analysis using clinical data from all adult patients with confirmed CDI in three South Korean hospitals. A total of 5,337 adult patients with CDI were included in this study, and 828 (15.5%) were classified as having severe CDI. The top variables selected by the machine learning models were maximum body temperature, platelet count, eosinophil count, oxygen saturation, Glasgow Coma Scale, serum albumin, and respiratory rate. After propensity score-matching, the SOFA score, white blood cell (WBC) count, serum albumin level, and ventilator use were significantly associated with severe CDI (P < 0.001 for all). The log-rank test of SOFA score ≥ 4 significantly differentiated severe CDI patients from the non-severe group. The use of fluoroquinolone was more related to CDI patients with ribotype 018 strains than to ribotype 014/020 (P < 0.001). Even after controlling for other variables using propensity score matching analysis, we found that the SOFA score was a clinical predictor of severe CDI. We also demonstrated that the use of fluoroquinolones in hospital settings could be associated with the PCR ribotype in patients with CDI.

Mortality prediction of patients in intensive care units using machine learning algorithms based on electronic health records.

Improving predictive models for intensive care unit (ICU) inpatients requires a new strategy that periodically includes the latest clinical data and can be updated to reflect local characteristics. We extracted data from all adult patients admitted to the ICUs of two university hospitals with different characteristics from 2006 to 2020, and a total of 85,146 patients were included in this study. Machine learning algorithms were trained to predict in-hospital mortality. The predictive performance of conventional scoring models and machine learning algorithms was assessed by the area under the receiver operating characteristic curve (AUROC). The conventional scoring models had various predictive powers, with the SAPS III (AUROC 0.773 [0.766-0.779] for hospital S) and APACHE III (AUROC 0.803 [0.795-0.810] for hospital G) showing the highest AUROC among them. The best performing machine learning models achieved an AUROC of 0.977 (0.973-0.980) in hospital S and 0.955 (0.950-0.961) in hospital G. The use of ML models in conjunction with conventional scoring systems can provide more useful information for predicting the prognosis of critically ill patients. In this study, we suggest that the predictive model can be made more robust by training with the individual data of each hospital.

TREX1 Deficiency Induces ER Stress-Mediated Neuronal Cell Death by Disrupting Ca2+ Homeostasis.

TREX1 is an exonuclease that degrades extranuclear DNA species in mammalian cells. Herein, we show a novel mechanism by which TREX1 interacts with the BiP/GRP78 and TREX1 deficiency triggers ER stress through the accumulation of single-stranded DNA and activates unfolded protein response (UPR) signaling via the disruption of the TREX1-BiP/GRP78 interaction. In TREX1 knockdown cells, the activation of ER stress signaling disrupted ER Ca2+ homeostasis via the ERO1α-IP3R1-CaMKII pathway, leading to neuronal cell death. Moreover, TREX1 knockdown dysregulated the Golgi-microtubule network through Golgi fragmentation and decreased Ac-α-tubulin levels, contributing to neuronal injury. These alterations were also observed in neuronal cells harboring a TREX1 mutation (V91M) that has been identified in hereditary spastic paraplegia (HSP) patients in Korea. Notably, this mutation leads to defects in the TREX1-BiP/GRP78 interaction and mislocalization of TREX1 from the ER and possible disruption of the Golgi-microtubule network. In summary, the current study reveals TREX1 as a novel regulator of the BiP/GRP78 interaction and shows that TREX1 deficiency promotes ER stress-mediated neuronal cell death, which indicates that TREX1 may hold promise as a therapeutic target for neurodegenerative diseases such as HSP.

Corrigendum: Characteristics of Genetic Variations Associated With Lennox-Gastaut Syndrome in Korean Families.

[This corrects the article DOI: 10.3389/fgene.2020.590924.].

Major Bloodstream Infection-Causing Bacterial Pathogens and Their Antimicrobial Resistance in South Korea, 2017-2019: Phase I Report From Kor-GLASS.

To monitor national antimicrobial resistance (AMR), the Korea Global AMR Surveillance System (Kor-GLASS) was established. This study analyzed bloodstream infection (BSI) cases from Kor-GLASS phase I from January 2017 to December 2019. Nine non-duplicated Kor-GLASS target pathogens, including Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter spp., and Salmonella spp., were isolated from blood specimens from eight sentinel hospitals. Antimicrobial susceptibility testing, AMR genotyping, and strain typing were carried out. Among the 20,041 BSI cases, 15,171 cases were caused by one of the target pathogens, and 12,578 blood isolates were collected for the study. Half (1,059/2,134) of S. aureus isolates were resistant to cefoxitin, and 38.1% (333/873) of E. faecium isolates were resistant to vancomycin. Beta-lactamase-non-producing ampicillin-resistant and penicillin-resistant E. faecalis isolates by disk diffusion method were identified, but the isolates were confirmed as ampicillin-susceptible by broth microdilution method. Among E. coli, an increasing number of isolates carried the bla CTX-M-27 gene, and the ertapenem resistance in 1.4% (30/2,110) of K. pneumoniae isolates was mostly (23/30) conferred by K. pneumoniae carbapenemases. A quarter (108/488) of P. aeruginosa isolates were resistant to meropenem, and 30.5% (33/108) of those carried acquired carbapenemase genes. Over 90% (542/599) of A. baumannii isolates were imipenem-resistant, and all except one harbored the bla OXA-23 gene. Kor-GLASS provided comprehensive AMR surveillance data, and the defined molecular mechanisms of resistance helped us to better understand AMR epidemiology. Comparative analysis with other GLASS-enrolled countries is possible owing to the harmonized system provided by GLASS.

Coiled-coil domain containing 50-V2 protein positively regulates neurite outgrowth.

The coiled-coil domain containing 50 (CCDC50) protein is a phosphotyrosine-dependent signalling protein stimulated by epidermal growth factor. It is highly expressed in neuronal cells in the central nervous system; however, the roles of CCDC50 in neuronal development are largely unknown. In this study, we showed that the depletion of CCDC50-V2 impeded the neuronal development process, including arbor formation, spine density development, and axonal outgrowth, in primary neurons. Mechanistic studies revealed that CCDC50-V2 positively regulated the nerve growth factor receptor, while it downregulated the epidermal growth factor receptor pathway. Importantly, JNK/c-Jun activation was found to be induced by the CCDC50-V2 overexpression, in which the interaction between CCDC50-V2 and JNK2 was also observed. Overall, the present study demonstrates a novel mechanism of CCDC50 function in neuronal development and provides new insight into the link between CCDC50 function and the aetiology of neurological disorders.

Quantitative Augmented Reality-Assisted Free-Hand Orthognathic Surgery Using Electromagnetic Tracking and Skin-Attached Dynamic Reference.

The purpose of this study was to develop a quantitative AR-assisted free-hand orthognathic surgery method using electromagnetic (EM) tracking and skin-attached dynamic reference. The authors proposed a novel, simplified, and convenient workflow for augmented reality (AR)-assisted orthognathic surgery based on optical marker-less tracking, a comfortable display, and a non-invasive, skin-attached dynamic reference frame. The 2 registrations between the physical (EM tracking) and CT image spaces and between the physical and AR camera spaces, essential processes in AR-assisted surgery, were pre-operatively performed using the registration body complex and 3D depth camera. The intraoperative model of the maxillary bone segment (MBS) was superimposed on the real patient image with the simulated goal model on a flat-panel display, and the MBS was freely handled for repositioning with respect to the skin-attached dynamic reference tool (SRT) with quantitative visualization of landmarks of interest using only EM tracking. To evaluate the accuracy of AR-assisted Le Fort I surgery, the MBS of the phantom was simulated and repositioned by 6 translational and three rotational movements. The mean absolute deviations (MADs) between the simulation and post-operative positions of MBS landmarks by the SRT were 0.20, 0.34, 0.29, and 0.55 mm in x- (left lateral, right lateral), y- (setback, advance), and z- (impaction, elongation) directions, and RMS, respectively, while those by the BRT were 0.23, 0.37, 0.30, and 0.60 mm. There were no significant differences between the translation and rotation surgeries or among surgeries in the x-, y-, and z-axes for the SRT. The MADs in the x-, y-, and z-axes exhibited no significant differences between the SRT and BRT. The developed method showed high accuracy and reliability in free-hand orthognathic surgery using EM tracking and skin-attached dynamic reference.

Clinical Characteristics and Disease Progression in Early-Stage COVID-19 Patients in South Korea.

A rapid increase in the number of patients with coronavirus disease 19 (COVID-19) may overwhelm the available medical resources. We aimed to evaluate risk factors for disease severity in the early stages of COVID-19. The cohort comprised 293 patients with COVID-19 from 5 March 2020, to 18 March 2020. The Korea Centers for Disease Control and Prevention (KCDC) classification system was used to triage patients. The clinical course was summarized, including the impact of drugs (angiotensin II receptor blockers [ARB], ibuprofen, and dipeptidyl peptidase-4 inhibitors [DPP4i]) and the therapeutic effect of lopinavir/ritonavir. After adjusting for confounding variables, prior history of drug use, including ARB, ibuprofen, and DPP4i was not a risk factor associated with disease progression. Patients treated with lopinavir/ritonavir had significantly shorter progression-free survival than those not receiving lopinavir/ritonavir. KCDC classification I clearly distinguished the improvement/stabilization group from the progression group of COVID-19 patients (AUC 0.817; 95% CI, 0.740-0.895).

Characteristics of Genetic Variations Associated With Lennox-Gastaut Syndrome in Korean Families.

Lennox-Gastaut syndrome (LGS) is a severe type of childhood-onset epilepsy characterized by multiple types of seizures, specific discharges on electroencephalography, and intellectual disability. Most patients with LGS do not respond well to drug treatment and show poor long-term prognosis. Approximately 30% of patients without brain abnormalities have unidentifiable causes. Therefore, accurate diagnosis and treatment of LGS remain challenging. To identify causative mutations of LGS, we analyzed the whole-exome sequencing data of 17 unrelated Korean families, including patients with LGS and LGS-like epilepsy without brain abnormalities, using the Genome Analysis Toolkit. We identified 14 mutations in 14 genes as causes of LGS or LGS-like epilepsy. 64 percent of the identified genes were reported as LGS or epilepsy-related genes. Many of these variations were novel and considered as pathogenic or likely pathogenic. Network analysis was performed to classify the identified genes into two network clusters: neuronal signal transmission or neuronal development. Additionally, knockdown of two candidate genes with insufficient evidence of neuronal functions, SLC25A39 and TBC1D8, decreased neurite outgrowth and the expression level of MAP2, a neuronal marker. These results expand the spectrum of genetic variations and may aid the diagnosis and management of individuals with LGS.

A Novel X-Linked Variant of IQSEC2 is Associated with Lennox-Gastaut Syndrome and Mild Intellectual Disability in Three Generations of a Korean Family.

Aim: Lennox-Gastaut syndrome (LGS) is a severe type of childhood-onset epilepsy with multiple types of seizures, specific discharges on electroencephalography, and intellectual disability. However, LGS-related genes are largely unknown. To identify causative genes related to LGS, we collected and analyzed data from a three-generation Korean family in which one member had LGS and two had intellectual disability. Methods: Genomic DNAs were extracted from blood samples of all participants and used in whole-exome sequencing (WES). Genetic variants were detected by the Genome Analysis Toolkit and confirmed by Sanger sequencing. Variant pathogenicity was evaluated by prediction programs and the American College of Medical Genetics criteria. The LGS patient had generalized slow spike-and-wave discharges, multiple types of seizures, and developmental delay. Results: Analyses of the WES data from the family revealed a novel variant (c.1048G>A, p.Ala350Thr) in the IQ motif and Sec7 domain 2 (IQSEC2). This variant is within a highly evolutionarily conserved IQ-like motif, indicating a decrease in the calmodulin-binding capacity or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid transmission. The hemizygous variant in the male with LGS was a maternally inherited X-linked variant from the heterozygous maternal grandmother and mother, both of whom had intellectual disability. Conclusion: These findings indicate that the variant of IQSEC2 triggered both LGS and intellectual disability dependent on sex in this family. We report a novel X-linked inherited IQSEC2 variant for LGS and intellectual disability, which enhances the spectrum of variants in the IQ-like motif of IQSEC2.