Mosaic variegated aneuploidy syndrome with tetraploid, and predisposition to male infertility triggered by mutant CEP192.

In this study, we report on mosaic variegated aneuploidy (MVA) syndrome with tetraploidy and predisposition to infertility in a family. Sequencing analysis identified that the CEP192 biallelic variants (c.1912C>T, p.His638Tyr and c.5750A>G, p.Asn1917Ser) segregated with microcephaly, short stature, limb-extremity dysplasia, and reduced testicular size, while CEP192 monoallelic variants segregated with infertility and/or reduced testicular size in the family. In 1,264 unrelated patients, variant screening for CEP192 identified a same variant (c.5750A>G, p.Asn1917Ser) and other variants significantly associated with infertility. Two lines of Cep192 mice model that are equivalent to human variants were generated. Embryos with Cep192 biallelic variants arrested at E7 because of cell apoptosis mediated by MVA/tetraploidy cell acumination. Mice with heterozygous variants replicated the predisposition to male infertility. Mouse primary embryonic fibroblasts with Cep192 biallelic variants cultured in vitro showed abnormal morphology, mitotic arresting, and disruption of spindle formation. In patient epithelial cells with biallelic variants cultured in vitro, the number of cells arrested during the prophase increased because of the failure of spindle formation. Accordingly, we present mutant CEP192, which is a link for the MVA syndrome with tetraploidy and the predisposition to male infertility.

Genome-Wide Analysis of the Membrane Attack Complex and Perforin Genes and Their Expression Pattern under Stress in the Solanaceae.

The Membrane Attack Complex and Perforin (MACPF) proteins play a crucial role in plant development and adaptation to environmental stresses. Heretofore, few MACPF genes have been functionally identified, leaving gaps in our understanding of MACPF genes in other plants, particularly in the Solanaceae family, which includes economically and culturally significant species, such as tomato, potato, and pepper. In this study, we have identified 26 MACPF genes in three Solanaceae species and in the water lily, which serves as the base group for angiosperms. Phylogenetic analysis indicates that angiosperm MACPF genes could be categorized into three distinct groups, with another moss and spikemoss lineage-specific group, which is further supported by the examination of gene structures and domain or motif organizations. Through inter-genome collinearity analysis, it is determined that there are 12 orthologous SolMACPF gene pairs. The expansion of SolMACPF genes is primarily attributed to dispersed duplications, with purifying selection identified as the principal driving force in their evolutionary process, as indicated by the ω values. Furthermore, the analysis of expression patterns revealed that Solanaceae genes are preferentially expressed in reproductive tissues and regulated by various environmental stimuli, particularly induced by submergence. Taken together, these findings offer valuable insights into and a fresh perspective on the evolution and function of SolMACPF genes, thereby establishing a foundation for further investigations into their phenotypic and functional characteristics.

A Study of Familial Amyloid Polyneuropathy Induced by the TTR Val30Leu Mutation in China.

INTRODUCTION: Familial amyloid polyneuropathy is currently prevalent worldwide as the transthyretin (TTR) Val30Met mutation, and there are other types of mutations. The purpose of this study was to understand the clinical manifestations, electrophysiological characteristics, and outcomes of hormone-related therapy in patients with the TTR Val30Leu mutation in China. METHODS: Clinical data were collected from 9 members of a family with the TTR Val30Leu mutation in China, and blood samples of 7 members of the family were sequenced. The electrophysiological examinations of 4 of them were collected and analysed. RESULTS: A total of 7 people had the TTR gene c.148G>T missense mutation and the TTR protein Val30Leu mutation in this family, and the positive members all had similar symptoms, such as limb paraesthesia and gastrointestinal symptoms. In addition, electrophysiological examination showed abnormal nerve conduction velocity in all 4 patients. CONCLUSIONS: The clinical manifestations of this mutation involve mainly limb sensory or motor disorders or gastrointestinal symptoms or both, and the electrophysiological examination shows neurogenic damage.

The association between ECG criteria and Echo criteria for left ventricular hypertrophy in a general Chinese population.

BACKGROUND: Several ECG criteria have been widely used for diagnosis of left ventricular hypertrophy (LVH) in clinical practice. However, their performance in a general Chinese population is limited. METHODS AND RESULTS: A multi-stage, stratified cluster sampling across China was performed and 7415 representative Chinese adults aged 18-85 years were analyzed. ECG was collected by using GE MAC 5500 machine. The association between five ECG-LVH criteria (i.e., Peguero-Lo Presti, Cornell, Cornell product, Sokolow-Lyon and Sokolow-Lyon product) and echocardiographic LVH (Echo-LVH) was assessed by Pearson's correlation, diagnostic statistics like predictive values, and receiver operating characteristics (ROC) curve. We found that the prevalence of the Echo-LVH was 11% while ECG-LVH ranged from 3% to 27%. All ECG-LVH criteria had high negative predictive value (NPV) (89%) and specificity (73-96%) but low positive predictive value (PPV) (12-24%) and sensitivity (4-29%). The newly Peguero-Lo Presti criteria had higher sensitivity (29%) but lower specificity (73%) and accuracy (68%) compared with other criteria. Cornell product had the best diagnostic performance (AUC: 0.59), as well as the highest specificity (96%) and accuracy (86%) but lowest sensitivity (4%). Among single-lead components of ECG criteria, RaVL voltage and QRS duration performed relatively better than others. Hypertensive and older individuals had higher sensitivity but lower specificity and accuracy than their counterparts. CONCLUSION: ECG-LVH criteria had high NPV to detect Echo-LVH. Though with higher sensitivity, Peguero-Lo Presti criteria did not have better diagnostic performance to detect Echo-LVH. RaVL and QRS duration had stronger association with Echo-LVH among all single-lead components.

Effects of a high-fat diet on intracellular calcium (Ca2+) handling and cardiac remodeling in Wistar rats without hyperlipidemia.

A high-fat diet is often associated with cardiovascular diseases. Research has suggested that consumption of a high-fat diet for 10 weeks is associated with cardiac dysfunction, including arrhythmias, through alterations in cardiac remodeling and myocardial intracellular calcium (Ca2+) handling. In this study, rats were randomly divided into two groups: the standard diet (N = 5) and high-fat diet (N = 5) groups. To evaluate the effects of a high-fat diet on cardiac remodeling, we investigated the myocardium obtained from male Wistar rats fed a high-fat diet or standard diet for ten weeks via scanning electron microscopy, polarization microscopy, and RT-PCR. We found that compared with the standard diet cohort, the high-fat diet cohort exhibited increased levels of SERCA2a and SERCA2b mRNA and a decreased level of PLB mRNA (P < .05). These findings showed that a high-fat diet may lead to cardiac upregulation of Ca2+ transport-related genes in the sarcoplasmic reticulum. Additionally, we observed endocardial injury accompanied by focal dense layered collagen, increased spacing between endocardial cells that was often filled with collagen debris, and increased amounts of collagen fibers among enlarged cardiomyocytes in the high-fat diet cohort. The abnormal intracellular calcium (Ca2+) handling and cardiac remodeling may be contributing factors in arrhythmias and sudden cardiac death in high-fat diet-fed rats.

Outcomes of transvenous lead extraction in patients with lead perforation: A single-center experience.

BACKGROUND: Management of cardiac perforation caused by the lead of a cardiac implantable electronic device (CIED) is currently unclear. This study evaluated the outcomes of transvenous lead extraction (TLE) in patients with cardiac perforation caused by a transvenous lead. HYPOTHESIS: Removal of perforated lead by transvenous approach is safe and effective. METHODS: The medical records of all patients diagnosed with cardiac perforation by a pacing or defibrillator lead in Peking University People's Hospital from January 2008 to January 2019 were reviewed. We included patients who were managed by TLE. RESULTS: A total of 53 patients (30 men; mean age: 67 ± 15 years) with lead perforation managed by TLE were included. Most of the perforated leads (94.9%) were pacemaker leads. Forty-three leads (81.1%) were implanted within 1 year. Ten patients with a high risk of hemopericardium underwent percutaneous subxiphoid pericardial puncture prior to TLE. All 53 culprit leads were removed completely without major complications. Simple traction with or without a locking stylet was sufficient in 51 patients (96.2%). Forty-eight patients (90.6%) had a new active-fixation lead reimplanted. No patients showed evidence of new-onset or worsening pericardial effusion during the procedure and hospital stay. During a median follow-up time of 16 months, no recurrence of symptoms associated with lead perforation or CIED-related infection were reported. CONCLUSION: In most patients with lead perforation, TLE can be a safe and effective management approach.

Transfemoral extraction of pacemaker and implantable cardioverter defibrillator leads using Needle's Eye Snare: a single-center experience of more than 900 leads.

The femoral approach with the Needle's Eye Snare (NES) is often used for bailout after failure of the superior approach for transvenous lead extraction (TLE). The safety and efficacy of the NES as a first-line tool for TLE remain unclear. The medical records of patients who underwent TLE via the femoral approach utilizing the NES from May 2014 to June 2019 in Peking University People's Hospital were retrospectively reviewed. Nine hundred and eighty-five leads were extracted in 492 patients (369 men; mean age 72.8 ± 29.0 years). The median (range) number of leads extracted per patient was 2 (1-6). The mean indwelling time of all extracted leads was 112.6 ± 52.0 months. The complete procedure success rate, clinical success rate, and failure rate were 94.1% (463/492), 97.8% (481/492), and 1.1% (11/492), respectively. Major complications including death occurred in nine patients (1.9%), of whom eight developed cardiac tamponade. Among these eight patients, emergency pericardiocentesis followed by rescue surgical repair if necessary was successful in 6 (75.0%) and failed in 2 (25.0%). No significant differences were found in the clinical success rate or major complications rate between patients with pacemakers and implantable cardioverter defibrillators, or between patients with infected and uninfected leads. A femoral approach with the NES is safe and effective for TLE of both pacing and defibrillator leads and could be considered a first-line approach. Cardiac tamponade was the most frequent cardiovascular complication. A strategy of emergency pericardiocentesis followed by a rescue surgical approach seems to be reasonable technique to treat a cardiac tamponade.

Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer: A real-world retrospective study in Chinese patients.

OBJECTIVE: To assess the long-term effectiveness and safety of trastuzumab in adjuvant therapy for Chinese patients with early-stage human epidermal growth factor 2 (HER2)-positive breast cancer in a real-world setting. METHODS: This retrospective observational study analyzed the medical records of HER2-positive breast cancer patients between 2000 and 2012 at the Chinese Academy of Medical Sciences. Patients who received adjuvant chemotherapy alone or adjuvant chemotherapy followed by/combined with trastuzumab were included. The Kaplan-Meier method was used to estimate disease-free survival (DFS) and overall survival (OS). Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated using the Cox regression model. RESULTS: Of the 1,348 patients analyzed, 909 received chemotherapy alone and 439 received chemotherapy plus trastuzumab. The 3-year, 5-year and 10-year DFS rates were 83.70%, 76.38% and 68.94%, respectively, in the chemotherapy-alone cohort, and 90.21%, 86.19% and 83.45% in the chemotherapy plus trastuzumab cohort. The 3-year, 5-year and 10-year OS rates were 96.10%, 91.40% and 81.88% in the chemotherapy-alone cohort, and 98.17%, 94.91% and 90.01% in the chemotherapy plus trastuzumab cohort. The chemotherapy plus trastuzumab group had a significantly lower risk of disease recurrence and death than the chemotherapy-alone group (DFS: HR=0.50, 95% CI, 0.37-0.68; P<0.001; OS: HR=0.53, 95% CI, 0.34-0.81; P=0.004) after adjusting for covariates. In the 439 patients treated with trastuzumab, multivariate analysis suggested that lymph node positivity, higher T stages, and hormone receptor-negative status were significantly associated with higher risks of disease recurrence, and lymph node positivity and hormone receptor-negative status were significantly associated with higher risks of death. Grade 3/4 adverse events (incidence ≥1%) were more common in patients receiving trastuzumab (54.44%vs. 15.73%). CONCLUSIONS: Early-stage HER2-positive breast cancer patients treated with trastuzumab plus adjuvant chemotherapy have a significant survival benefit compared with chemotherapy-alone in real-world settings. Lymph node positivity, hormone receptor-negative status, and higher T stages may be associated with higher risks of recurrence, and effective therapy for patients with these factors is required.

[Value of ventricular tachycardia score in diagnosing pre-excited tachycardia].

OBJECTIVE: To investigate the value of ventricular tachycardia (VT) score in diagnosing pre-excited tachycardia.
 Methods: Twelve-lead electrocardiograph results were obtained from 30 patients at pre-excited tachycardia attacking stage who were diagnosed by electrophysiology. We scored pre-excitation tachycardia based on the VT score. To analyze the electrocardiogram of pre-excited tachycardia using 7 diagnostic indicators of the VT score and calculate the specificity of 7 diagnostic indicators and right superior axis (-90º to ±180º), the differences were compared among VT score of 2 points and brugada, Wellens, and Vereckei algorithms in diagnosing pre-excited tachycardia. According to the specificity of Vereckei, Wellens, and Brugada algorithms, and VT scores from low to high, their prediction value and differences were analyzed.
 Results: Single indicator such as atrioventricular (AV) dissociation or right superior axis (-90º to ±180º) showed the highest specificity (100%) for identifying pre-excited tachycardia. No patient with VT score was ≥3 points, and the specificity was 100%. The specificity of VT score of 2 point was higher than that of Brugada, Wellens, or Vereckei algorithms in the diagnosing pre-excited tachycardia (76.7% vs 50.0%, 23.3% or 20.0%, P<0.05). The specificity of Vereckei, Wellens, and Brugada algorithms and VT score were gradually increased after each of stepwise individually eliminated VT (20.0%, 40.0%, 66.7%, 83.3%, P<0.05). However, there was no significant difference in the specificity in the remaining false positive cases between the 4 methods and VT score.
 Conclusion: VT score ≥3 points can identify pre-excited tachycardia and VT with 100% specificity. VT score of 2 points cannot completely distinguish pre-excited tachycardia from VT, but specificity of VT score with 2 points is obviously higher than that of Brugada, Wellens, and Vereckei algorithms.

Remodeling of myocardial energy and metabolic homeostasis in a sheep model of persistent atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common progressive cardiac arrhythmia and is often associated with rapid contraction in both atria and ventricles. The role of atrial energy and metabolic homeostasis in AF progression is under-investigated. OBJECTIVES: To determine the remodeling of energy metabolism during persistent AF and the effect of eplerenone (EPL), an aldosterone inhibitor, on metabolic homeostasis. METHODS: A nonsustained atrial pacing sheep model was developed to simulate the progression of AF from paroxysmal to persistent. Metabolomic and proteomic analyses at termination of the experiment were used to analyze atrial tissues obtained from sheep in sham, sugar pill (SP) and EPL-treated groups. RESULTS: Proteomic analysis indicated that compared to the sham group, in SP group, fatty acid (FA) synthesis, FA oxidation, tricarboxylic acid (TCA) cycle processes and amino acids (AAs) transport and metabolism were reduced, while glycolytic processes were increased. In metabolomic analysis, the levels of intermediate metabolites of the glycolytic pathways, including 2-phosphoglyceric acid (2 PG), 1,3-bisphosphoglyceric acid (1,3 PG), and pyruvate, HBP (uridine diphosphate-N-acetylglucosamine, UDP-GlcNAc), TCA (citrate) and AAs were greater while the levels of the majority of lipid classes, including phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylglycerol (PG), glycerophosphoglycerophosphates (PGP), glycerophosphoinositols (PI) and glycerophosphoserines (PS), were decreased in the atria of SP group than in those of sham group. EPL-pretreatment decreased the expression of glut4 and increased the content of acylcarnitines and lipids, such as lyso phospholipids, phospholipids and neutral lipids. CONCLUSION: In the metabolic remodeling during AF, glucose and lipid metabolism were up- and down-regulated, respectively, to sustain TCA cycle anaplerosis. EPL partialy reversed the metabolic shifting.

CLCN7 and TCIRG1 mutations in a single family: Evidence for digenic inheritance of osteopetrosis.

Osteopetrosis is a monogenic condition with various inheritance patterns, including autosomal dominant, autosomal recessive and X­linked. Several disease­causing genes have been identified and three distinguished types of osteopetrosis have been reported. In the present study, a family with osteopetrosis was investigated. Two novel mutations in chloride voltage­gated channel 7 (CLCN7) and T cell immune regulator 1 (TCIRG1) were identified by exome sequencing, Sanger sequencing and microsatellite marker analysis. The CLCN7 mutation occurred in amino acid R286, the same position as previously reported. The TCIRG1 mutation occurred on a splicing site of exon 15, thereby leading to a truncated transcript. These two mutations were undetected in 496 ethnic­matched controls. To the best of our knowledge, this is the first report of human osteopetrosis involving digenic inheritance in a single family, which has important implications for decisions on clinical therapeutic regimen, prognosis evaluation and antenatal diagnosis.

Video-Assisted Thoracoscopic Left Cardiac Sympathetic Denervation in Chinese Patients with Long QT Syndrome.

Long QT syndrome is a rare but potentially lethal cardiac channelopathy. The primary aim of the study was to investigate the long-term effects of video-assisted thoracoscopic (VATS) left cardiac sympathetic denervation (LCSD) in Chinese patients with long QT syndrome.VATS-LCSD was performed in eight Chinese patients with LQTS. Twelve-lead ECGs and 24-hour Holter monitoring ECGs were recorded before and after surgery. The medical charts were reviewed to obtain patient data, and the patients who had been lost to follow-up were contacted through telephone.The average QTc was shortened from 534 ± 52.7 to 503 ± 43.7 ms (P = 0.030) 24 hours post-surgery and down to 486 ± 34.8 ms (P = 0.021) 1 week post-surgery, with the heart rate unchanged. The average QT dispersion was reduced from 67 ± 17.5 to 21 ± 3.9 ms (P < 0.001) 24 hours post-surgery and remained shortened 1 week later (30 ± 8.1 ms, P < 0.001). Moreover, the 24-hour ECG showed that the QTc was shortened from 552 ± 95.9 to 497 ± 19.7 ms at the minimum heart rate (P = 0.008), and was decreased from 594 ± 144 to 495 ± 74.1 ms at the maximum heart rate (P= 0.04), while the minimum and maximum heart rates were comparable before and after surgery. No death was observed during the follow-up period and the clinical symptoms improved in all patients. The annual event rate decreased from 4 ± 3.50 to 0.63 ± 1.37 events/year (P = 0.034) after surgery.These findings indicate that LCSD shortens the QTc, with the heart rate remaining unchanged. QTd might be a useful parameter for evaluating the efficacy of VATS-LCSD. LCSD could improve patients' life quality by reducing cardiac events.

XRCC2 mutation causes meiotic arrest, azoospermia and infertility.

BACKGROUND: Meiotic homologous recombination (HR) plays an essential role in gametogenesis. In most eukaryotes, meiotic HR is mediated by two recombinase systems: ubiquitous RAD51 and meiosis-specific DMC1. In the RAD51-mediated HR system, RAD51 and five RAD51 paralogues are essential for normal RAD51 function, but the role of RAD51 in human meiosis is unclear. The knockout of Rad51 or any Rad51 paralogue in mice exhibits embryonic lethality. We investigated a family with meiotic arrest, azoospermia and infertility but without other abnormalities. METHODS: Homozygosity mapping and whole-exome sequencing were performed in a consanguineous family. An animal model carrying a related mutation was created by using a CRISPR/Cas9 system. RESULTS: We identified a 1 bp homozygous substitution (c.41T>C/p.Leu14Pro) on a RAD51 paralogue, namely, XRCC2, in the consanguineous family. We did not detect any XRCC2 recessive mutation in a cohort of 127 males with non-obstructive-azoospermia. Knockin mice with Xrcc2-c.T41C/p.Leu14Pro mutation were generated successfully by the CRISPR/Cas9 method. The homozygotes survived and exhibited meiotic arrest, azoospermia, premature ovarian failure and infertility. CONCLUSION: A XRCC2 recessive mutation causing meiotic arrest and infertility in humans was duplicated with knockin mice. Our results revealed a new Mendelian hereditary entity and provided an experimental model of RAD51-HR gene defect in mammalian meiosis.

T Wave Safety Margin during the Process of ICD Implantation As a Novel Predictor of T Wave Oversensing.

Introduction: T wave oversensing (TWOS) is a major drawback of implantable cardioverter defibrillator (ICD) and data on predictors of TWOS in ICD is limited. We aimed to calculate a novel index of T wave safety margin (TWSM) and assess its potential for evaluating TWOS during the procedure of ICD implantation. Methods and Results: Thirty-two consecutive patients with ICD implantation were enrolled. During each procedure of ICD implantation, different ICD generators were connected to implanted sensing lead through active-fixation leads and bridging cables. R and T wave amplitudes were measured on ICD printouts according to the gain. The ICDs were programed to the most sensitive settings to reveal possible TWOS. A novel index TWSM was calculated according to the corresponding sensing algorithm of ICD. There was discrepancy of R wave amplitudes measured by different ICDs (P < 0.01). In Fortify and Teligen ICDs, T wave amplitudes showed no difference (P > 0.05) and TWSMs were sufficiently high (post sensing: 13.0 ± 7.6 and 28.3 ± 16.5, respectively, post pacing: 5.0 ± 2.2 and 4.6 ± 0.9, respectively). In nine patients with 10 TWOS episodes detected during the procedure of ICD implantation, generators with the highest TWSM were chosen. Only one TWOS episode during pacing was recorded during the 25 ± 7 mo follow-up period. Conclusions: We first propose the index of TWSM during ICD implantation as a potentially efficient predictor for TWOS. Evaluation of TWSM might help to reduce TWOS episodes in patients with high risk of TWOS. Prospective studies are warranted to validate this index and its potential to reduce TWOS episodes.

The effects of high-frequency rTMS over the left DLPFC on cognitive control in young healthy participants.

A large body of evidence suggests that repetitive transcranial magnetic stimulation (rTMS) is clinically effective in treating neuropsychiatric disorders and multiple sessions are commonly used. However, it is unknown whether multiple sessions of rTMS improve cognitive control, which is a function of the neural circuitry of the left dorsolateral prefrontal cortex (DLPFC)-cingulate cortex in healthy individuals. In addition, it is still unclear which stages of neural processing are altered by rTMS. In this study, we investigated the effects of high-frequency rTMS on cognitive control and explored the time course changes of cognitive processing after rTMS using event-related potentials (ERPs). For seven consecutive days, 25 young healthy participants underwent one 10-Hz rTMS session per day in which stimulation was applied over the left DLPFC, and a homogeneous participant group of 25 individuals received a sham rTMS treatment. A Stroop task was performed, and an electroencephalogram (EEG) was recorded. The results revealed that multiple sessions of rTMS can decrease reaction time (RTs) under both congruent and incongruent conditions and also increased the amplitudes of both N2 and N450 compared with sham rTMS. The negative correlations between the mean amplitudes of both N2 and N450 and the RTs were found, however, the latter correlation were restricted to incongruent trials and the correlation was enhanced significantly by rTMS. This observation supports the view that high-frequency rTMS over the left DLPFC can not only recruit more neural resources from the prefrontal cortex by inducing an electrophysiologically excitatory effect but also enhance efficiency of resources to deploy for conflict resolution during multiple stages of cognitive control processing in healthy young people.

BMPR1B mutation causes Pierre Robin sequence.

BACKGROUND: We investigated a large family with Pierre Robin sequence (PRS). AIM OF THE STUDY: This study aims to determine the genetic cause of PRS. RESULTS: The reciprocal translocation t(4;6)(q22;p21) was identified to be segregated with PRS in a three-generation family. Whole-genome sequencing and Sanger sequencing successfully detected breakpoints in the intragenic regions of BMRP1B and GRM4. We hypothesized that PRS in this family was caused by (i) haploinsufficiency for BMPR1B or (ii) a gain of function mechanism mediated by the BMPR1B-GRM4 fusion gene. In an unrelated family, we identified another BMPR1B-splicing mutation that co-segregated with PRS. CONCLUSION: We detected two BMPR1B mutations in two unrelated PRS families, suggesting that BMPR1B disruption is probably a cause of human PRS. METHODS: GTG banding, comparative genomic hybridization, whole-genome sequencing, and Sanger sequencing were performed to identify the gene causing PRS.

The Phenotypic Spectrum of a Mutation Hotspot Responsible for the Short QT Syndrome.

OBJECTIVES: This study sought to evaluate the phenotypic and functional expression of an apparent hotspot mutation associated with short QT syndrome (SQTS). BACKGROUND: SQTS is a rare channelopathy associated with a high risk of life-threatening arrhythmias and sudden cardiac death (SCD). METHODS: Probands diagnosed with SQTS and their family members were evaluated clinically and genetically. KCNH2 wild-type (WT) and mutant genes were transiently expressed in HEK293 cells, and currents were recorded using whole-cell patch clamp and action potential (AP) clamp techniques. RESULTS: KCNH2-T618I was identified in 18 members of 7 unrelated families (10 men; median age: 24.0 years). All carriers showed 100% penetrance with variable expressivity. Eighteen members in 7 families had SCD. The average QTc intervals of probands and all carriers was 294.1 ± 23.8 ms and 313.2 ± 23.8 ms, respectively. Seven carriers received an implantable cardioverter-defibrillator. Quinidine with adequate plasma levels was effective in prolonging QTc intervals among 5 cases, but 3 cases still had premature ventricular contraction or nonsustained ventricular tachycardia. Bepridil successfully prevented drug-refractory ventricular fibrillation in 1 case with 19-ms prolongation of the QTc interval. Functional studies with KCNE2 revealed a significant increase of IKr (rapidly activating delayed rectifier potassium channel) tail-current density in homozygous (119.0%) and heterozygous (74.6%) expression compared with WT. AP clamp recordings showed IKr was larger, and peak repolarizing current occurred earlier in mutant versus WT channels. CONCLUSIONS: We reported the clinical characteristics and biophysical properties of the highly frequent mutation that contributes to genetically identified SQTS probands. These findings extend our understanding of the spectrum of KCNH2 channel defects in SQTS.