Detection of a novel pathogenic variant in KCNH2 associated with long QT syndrome 2 using whole exome sequencing.

BACKGROUND: Long QT syndrome (LQTS) is a cardiac channelopathy characterized by impaired myocardial repolarization that predisposes to life-threatening arrhythmias. This study aimed to elucidate the genetic basis of LQTS in an affected Iranian family using whole exome sequencing (WES). METHODS: A 37-year-old woman with a personal and family history of sudden cardiac arrest and LQTS was referred for genetic study after losing her teenage daughter due to sudden cardiac death (SCD). WES was performed and variants were filtered and prioritized based on quality, allele frequency, pathogenicity predictions, and conservation scores. Sanger sequencing confirmed segregation in the family. RESULTS: WES identified a novel heterozygous frameshift variant (NM_000238.4:c.3257_3258insG; pGly1087Trpfs*32) in the KCNH2 encoding the α-subunit of the rapid delayed rectifier potassium channel responsible for cardiac repolarization. This variant, predicted to cause a truncated protein, is located in the C-terminal region of the channel and was classified as likely pathogenic based on ACMG guidelines. The variant was absent in population databases and unaffected family members. CONCLUSION: This study reports a novel KCNH2 frameshift variant in an Iranian family with LQTS, expanding the spectrum of disease-causing variants in this gene. Our findings highlight the importance of the C-terminal region in KCNH2 for proper channel function and the utility of WES in identifying rare variants in genetically heterogeneous disorders like LQTS. Functional characterization of this variant is warranted to fully elucidate its pathogenic mechanisms and inform personalized management strategies.

Whole-exome sequencing revealed a likely pathogenic variant in NF1 causing neurofibromatosis type I and Arrhythmogenic Cardiomyopathy.

BACKGROUND: Neurofibromatosis type I (NF1) is a genetic disorder characterized by the tumor's development in nerve tissue. Complications of NF1 can include pigmented lesions, skin neurofibromas, and heart problems such as cardiomyopathy. In this study, we performed whole-exome sequencing (WES) on an Iranian patient with NF1 to identify the genetic cause of the disease. METHODS: Following clinical assessment, WES was used to identify genetic variants in a family with a son suffering from NF1. No symptomatic manifestations were observed in other family members. In the studied family, in silico and segregation analysis were applied to survey candidate variants. RESULTS: Clinical manifestations were consistent with arrhythmogenic cardiomyopathy (ACM). WES detected a likely pathogenic heterozygous missense variant, c.3277G > A:p.Val1093Met, in the NF1 gene, confirmed by PCR and Sanger sequencing. The patient's parents and brother had a normal sequence at this locus. CONCLUSIONS: Although there is no cure for NF1, genetic tests, such as WES, can detect at-risk asymptomatic family members. Furthermore, cardiac evaluation could also help these patients before heart disease development.

A novel homozygous variant (c.5876T > C: p. Leu1959Pro) in DYSF segregates with limb-girdle muscular dystrophy: a case report.

BACKGROUND: Limb girdle muscular dystrophies (LGMDs) constitute a heterogeneous group of neuromuscular disorders with a very variable clinical presentation and overlapping traits. The clinical symptoms of LGMD typically appear in adolescence or early adulthood. Genetic variation in the dysferlin gene (DYSF) has been associated with LGMD. METHODS: We characterized a recessive LGMD in a young adult from consanguineous Irani families using whole-exome sequencing (WES) technology. Sanger sequencing was performed to verify the identified variant. Computational modeling and protein-protein docking were used to investigate the impact of the variant on the structure and function of the DYSF protein. RESULTS: By WES, we identified a novel homozygous missense variant in DYSF (NM_003494.4: c.5876T > C: p. Leu1959Pro) previously been associated with LGMD phenotypes. CONCLUSIONS: The identification and validation of new pathogenic DYSF variant in the present study further highlight the importance of this gene in LGMD.

Exploring TTN variants as genetic insights into cardiomyopathy pathogenesis and potential emerging clues to molecular mechanisms in cardiomyopathies.

The giant protein titin (TTN) is a sarcomeric protein that forms the myofibrillar backbone for the components of the contractile machinery which plays a crucial role in muscle disorders and cardiomyopathies. Diagnosing TTN pathogenic variants has important implications for patient management and genetic counseling. Genetic testing for TTN variants can help identify individuals at risk for developing cardiomyopathies, allowing for early intervention and personalized treatment strategies. Furthermore, identifying TTN variants can inform prognosis and guide therapeutic decisions. Deciphering the intricate genotype-phenotype correlations between TTN variants and their pathologic traits in cardiomyopathies is imperative for gene-based diagnosis, risk assessment, and personalized clinical management. With the increasing use of next-generation sequencing (NGS), a high number of variants in the TTN gene have been detected in patients with cardiomyopathies. However, not all TTN variants detected in cardiomyopathy cohorts can be assumed to be disease-causing. The interpretation of TTN variants remains challenging due to high background population variation. This narrative review aimed to comprehensively summarize current evidence on TTN variants identified in published cardiomyopathy studies and determine which specific variants are likely pathogenic contributors to cardiomyopathy development.

A novel likely pathogenic homozygous RBCK1 variant in dilated cardiomyopathy with muscle weakness.

AIMS: Polyglucosan body myopathy 1 (PGBM1) is a type of glycogen storage disease where polyglucosan accumulation leads to cardiomyopathy and skeletal muscle myopathy. Variants of RBCK1 is related with PGBM1. We present a newly discovered pathogenic RBCK1 variant resulting in dilated cardiomyopathy (DCM) and a comprehensive literature review. METHODS AND RESULTS: Whole-exome sequencing (WES) was utilized to detect genetic variations in a 7-year-old girl considered the proband. Sanger sequencing was performed to validate the variant in the patient and all the available family members, whether affected or unaffected. The variant's pathogenicity was assessed by conducting a cosegregation analysis within the family with in silico predictive software. WES showed that the proband's RBCK1 gene contained a missense likely pathogenic homozygous nucleotide variant, c.598_599insT: p.His200LeufsTer14 (NM_001323956.1), in exon 8. The computational analysis supported the variant's pathogenicity. The variant was identified in a heterozygous form among all the healthy members of the family. Variants with changes in N-terminal part of the protein were more likely to manifest immunodeficiency and auto-inflammation than those with C-terminal protein modifications according to prior variations of RBCK1 reported in the literature. CONCLUSIONS: Our study offers novel findings indicating an RBCK1 variant in individuals of Iranian ancestry presenting with DCM leading to heart transplantation and myopathy without immunodeficiency or auto-inflammation.

A novel pathogenic variant in the carnitine transporter gene, SLC22A5, in association with metabolic carnitine deficiency and cardiomyopathy features.

BACKGROUND: Primary carnitine deficiency (PCD) denotes low carnitine levels with an autosomal recessive pattern of inheritance. Cardiomyopathy is the most common cardiac symptom in patients with PCD, and early diagnosis can prevent complications. Next-generation sequencing can identify genetic variants attributable to PCD efficiently. OBJECTIVE: We aimed to detect the genetic cause of the early manifestations of hypertrophic cardiomyopathy and metabolic abnormalities in an Iranian family. METHODS: We herein describe an 8-year-old boy with symptoms of weakness and lethargy diagnosed with PCD through clinical evaluations, lab tests, echocardiography, and cardiac magnetic resonance imaging. The candidate variant was confirmed through whole-exome sequencing, polymerase chain reaction, and direct Sanger sequencing. The binding efficacy of normal and mutant protein-ligand complexes were evaluated via structural modeling and docking studies. RESULTS: Clinical evaluations, echocardiography, and cardiac magnetic resonance imaging findings revealed hypertrophic cardiomyopathy as a clinical presentation of PCD. Whole-exome sequencing identified a new homozygous variant, SLC22A5 (NM_003060.4), c.821G > A: p.Trp274Ter, associated with carnitine transport. Docking analysis highlighted the impact of the variant on carnitine transport, further indicating its potential role in PCD development. CONCLUSIONS: The c.821G > A: p.Trp274Ter variant in SLC22A5 potentially acted as a pathogenic factor by reducing the binding affinity of organic carnitine transporter type 2 proteins for carnitine. So, the c.821G > A variant may be associated with carnitine deficiency, metabolic abnormalities, and cardiomyopathic characteristics.

Whole-exome sequencing reveals a likely pathogenic LMNA variant causing hypertrophic cardiomyopathy.

OBJECTIVE: We studied the clinical and molecular features of a family with hypertrophic cardiomyopathy (HCM). BACKGROUND: A very heterogeneous disease affecting the heart muscle, HCM is mostly caused by variants in the proteins of sarcomeres. The detection of HCM pathogenic variants can affect the handling of patients and their families. METHODS: Whole-exome sequencing (WES) was performed to assess the genetic cause(s) of HCM in a consanguineous Iranian family. RESULTS: Missense likely pathogenic variant c.1279C>T (p.Arg427Cys) within exon 7 of the LMNA gene (NM_170707) was found. The segregations were confirmed by polymerase chain reaction-based Sanger sequencing. CONCLUSIONS: Variant c.1279C>T (p.Arg427Cys) in the LMNA gene seemed to have been the cause of HCM in the family. A few LMNA gene variants related to HCM phenotypes have been recognized so far. Identifying HCM genetic basis confers significant opportunities to understand how the disease can develop and, by extension, how this progression can be arrested. Our study supports WES effectiveness for first-tier variant screening of HCM in a clinical setting.

Catecholaminergic polymorphic ventricular tachycardia (and seizure) caused by a novel homozygous likely pathogenic variant in CASQ2 gene.

BACKGROUND: Although structural heart disease is frequently present among patients who experience sudden cardiac death (SCD), inherited arrhythmia syndromes can also play an important role in the occurrence of SCD. CPVT2, which is the second-most prevalent form of CPVT, arises from an abnormality in the CASQ2 gene. OBJECTIVE: We represent a novel CASQ2 variant that causes CPVT2 and conduct a comprehensive review on this topic. METHODS: The proband underwent Whole-exome sequencing (WES) in order to ascertain the etiology of CPVT. Subsequently, the process of segregating the available family members was carried out through the utilization of PCR and Sanger Sequencing. We searched the google scholar and PubMed/Medline for studies reporting CASQ2 variants, published up to May 10,2023. We used the following mesh term "Calsequestrin" and using free-text method with terms including "CASQ2","CASQ2 variants", and "CASQ2 mutation". RESULTS: The CASQ2 gene was found to contain an autosomal recessive nonsense variant c.268_269insTA:p.Gly90ValfsTer4, which was identified by WES. This variant was determined to be the most probable cause of CPVT in the pedigree under investigation. CONCLUSION: CASQ2 variants play an important role in pathogenesis of CPVT2. Notabely, based on results of our study and other findings in the literature the variant in this gene may cause an neurological signs in the patients with CPVT2. Further studies are needed for more details about the role of this gene in CPVT evaluation, diagnosis, and gene therapy.

Genetic Variations in the Human Angiotensin-ConvertingEnzyme 2 and Susceptibility to Coronavirus Disease-19.

Background: Health and economies are both affected by the coronavirus disease-19 (COVID-19) global pandemic. Angiotensin-converting enzyme 2 (ACE2) is a polymorphic enzyme that is a part of the renin-angiotensin system, and it plays a crucial role in viral entry. Previous investigations and studies revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and ACE2 have a considerable association. Recently, ACE2 variants have been described in human populations in association with cardiovascular and pulmonary conditions. In this study, genetic susceptibility to COVID-19 in different populations was investigated. Methods and Results: We evaluated the identified variants based on the predictive performance of 5 deleteriousness-scoring methods and the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. The results indicated 299 variants within the ACE2 gene. The variants were analyzed by different in-silico analysis tools to assess their functional effects. Ultimately, 5 more deleterious variants were found in the ACE2 gene. Conclusions: Collecting more information about the variations in binding affinity between SARS-CoV-2 and host-cell receptors due to ACE2 variants leads to progress in treatment strategies for COVID-19. The evidence accumulated in this study showed that ACE2 variants in different populations may be associated with the genetic susceptibility, symptoms, and outcome of SARS-CoV-2 infection.

Novel pathogenic variant in MED12 causing non-syndromic dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of sudden cardiac death and heart failure. Up to 50% of all DCM cases have a genetic background, with variants in over 250 genes reported in association with DCM. Whole-exome sequencing (WES) is a powerful tool to identify variants underlying genetic cardiomyopathies. Via WES, we sought to identify DCM causes in a family with 2 affected patients. METHODS: WES was performed on the affected members of an Iranian family to identify the genetic etiology of DCM. The candidate variant was segregated via polymerase chain reaction and Sanger sequencing. Computational modeling and protein-protein docking were performed to survey the impact of the variant on the structure and function of the protein. RESULTS: A novel single-nucleotide substitution (G > A) in exon 9 of MED12, c.1249G > A: p.Val417Ile, NM_005120.3, was identified. The c.1249G > A variant was validated in the family. Bioinformatic analysis and computational modeling confirmed that c.1249G > A was the pathogenic variant responsible for the DCM phenotype. CONCLUSION: We detected a novel DCM-causing variant in MED12 using WES. The variant in MED12 may decrease binding to cyclin-dependent kinase 8 (CDK8), affect its activation, and cause alterations in calcium-handling gene expression in the heart, leading to DCM.

Whole-exome sequencing uncovers a novel EFEMP2 gene variant (c.C247T) associated with dominant nonsyndromic thoracic aortic aneurysm.

BACKGROUND: Thoracic aortic aneurysm (TAA) is a multifactorial disorder. Familial TAA, which is more clinically aggressive, is associated with a high risk of lethal dissection or rupture. Genetic evaluation can provide TAA patients with personalized treatment and help in predicting risk to family members. OBJECTIVE: The purpose of this investigation was to report a likely pathogenic variant in the EFEMP2 gene that may contribute to TAA in a family with a documented history of the condition. METHODS: In the index patient, the causative genetic predisposition was identified using whole-exome sequencing. The potential likely pathogenic effect of the candidate variant was further analyzed through bioinformatics analysis, homology modeling, and molecular docking. RESULTS: The results revealed a likely pathogenic heterozygous variant, c.247C>T p.Arg83Cys, in exon 4 of the EFEMP2 gene (NM_016938), which was predicted to have disease-causing effects by MutationTaster, PROVEAN, SIFT, and CADD (phred score = 27.6). CONCLUSION: In this study, a likely pathogenic variant in the EFEMP2 gene was identified in an Iranian family with a dominant pattern of autosomal inheritance of TAA. This finding underscores the importance of conducting molecular genetic evaluations in families with nonsyndromic TAA and the significance of early detection of at-risk family members.

Polymorphism of rs599839 in the PSRC1 gene is associated with coronary artery disease in an Iranian population.

Introduction: Coronary artery disease (CAD) is the leading health complication worldwide because of its high prevalence and mortality. The association between CAD susceptibility and the rs599839 (C/T) polymorphism in the human proline and serine-rich coiled-coil (PSRC1) was reported in a genome-wide association study. To validate this association, we performed this case-control study to genotype the 1p13.3 (rs599839) locus in a sample of the Iranian population with CAD (stenosis≥70% in≥1 coronary artery). Methods: We performed an association analysis with PCR and Sanger sequencing of rs599839 (C/T) polymorphism and CAD risk in 280 CAD patients and 287 healthy controls defined as a coronary calcium score of zero and no noncalcified plaques in coronary computed tomography angiography. SPSS, version 16.0, was applied for statistical analysis. Results: The rs599839 (C/T) locus showed a significant association with CAD (P value<0.001). TT and CT genotypes were associated with CAD (P value<0.001). Furthermore, the dominant status (TT+CT vs. CC) was associated with an increased risk of CAD (OR, 9.14; 95% CI, 3.77 to 22.15; and P value<0.001). Conclusion: The study findings indicate strong evidence for rs599839 (C/T) association with CAD risk.

Comparison of Machine Learning Algorithms Using Manual/Automated Features on 12-Lead Signal Electrocardiogram Classification: A Large Cohort Study on Students Aged Between 6 to 18 Years Old.

PROPOSE: An electrocardiogram (ECG) has been extensively used to detect rhythm disturbances. We sought to determine the accuracy of different machine learning in distinguishing abnormal ECGs from normal ones in children who were examined using a resting 12-Lead ECG machine, and we also compared the manual and automated measurement using the modular ECG Analysis System (MEANS) algorithm of ECG features. METHODS: Altogether, 10745 ECGs were recorded for students aged 6 to 18. Manual and automatic ECG features were extracted for each participant. Features were normalized using Z-score normalization and went through the student's t-test and chi-squared test to measure their relevance. We applied the Boruta algorithm for feature selection and then implemented eight classifier algorithms. The dataset was split into training (80%) and test (20%) partitions. The performance of the classifiers was evaluated on the test data (unseen data) by 1000 bootstrap, and sensitivity (SEN), specificity (SPE), AUC, and accuracy (ACC) were reported. RESULTS: In univariate analysis, the highest performance was heart rate and RR interval in the manual dataset and heart rate in an automated dataset with AUC of 0.72 and 0.71, respectively. The best classifiers in the manual dataset were random forest (RF) and quadratic-discriminant-analysis (QDA) with AUC, ACC, SEN, and SPE equal to 0.93, 0.98, 0.69, 0.99, and 0.90, 0.95, 0.75, 0.96, respectively. In the automated dataset, QDA (AUC: 0.89, ACC:0.92, SEN:0.71, SPE:0.93) and stack learning (SL) (AUC:0.89, ACC:0.96, SEN:0.61, SPE:0.99) reached best performances. CONCLUSION: This study demonstrated that the manual measurement of 12-Lead ECG features had better performance than the automated measurement (MEANS algorithm), but some classifiers had promising results in discriminating between normal and abnormal cases. Further studies can help us evaluate the applicability and efficacy of machine-learning approaches for distinguishing abnormal ECGs in community-based investigations in both adults and children.

Arrhythmogenic left ventricular cardiomyopathy caused by a novel likely pathogenic DSP mutation, p.K1165Rfs*8, in a family with sudden cardiac death.

OBJECTIVE: We conducted an investigation into the clinical and molecular characteristics of Arrhythmogenic left ventricular cardiomyopathy (ALVC) caused by a novel likely pathogenic mutation in an Iranian pedigree with sudden cardiac death (SCD). BACKGROUND: ALVC is a genetically inherited myocardial disease characterized by the substitution of fibro-fatty tissue in the left ventricular myocardium, predominantly inherited in an autosomal dominant pattern and is commonly associated with genes involved in encoding desmosomal proteins, specifically Desmoplakin (DSP). METHODS: The patient and available family members underwent a comprehensive clinical assessment, including Cardiac magnetic resonance (CMR) imaging, along with Whole-exome sequencing (WES). The identified variant was confirmed and segregated by Polymerase chain reaction (PCR) and Sanger sequencing in the family members. RESULTS: A novel likely pathogenic heterozygous variant, DSP (NM_004415.4), c.3492_3498del, p.K1165Rfs*8 was discovered in the proband. This variant is likely to be the primary reason for ALVC in this specific family. This variant was confirmed by Sanger sequencing and segregated in other affected members of the family. CONCLUSION: We identified a novel likely pathogenic variant in the DSP gene, which has been identified as the cause of ALVC in an Iranian family. Our investigation underscores the importance of genetic testing, specifically WES, for individuals suspected of ALVC and have a family history of SCD.

A novel heterozygous missense MYH7 mutation potentially causes an autosomal dominant form of myosin storage myopathy with dilated cardiomyopathy.

BACKGROUND: The MYH7 gene, which encodes the slow/ß-cardiac myosin heavy chain, is mutated in myosin storage myopathy (MSM). The clinical spectrum of MSM is quite heterogeneous in that it ranges from cardiomyopathies to skeletal myopathies or a combination of both, depending on the affected region. In this study, we performed clinical and molecular examinations of the proband of an Iranian family with MSM in an autosomal dominant condition exhibiting proximal muscle weakness and dilated cardiomyopathy. METHODS: Following thorough clinical and paraclinical examinations, whole-exome sequencing `was performed on the proband (II-5). Pathogenicity prediction of the candidate variant was performed through in-silico analysis. Co-segregation analysis of the WES data among the family members was carried out by PCR-based Sanger sequencing. RESULTS: A novel heterozygous missense variant, MYH7 (NM_000257): c.C1888A: p.Pro630Thr, was found in the DNA of the proband and his children and confirmed by Sanger sequencing. The in-silico analysis revealed that p.Pro630Thr substitution was deleterious. The novel sequence variant fell within a highly conserved region of the head domain. Our findings expand the spectrum of MYH7 mutations. CONCLUSIONS: This finding could improve genetic counseling and prenatal diagnosis in families with clinical manifestations associated with MYH7-related myopathy.

Prediction of Parkinson's disease pathogenic variants using hybrid Machine learning systems and radiomic features.

PURPOSE: In Parkinson's disease (PD), 5-10% of cases are of genetic origin with mutations identified in several genes such as leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA). We aim to predict these two gene mutations using hybrid machine learning systems (HMLS), via imaging and non-imaging data, with the long-term goal to predict conversion to active disease. METHODS: We studied 264 and 129 patients with known LRRK2 and GBA mutations status from PPMI database. Each dataset includes 513 features such as clinical features (CFs), conventional imaging features (CIFs) and radiomic features (RFs) extracted from DAT-SPECT images. Features, normalized by Z-score, were univariately analyzed for statistical significance by the t-test and chi-square test, adjusted by Benjamini-Hochberg correction. Multiple HMLSs, including 11 features extraction (FEA) or 10 features selection algorithms (FSA) linked with 21 classifiers were utilized. We also employed Ensemble Voting (EV) to classify the genes. RESULTS: For prediction of LRRK2 mutation status, a number of HMLSs resulted in accuracies of 0.98 ± 0.02 and 1.00 in 5-fold cross-validation (80% out of total data points) and external testing (remaining 20%), respectively. For predicting GBA mutation status, multiple HMLSs resulted in high accuracies of 0.90 ± 0.08 and 0.96 in 5-fold cross-validation and external testing, respectively. We additionally showed that SPECT-based RFs added value to the specific prediction of of GBA mutation status. CONCLUSION: We demonstrated that combining medical information with SPECT-based imaging features, and optimal utilization of HMLS can produce excellent prediction of the mutations status in PD patients.

Identification of a novel pathogenic variant in KCNH2 in an Iranian family with long QT syndrome 2 by whole-exome sequencing.

Background: Long QT syndrome (LQTS) is a lethal cardiac condition. However, the clinical implementation of genetic testing has now made LQTS eminently treatable. Next-generation sequencing has remarkable potential for both clinical diagnostics and research of LQTS. Here, we investigated the genetic etiology in an LQTS-suspected Iranian pedigree by whole-exome sequencing and collected all KCNH2 variants with consensus based on publications. Methods: WES was performed on the proband of this pedigree to reveal the underlying cause of sudden cardiac death (SCD). The variant found was validated and segregated by polymerase chain reaction and Sanger sequencing. Based on the literature review, KCNH2 variants were retrospectively analyzed to identify pathogenic variants, likely pathogenic variants, and variants of uncertain significance by using different prediction tools. Results: WES identified an autosomal dominant nonsense variant, c.1425C>A: p.Tyr475Ter, in the KCNH2 gene, which appeared to be the most likely cause of LQTS in this pedigree. Moreover, our comprehensive literature review yielded 511 KCNH2 variants in association with the LQTS phenotype, with c.3002G>A (CADD Phred=49) being the most pathogenic variant. Conclusions: Variants in the KCNH2 gene are considered a major cause of LQTS worldwide. The detected c.1425C>A is a novel variant to be reported from Iran for the first time. This result indicates the importance of KCNH2 screening in a pedigree with SCD cases.

Role of non-coding variants in cardiovascular disease.

Cardiovascular diseases (CVDs) constitute one of the significant causes of death worldwide. Different pathological states are linked to CVDs, which despite interventions and treatments, still have poor prognoses. The genetic component, as a beneficial tool in the risk stratification of CVD development, plays a role in the pathogenesis of this group of diseases. The emergence of genome-wide association studies (GWAS) have led to the identification of non-coding parts associated with cardiovascular traits and disorders. Variants located in functional non-coding regions, including promoters/enhancers, introns, miRNAs and 5'/3' UTRs, account for 90% of all identified single-nucleotide polymorphisms associated with CVDs. Here, for the first time, we conducted a comprehensive review on the reported non-coding variants for different CVDs, including hypercholesterolemia, cardiomyopathies, congenital heart diseases, thoracic aortic aneurysms/dissections and coronary artery diseases. Additionally, we present the most commonly reported genes involved in each CVD. In total, 1469 non-coding variants constitute most reports on familial hypercholesterolemia, hypertrophic cardiomyopathy and dilated cardiomyopathy. The application and identification of non-coding variants are beneficial for the genetic diagnosis and better therapeutic management of CVDs.

Development of a patients' satisfaction analysis system using machine learning and lexicon-based methods.

BACKGROUND: Patients' rights are integral to medical ethics. This study aimed to perform sentiment analysis and opinion mining on patients' messages by a combination of lexicon-based and machine learning methods to identify positive or negative comments and to determine the different ward and staff names mentioned in patients' messages. METHODS: The level of satisfaction and observance of the rights of 250 service recipients of the hospital was evaluated through the related checklists by the evaluator. In total, 822 Persian messages, composed of 540 negative and 282 positive comments, were collected and labeled by the evaluator. Pre-processing was performed on the messages and followed by 2 feature vectors which were extracted from the messages, including the term frequency-inverse document frequency (TFIDF) vector and a combination of the multifeature (MF) (a lexicon-based method) and TFIDF (MF + TFIDF) vectors. Six feature selectors and 5 classifiers were used in this study. For the evaluations, 5-fold cross-validation with different metrics including area under the receiver operating characteristic curve (AUC), accuracy (ACC), F1 score, sensitivity (SEN), specificity (SPE) and Precision-Recall Curves (PRC) were reported. Message tag detection, which featured different hospital wards and identified staff names mentioned in the study patients' messages, was implemented by the lexicon-based method. RESULTS: The best classifier was Multinomial Naïve Bayes in combination with MF + TFIDF feature vector and SelectFromModel (SFM) feature selection (ACC = 0.89 ± 0.03, AUC = 0.87 ± 0.03, F1 = 0.92 ± 0.03, SEN = 0.93 ± 0.04, and SPE = 0.82 ± 0.02, PRC-AUC = 0.97). Two methods of assessment by the evaluator and artificial intelligence as well as survey systems were compared. CONCLUSION: Our results demonstrated that the lexicon-based method, in combination with machine learning classifiers, could extract sentiments in patients' comments and classify them into positive and negative categories. We also developed an online survey system to analyze patients' satisfaction in different wards and to remove conventional assessments by the evaluator.

A novel stop-gain pathogenic variant in the KCNQ1 gene causing long QT syndrome 1.

BACKGROUND: Inherited primary arrhythmias, such as long QT (LQT) syndromes, are electrical abnormalities of the heart mainly due to variants in 3 genes. We herein describe a novel stop-gain pathogenic variant in the KCNQ1 gene in an Iranian child with LQT syndrome 1. METHODS: The patient and his family underwent clinical evaluation, electrocardiographic Holter monitoring, and whole-exome sequencing. Sanger sequencing and segregation analysis were used to confirm the variant in the patient and his family, respectively. The pathogenicity of the variant was checked via an in silico analysis. RESULTS: The proband suffered from bradycardia and had experienced syncope without stress. The corrected QT interval was 470 ms (the Schwartz score ≥ 3.5), and the Holter monitoring showed sinus rhythm, infrequent premature atrial contractions, and a prolonged QT interval in some leads. Whole-exome and Sanger sequencing showed c.968G > A in 3 affected family members. According to the American College of Medical Genetics and Genomics criteria, c.968G > A was classified as a pathogenic variant. CONCLUSIONS: The KCNQ1 gene is the main cause of LQT syndromes in our population. The common genes of LQT syndromes should be studied in our country's different ethnicities to determine the exact role of these genes in these subpopulations.