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Long QT Syndrome (LQTS) is a rare, inherited channelopathy characterized by cardiac repolarization dysfunction, leading to a prolonged rate-corrected QT interval in patients who are at risk for malignant ventricular tachyarrhythmias, syncope, and even sudden cardiac death. A complex genetic origin, variable expressivity as well as incomplete penetrance make the diagnosis a clinical challenge. In the last 10 years, there has been a continuous improvement in diagnostic and personalized treatment options. Therefore, several factors such as sex, age diagnosis, QTc interval, and genetic background may contribute to risk stratification of patients, but it still currently remains as a main challenge in LQTS. It is widely accepted that sex is a risk factor itself for some arrhythmias. Female sex has been suggested as a risk factor in the development of malignant arrhythmias associated with LQTS. The existing differences between the sexes are only manifested after puberty, being the hormones the main inducers of arrhythmias. Despite the increased risk in females, no more than 10% of the available publications on LQTS include sex-related data concerning the risk of malignant arrhythmias in females. Therein, the relevance of our review data update concerning women and LQTS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Díez-Escuté, Arbelo, Martinez Barrios, Cerralbo, Cesar, Cruzalegui, Chipa, Fiol, Zschaeck, Hernández, Campuzano and Sarquella-Brugada.)

Background: Laminopathies are caused by rare alterations in LMNA , leading to a wide clinical spectrum. Though muscular dystrophy begins at early ages, disease progression is different in each patient. We investigated variability in laminopathy phenotypes by performing a targeted genetic analysis of patients diagnosed with LMNA -related muscular dystrophy to identify rare variants in alternative genes, thereby explaining phenotypic differences. Methods: We analyzed 105 genes associated with muscular diseases by targeted sequencing in 26 pediatric patients of different countries, diagnosed with any LMNA -related muscular dystrophy. Family members were also clinically assessed and genetically analyzed. Results: All patients carried a pathogenic rare variant in LMNA . Clinical diagnoses included Emery-Dreifuss muscular dystrophy (EDMD, 13 patients), LMNA -related congenital muscular dystrophy (L-CMD, 11 patients), and limb-girdle muscular dystrophy 1B (LGMD1B, 2 patients). In 9 patients, 10 additional rare genetic variants were identified in 8 genes other than LMNA . Genotype-phenotype correlation showed additional deleterious rare variants in five of the nine patients (3 L-CMD and 2 EDMD) with severe phenotypes. Conclusion: Analysis f known genes related to muscular diseases in close correlation with personalized clinical assessments may help identify additional rare variants of LMNA potentially associated with early onset or most severe disease progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cesar, Coll, Fiol, Fernandez-Falgueras, Cruzalegui, Iglesias, Moll, Perez-Serra, Martínez-Barrios, Ferrer-Costa, Olmo, Puigmulè, Alcalde, Lopez, Pico, Berrueco, Brugada, Zschaeck, Natera-de Benito, Carrera-García, Exposito-Escudero, Ortez, Nascimento, Brugada, Sarquella-Brugada and Campuzano.)

Introduction: LMNA-related muscular dystrophy is a rare entity that produce "laminopathies" such as Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B (LGMD1B), and LMNA-related congenital muscular dystrophy (L-CMD). Heart failure, malignant arrhythmias, and sudden death may occur. No consensus exists on cardiovascular management in pediatric laminopathies. The aim was to perform an exhaustive cardiologic follow-up in pediatric patients diagnosed with LMNA-related muscular dystrophy. Methods: Baseline cardiac work-up consisted of clinical assessment, transthoracic Doppler echocardiography, 12-lead electrocardiogram, electrophysiological study, and implantation of a long-term implantable cardiac loop recorder (ILR). Results: We enrolled twenty-eight pediatric patients diagnosed with EDMD (13 patients), L-CMD (11 patients), LGMD1B (2 patients), and LMNA-related mild weakness (2 patients). Follow-up showed dilated cardiomyopathy (DCM) in six patients and malignant arrhythmias in five (four concomitant with DCM) detected by the ILR that required implantable cardioverter defibrillator (ICD) implantation. Malignant arrhythmias were detected in 20% of our cohort and early-onset EDMD showed worse cardiac prognosis. Discussion: Patients diagnosed with early-onset EDMD are at higher risk of DCM, while potentially life-threatening arrhythmias without DCM appear earlier in L-CMD patients. Early onset neurologic symptoms could be related with worse cardiac prognosis. Specific clinical guidelines for children are needed to prevent sudden death., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AF declared a shared affiliation with the authors ID, MG, SQR to the handling editor at the time of review., (Copyright © 2023 Cesar, Campuzano, Cruzalegui, Fiol, Moll, Martínez-Barrios, Zschaeck, Natera-de Benito, Ortez, Carrera, Expósito, Berrueco, Bautista-Rodriguez, Dabaj, Gómez García-de-la-Banda, Quijano-Roy, Brugada, Nascimento and Sarquella-Brugada.)

A proper interpretation of the pathogenicity of rare variants is crucial before clinical translation. Ongoing addition of new data may modify previous variant classifications; however, how often a reanalysis is necessary remains undefined. We aimed to extensively reanalyze rare variants associated with inherited channelopathies originally classified 5 years ago and its clinical impact. In 2016, rare variants identified through genetic analysis were classified following the American College of Medical Genetics and Genomics' recommendations. Five years later, we have reclassified the same variants following the same recommendations but including new available data. Potential clinical implications were discussed. Our cohort included 49 cases of inherited channelopathies diagnosed in 2016. Update show that 18.36% of the variants changed classification mainly due to improved global frequency data. Reclassifications mostly occurred in minority genes associated with channelopathies. Similar percentage of variants remain as deleterious nowadays, located in main known genes (SCN5A, KCNH2 and KCNQ1). In 2016, 69.38% of variants were classified as unknown significance, but now, 53.06% of variants are classified as such, remaining the most common group. No management was modified after translation of genetic data into clinics. After 5 years, nearly 20% of rare variants associated with inherited channelopathies were reclassified. This supports performing periodic reanalyses of no more than 5 years since last classification. Use of newly available data is necessary, especially concerning global frequencies and family segregation. Personalized clinical translation of rare variants can be crucial to management if a significant change in classification is identified., (© 2021. The Author(s).)

Brugada syndrome (BrS) is classified as an inherited cardiac channelopathy attributed to dysfunctional ion channels and/or associated proteins in cardiomyocytes rather than to structural heart alterations. However, hearts of some BrS patients exhibit slight histologic abnormalities, suggesting that BrS could be a phenotypic variant of arrhythmogenic cardiomyopathy. We performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) criteria. Our comprehensive analysis of structural findings did not reveal enough definitive evidence for reclassification of BrS as a cardiomyopathy. The collection and comprehensive analysis of new cases with a definitive BrS diagnosis are needed to clarify whether some of these structural features may have key roles in the pathophysiological pathways associated with malignant arrhythmogenic episodes., Competing Interests: The authors declare no conflict of interest.

Brugada syndrome (BrS) was initially described in 1992 by Josep and Pedro Brugada as an arrhythmogenic disease characterized by ST segment elevation in the right precordial leads and increased risk of sudden cardiac death (SCD). Alterations in the SCN5A gene are responsible for approximately 30% of cases of BrS, following an autosomal dominant pattern of inheritance. However, despite its autosomal transmission, sex-related differences are widely accepted. BrS is more prevalent in males than in females (8-10 times), with males having a 5.5-fold higher risk of SCD. There are also differences in clinical presentation, with females being more frequently asymptomatic and older than males at the time of diagnosis. Some factors have been identified that could explain these differences, among which testosterone seems to play an important role. However, only 30% of the available publications on the syndrome include sex-related information. Therefore, current findings on BrS are based on studies conducted mainly in male population, despite the wide acceptance of gender differences. The inclusion of complete clinical and demographic information in future publications would allow a better understanding of the phenotypic variability of BrS in different age and sex groups helping to improve the diagnosis, management and risk management of SCD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Martínez-Barrios, Arbelo, Cesar, Cruzalegui, Fiol, Díez-Escuté, Hernández, Brugada, Brugada, Campuzano and Sarquella-Brugada.)

The titin gene ( TTN ) is associated with several diseases, including inherited arrhythmias. Most of these diagnoses are attributed to rare TTN variants encoding truncated forms, but missense variants represent a diagnostic challenge for clinical genetics. The proper interpretation of genetic data is critical for translation into the clinical setting. Notably, many TTN variants were classified before 2015, when the American College of Medical Genetics and Genomics (ACMG) published recommendations to accurately classify genetic variants. Our aim was to perform an exhaustive reanalysis of rare missense TTN variants that were classified before 2015, and that have ambiguous roles in inherited arrhythmogenic syndromes. Rare missense TTN variants classified before 2015 were updated following the ACMG recommendations and according to all the currently available data. Our cohort included 193 individuals definitively diagnosed with an inherited arrhythmogenic syndrome before 2015. Our analysis resulted in the reclassification of 36.8% of the missense variants from unknown to benign/likely benign. Of all the remaining variants, currently classified as of unknown significance, 38.3% showed a potential, but not confirmed, deleterious role. Most of these rare missense TTN variants with a suspected deleterious role were identified in patients diagnosed with hypertrophic cardiomyopathy. More than 35% of the rare missense TTN variants previously classified as ambiguous were reclassified as not deleterious, mainly because of improved population frequencies. Despite being inconclusive, almost 40% of the variants showed a potentially deleterious role in inherited arrhythmogenic syndromes. Our results highlight the importance of the periodical reclassification of rare missense TTN variants to improve genetic diagnoses and help increase the accuracy of personalized medicine.

Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40-50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype-phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype-phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families.

Introduction: Long QT syndrome is the main arrhythmogenic disease responsible for sudden death in infants, especially in the first days of life. Performing an electrocardiogram in newborns could enable early diagnosis and adoption of therapeutic measures focused on preventing lethal arrhythmogenic events. However, the inclusion of an electrocardiogram in neonatal screening protocols still remains a matter of discussion. To comprehensively analyse the potential clinical value of performing an electrocardiogram and subsequent follow-up in a cohort of newborns. Methods: Electrocardiograms were performed in 685 neonates within the first week of life. One year follow-up was performed if QTc > 450 ms identified. Comprehensive genetic analysis using massive sequencing was performed in all cases with QTc > 470 ms. Results: We identified 54 neonates with QTc > 450 ms/ <470 ms; all normalized QTc values within 6 months. Eight cases had QTc > 480 ms at birth and, if persistent, pharmacological treatment was administrated during follow-up. A rare variant was identified as the potential cause of long QT syndrome in five cases. Three cases showed a family history of sudden arrhythmogenic death. Conclusions: Our prospective study identifies 0.14% of cases with a definite long QT, supporting implementation of electrocardiograms in routine pediatric protocols. It is an effective, simple and non-invasive approach that can help prevent sudden death in neonates and their relatives. Genetic analyses help to unravel the cause of arrhythmogenic disease in diagnosing neonates. Further, clinical assessment and genetic analysis of relatives allowed early identification of family members at risk of arrhythmias helping to adopt preventive personalized measures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sarquella-Brugada, García-Algar, Zambrano, Fernández-Falgueres, Sailer, Cesar, Sebastiani, Martí-Almor, Aurensanz, Cruzalegui, Merchan, Coll, Pérez-Serra, Olmo, Fiol, Iglesias, Ferrer-Costa, Puigmulé, Lopez, Pico, Arbelo, Jordà, Brugada, Brugada and Campuzano.)

Genetic interpretation of rare variants associated with arrhythmogenic cardiomyopathy (ACM) is essential due to their diagnostic implications. New data may relabel previous variant classifications, but how often reanalysis is necessary remains undefined. Five years ago, 39 rare ACM-related variants were identified in patients with features of cardiomyopathy. These variants were classified following the American College of Medical Genetics and Genomics' guidelines. In the present study, we reevaluated these rare variants including novel available data. All cases carried one rare variant classified as being of ambiguous significance (82.05%) or likely pathogenic (17.95%) in 2016. In our comprehensive reanalysis, the classification of 30.77% of these variants changed, mainly due to updated global frequencies. As in 2016, nowadays most variants were classified as having an uncertain role (64.1%), but the proportion of variants with an uncertain role was significantly decreased (17.95%). The percentage of rare variants classified as potentially deleterious increased from 17.95% to 23.07%. Moreover, 83.33% of reclassified variants gained certainty. We propose that periodic genetic reanalysis of all rare variants associated with arrhythmogenic cardiomyopathy should be undertaken at least once every five years. Defining the roles of rare variants may help clinicians obtain a definite diagnosis.

Aim: To perform a comprehensive phenotype-genotype correlation of all rare variants in Triadin leading to malignant arrhythmias in pediatrics. Methods: Triadin knockout syndrome is a rare entity reported in pediatric population. This syndrome is caused by rare variants in the TRDN gene. Malignant ventricular arrhythmias and sudden cardiac death can be a primary manifestation of disease. Although pharmacological measures are effective, some patients require an implantable defibrillator due to high risk of arrhythmogenic episodes. Main Results: Fourteen rare genetic alterations in TRDN have been reported to date. All of these potentially pathogenic alterations are located in a specific area of TRDN , highlighting this hot spot as an arrhythmogenic gene region. Conclusions: Early recognition and comprehensive interpretation of alterations in Triadin are crucial to adopt preventive measures and avoid malignant arrhythmogenic episodes in pediatric population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sarquella-Brugada, Fernandez-Falgueras, Cesar, Arbelo, Jordà, García-Álvarez, Cruzalegui, Merchan, Fiol, Brugada, Brugada and Campuzano.)

Short QT syndrome, one of the most lethal entities associated with sudden cardiac death, is a rare genetic disease characterized by short QT intervals detected by electrocardiogram. Several genetic variants are causally linked to the disease, but there has yet to be a comprehensive analysis of variants among patients with short QT syndrome. To fill this gap, we performed an exhaustive study of variants currently catalogued as deleterious in short QT syndrome according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Analysis of the 32 variants described in the literature determined that only nine (28.12%) have a conclusive pathogenic role. All definitively pathogenic variants are located in KCNQ1 , KCNH2 , or KCNJ2 ; three genes encoding potassium channels. Other variants located in genes encoding calcium or sodium channels are associated with electrical alterations concomitant with shortened QT intervals but do not guarantee a diagnosis of short QT syndrome. We recommend caution regarding previously reported variants classified as pathogenic. An exhaustive re-analysis is necessary to clarify the role of each variant before routinely translating genetic findings to the clinical setting.

Cardiomyopathies are a heterogeneous group of inherited cardiac diseases characterized by progressive myocardium abnormalities associated with mechanical and/or electrical dysfunction. Massive genetic sequencing technologies allow a comprehensive genetic analysis to unravel the cause of disease. However, most identified genetic variants remain of unknown clinical significance due to incomplete penetrance and variable expressivity. Therefore, genetic interpretation of variants and translation into clinical practice remain a current challenge. We performed retrospective comprehensive clinical assessment and genetic analysis in six families, four diagnosed with arrhythmogenic cardiomyopathy, and two diagnosed with hypertrophic cardiomyopathy (HCM). Genetic testing identified three rare variants (two non-sense and one small indel inducing a frameshift), each present in two families. Although each variant is currently classified as pathogenic and the cause of the diagnosed cardiomyopathy, the onset and/or clinical course differed in each patient. New genetic technology allows comprehensive yet cost-effective genetic analysis, although genetic interpretation, and clinical translation of identified variants should be carefully done in each family in a personalized manner.

Background: Sudden death of a newborn is a rare entity, which may be caused by genetic cardiac arrhythmias. Among these diseases, Long QT syndrome is the most prevalent arrhythmia in neonates, but other diseases such as Brugada syndrome, Short QT syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia also cause sudden death in infants. All these entities are characterized by well-known alterations in the electrocardiogram and the first symptom of the disease may be an unexpected death. Despite the low prevalence of these diseases, the performance of an electrocardiogram in the first hours or days after birth could help identify these electrical disruptions and adopt preventive measures. In recent years, there has been an important impulse by some experts in the scientific community towards the initiation of a newborn electrocardiogram-screening program, for the detection of these electrocardiographic abnormalities. In addition, the use of genetic analysis in neonates could identify the cause of these heart alterations. Identification of relatives carrying the genetic alteration associated with the disease allows adoption of measures to prevent lethal episodes., Conclusion: Recent technological advances enable a comprehensive genetic screening of a large number of genes in a cost-effective way. However, the interpretation of genetic data and its translation into clinical practice are the main challenges for cardiologists and geneticists. However, there is important controversy as to the clinical value, and cost-effectiveness of the use of electrocardiogram as well as of genetic testing to detect these cases. Our review focuses on these current matters of argue., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Cervical cancer incidence and mortality rates are significantly higher in low- and middle-income countries compared with the United States and other developed countries. This disparity is caused by decreased access to screening, often coupled with low numbers of trained providers offering cancer prevention and treatment services. However, similar disparities are also found in underserved areas of the United States, such as the Texas-Mexico border, where cervical cancer mortality rates are 30% higher than in the rest of Texas. To address these issues, we have adopted the Project ECHO (Extension for Community Healthcare Outcomes) program, a low-cost telementoring model previously proven to be successful in increasing local capacity, improving patient management skills, and ultimately improving patient outcomes in rural and underserved areas. We use the Project ECHO model to educate local providers in the management of cervical dysplasia in a low-resource region of Texas and have adapted it to inform strategies for the management of advanced cervical and breast cancer in Latin America and sub-Saharan Africa. This innovative approach, using ECHO, is part of a larger strategy to enhance clinical skills and develop collaborative projects between academic centers and partners in low-resource regions., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Melissa S. LopezNo relationship to discloseEllen S. BakerStock or Other Ownership: MerckAndrea M. MilbourneNo relationship to discloseRose M. GowenNo relationship to discloseAna M. RodriguezNo relationship to discloseCesaltina LorenzoniNo relationship to discloseCatherine MwabaResearch Funding: Mylan Zambia (Inst) Travel, Accommodations, Expenses: Fresenius Kabi South AfricaSusan Citonje MsadabweTravel, Accommodations, Expenses: AstraZenecaJosé Humberto TavaresNo relationship to discloseGeorgia Fontes-CintraNo relationship to discloseGustavo Zucca-MatthesNo relationship to discloseDonato Callegaro-FilhoNo relationship to discloseDanielle Ramos-MartinNo relationship to discloseIcaro Thiago de CarvalhoNo relationship to discloseRobson CoelhoNo relationship to discloseRenato Moretti-MarquesNo relationship to discloseThiago ChulamTravel, Accommodations, Expenses: A.C. Camargo Cancer CenterMila Pontremoli-SalcedoNo relationship to discloseFernanda NozarNo relationship to discloseVeronica FiolTravel, Accommodations, Expenses: UrufarmaMauricio MazaNo relationship to discloseSanjeev AroraNo relationship to discloseErnest T. HawkEmployment: MD Anderson Cancer Center Honoraria: National Cancer Institute, Huntsman Cancer Institute, Mayo Clinic Cancer Center, Kansas University Medical Center, Ohio State University Comprehensive Cancer Center, Roswell Park Cancer Institute, Simmons Comprehensive Cancer Center, University of Nebraska Medical Center, University of South Alabama Mitchell Cancer Institute, Johns Hopkins University, Oncology Nursing Society Conference, Weill Cornell Medical College, ASCO, American Association for Cancer Research Consulting or Advisory Role: Cancer Prevention Pharmaceuticals, PLx Pharma, POZEN Research Funding: National Institutes of Health/National Cancer Institute (Inst), the Cancer Prevention Research Institute of Texas (Inst), Cancer Prevention Pharmaceuticals (Inst) Patents, Royalties, Other Intellectual Property: John Wiley & Sons Travel, Accommodations, Expenses: National Cancer Institute, American Association for Cancer Research, Huntsman Cancer Institute, Kansas University Medical Center, Mayo Clinic Cancer Center, Ohio State University Comprehensive Cancer Center, Roswell Park Cancer Institute, Simmons Comprehensive Cancer Center, University of Nebraska Medical Center, Johns Hopkins University, Oncology Nursing Society Conference, Weill Cornell Medical College, ASCO, American Association for Cancer Research, American Cancer Society, Association of American Cancer Institutes—Cancer Center Administrators Forum, Alliance Prevention Committee, First Annual Meta-ECHO MeetingKathleen M. SchmelerResearch Funding: Becton Dickinson Patents, Royalties, Other Intellectual Property: UpToDate