INTRODUCTION AND OBJECTIVES:Left ventricular reverse remodeling (LVRR) is a key therapeutic goal in dilated cardiomyopathy (DCM). However, its genetic predictors and prognostic impact remain uncertain. METHODS:We analyzed genotyped DCM patients with serial echocardiograms from the Spanish DCM study. The main objective was to assess the influence of genotype on LVRR, defined by improvement in ejection fraction within 12± 6 months. Secondary endpoints included major adverse cardiovascular events, end-stage heart failure (HF), and major ventricular arrhythmias. RESULTS:A total of 711 patients were included (67% male, mean age 50.8 years, baseline ejection fraction 31%, 44% genotype positive). LVRR occurred in 39% of genotype-positive vs 47% of genotype-negative patients (P=.036). Independent predictors of LVRR were TTN variants, lower baseline ejection fraction, and HF admission at diagnosis. In contrast, desmosomal, nuclear envelope and motor sarcomeric gene variants were associated with a lower likelihood of LVRR. During a median follow-up of 4.5 years, 26% of patients with initial LVRR showed subsequent deterioration, which was more frequent among genotype-positive individuals (32% vs 22%, P=.054). Compared with patients with sustained LVRR, those with deterioration had worse outcomes, including higher rates of major cardiovascular events (25% vs 7%), end-stage HF (18% vs 1%), and ventricular arrhythmia (12% vs 4%) (all P <.05). CONCLUSIONS:Genotype is a major determinant of both initial and long-term LVRR. Loss of ejection fraction improvement is common and strongly associated with adverse outcomes.

BackgroundPsychotic disorders such as schizophrenia present a significant challenge to health care systems due to their high disability rates and treatment costs. With discontinuation rates for antipsychotics reaching over 40% in the first year and 80% after 3 years, it is crucial to tailor antipsychotic selection and dosing early in treatment. Personalized precision psychiatry, underpinned by pharmacogenetics, holds considerable potential in individualizing antipsychotic treatment for patients with first-episode psychosis. An internationally pioneering method called 5-step precision medicine (5SPM) focuses on the application of pharmacogenetics to clinical practice. The recently launched Prevention and Early Intervention in Mental Health (PRINT) program in Salamanca, Spain, integrates this method to enhance early intervention for adolescents and young people with first-episode psychosis. ObjectiveThe Clinical Utility of Early Intervention Including the 5SPM Method in First-Episode Psychosis (CLUMP) project aims to explore whether an early intervention model of personalized precision psychiatry including pharmacogenetics improves adherence to antipsychotic medicines and, therefore, clinical and functional outcomes in young people experiencing the first episode of a psychotic illness. MethodsTo achieve our objectives, we shall compare adherence to the first prescribed antipsychotic medication and clinical and functional outcomes between patients with first-episode psychosis. We shall compare 2 cohorts: cohort 1 will receive the recently introduced PRINT program including the 5SPM method, and cohort 2 will have received standard care provided by mental health services before the PRINT program implementation. The primary outcome to measure treatment adherence will be all-cause discontinuation proportions during the 1-year follow-up. Secondary outcome measures will include pragmatic efficacy, tolerability, and functional outcome measures. For additional comparative purposes, we shall analyze the environmental, clinical, and pharmacogenetic information of patients with psychotic disorders of more than 5 years of evolution and with other mental disorders whose data are currently stored and have been ethically approved for research use. A total of 300 patients will be included in the study. Analyses will include descriptive statistics, comparison tests, Kaplan-Meier survival curves, multivariate log rank tests, qualitative analysis, and cost-benefit evaluation. ResultsEthics approval was obtained in June 2023. Recruitment for the CLUMP project began in January 2025, and enrollment for cohort 1 will continue until May 2026. All data collection is expected to be completed by June 2027. Data analyses are estimated to take approximately 6 months. The project is scheduled to conclude in December 2027. ConclusionsThe CLUMP project is set to provide the first clear blueprint for implementing and evaluating the impact of personalized precision psychiatry based on pharmacogenetics in the context of early intervention programs for the benefit of young people experiencing the first episode of a severe mental illness such as schizophrenia. International Registered Report Identifier (IRRID)DERR1-10.2196/74408

A novel rare mutation in the pore region of Nav1.5 channels (p.L889V) has been found in three unrelated Spanish families that produces quite diverse phenotypic manifestations (Brugada syndrome, conduction disease, dilated cardiomyopathy, sinus node dysfunction, etc.) with variable penetrance among families. We clinically characterized the carriers and recorded the Na+ current (INa) generated by p.L889V and native (WT) Nav1.5 channels, alone or in combination, to obtain further insight into the genotypic–phenotypic relationships in patients carrying SCN5A mutations and in the molecular determinants of the Nav1.5 channel function. The variant produced a strong dominant negative effect (DNE) since the peak INa generated by p.L889V channels expressed in Chinese hamster ovary cells, either alone (−69.4 ± 9.0 pA/pF) or in combination with WT (−62.2 ± 14.6 pA/pF), was significantly (n ≥ 17, p < 0.05) reduced compared to that generated by WT channels alone (−199.1 ± 44.1 pA/pF). The mutation shifted the voltage dependence of channel activation and inactivation to depolarized potentials, did not modify the density of the late component of INa, slightly decreased the peak window current, accelerated the recovery from fast and slow inactivation, and slowed the induction kinetics of slow inactivation, decreasing the fraction of channels entering this inactivated state. The membrane expression of p.L889V channels was low, and in silico molecular experiments demonstrated profound alterations in the disposition of the pore region of the mutated channels. Despite the mutation producing a marked DNE and reduction in the INa and being located in a critical domain of the channel, its penetrance and expressivity are quite variable among the carriers. Our results reinforce the argument that the incomplete penetrance and phenotypic variability of SCN5A loss-of-function mutations are the result of a combination of multiple factors, making it difficult to predict their expressivity in the carriers despite the combination of clinical, genetic, and functional studies.

Background/Objectives: Develop a clinical and genetic characterization, in a group of small-for-gestational-age (SGA) patients who did not experience catch-up growth Methods: In an ambispective cohort study with (SGA) patients. These patients received one treatment with growth hormone (GH) over 14 years. This study analyzes their response to treatment and conducts a genetic analysis in order to identify cases with specific phenotypic and auxological characteristics, defined as presenting two or more dysmorphic traits and/or a stature below −3 SDS (standard deviation score). Whole-exome sequencing (WES) was performed on selected patients. Results: Forty-four SGA patients were examined, with an average age of 6.4 (2.49) years and an initial size of −3.3 SDS. The pubertal growth was 24.1 (5.2) cm in boys and 14.7 (4.3) cm in girls. WES in 11 SGA patients revealed conclusive genetic variants in eight, including two pathogenic ACAN variants, one 15q26.2-q26.3 deletion, and four variants of uncertain significance in other genes. Conclusions: Treatment with GH in SGA patients was shown to be effective, with a similar response in the group with positive genetic results and in the group who did not undergo a genetic study. Genetic testing based on auxological and clinical criteria proved highly cost-effective.

One of the most critical goals in healthcare is safe and effective drug therapy, which is directly related to an individual’s response to treatment. Precision medicine can improve drug safety in many scenarios, including polypharmacy, and it requires the development of new genetic characterization methods. In this report, we use real-time PCR, microarray techniques, and mass spectrometry (MALDI-TOF), which allows us to compare them and identify the potential benefits of technological improvements, leading to better quality medical care. These comparative studies, as part of our pharmacogenetic Five-Step Precision Medicine (5SPM) approach, reveal the superiority of mass spectrometry over the other methods analyzed and highlight the importance of updating the laboratory’s pharmacogenetic methodology to identify new variants with clinical impact.

La amiloidosis cardiaca por transtiretina (AC-ATTR) es una enfermedad prevalente con la edad. Se recomienda realizar sistemáticamente un estudio genético incluso en los pacientes más añosos. Nuestro objetivo ha sido realizar un análisis de la prevalencia de amiloidosis por transtiretina hereditaria (ATTRv) en ancianos (≥ 75 años) con AC-ATTR y sus implicaciones. Estudio observacional retrospectivo de la cohorte de pacientes ancianos con AC-ATTR diagnosticados de acuerdo con el protocolo internacional. Analizamos los resultados de la secuenciación del gen TTR, las características diferenciales y sus implicaciones clínicas. Entre 2016 y 2022 se diagnosticaron 130 pacientes ancianos (89% cohorte) con AC-ATTR (85% varones). En 8 pacientes de los 123 con estudio genético se identificó una variante patogénica en TTR (6,5%), iniciándose tratamiento específico en 4 sujetos (50%). El estudio familiar identificó otro caso y 6 portadores asintomáticos. No hubo diferencias significativas entre características basales ni en los eventos clínicos. La prevalencia de ATTRv en ancianos con AC-ATTR fue del 6,5%, sin observarse características diferenciales que permitan guiar una indicación selectiva del análisis genético. Cardiac transthyretin amyloidosis (CA-ATTR) is a prevalent disease with age. Genetic study is recommended, even in eldest patients. We aim to analyze the prevalence of hereditary transthyretin amyloidosis (ATTRv) in elderly patients (≥ 75 years) with CA-ATTR and its implications. Retrospective observational study of the cohort of elderly patients with CA-ATTR diagnosed according to the international recommended protocol. We analyze the results of sequencing TTR gene, the differential characteristics and their clinical implications. Between 2016 and 2022, 130 elderly patients (89% cohort) were diagnosed with CA-ATTR (85% male). In 8 of the 123 patients with a genetic study, a pathogenic variant in TTR was identified (6.5%), initiating specific treatment in 4 subjects (50%). The family study identified another case and 6 asymptomatic carriers. There were no significant differences between baseline characteristics or in clinical events. The prevalence of ATTRv in elderly patients with CA-ATTR was 6.5% without observing differential characteristics that allow guiding a selective indication of genetic analysis.

BACKGROUND AND OBJECTIVE:Cardiac transthyretin amyloidosis (CA-ATTR) is a prevalent disease with age. Genetic study is recommended, even in eldest patients. We aim to analyze the prevalence of hereditary transthyretin amyloidosis (ATTRv) in elderly patients (≥75years) with CA-ATTR and its implications. PATIENTS AND METHODOLOGY:Retrospective observational study of the cohort of elderly patients with CA-ATTR diagnosed according to the international recommended protocol. We analyze the results of sequencing TTR gene, the differential characteristics and their clinical implications. RESULTS:Between 2016 and 2022, 130 elderly patients (89% cohort) were diagnosed with CA-ATTR (85% male). In 8 of the 123 patients with a genetic study, a pathogenic variant in TTR was identified (6.5%), initiating specific treatment in 4 subjects (50%). The family study identified another case and 6 asymptomatic carriers. There were no significant differences between baseline characteristics or in clinical events. CONCLUSIONS:The prevalence of ATTRv in elderly patients with CA-ATTR was 6.5% without observing differential characteristics that allow guiding a selective indication of genetic analysis.

Precision medicine utilizing the genetic information of genes involved in the metabolism and disposition of drugs can not only improve drug efficacy but also prevent or minimize adverse events. Polypharmacy is common among multimorbid patients and is associated with increased adverse events. One of the main objectives in health care is safe and efficacious drug therapy, which is directly correlated to the individual response to treatment. Precision medicine can increase drug safety in many scenarios, including polypharmacy. In this report, we share our experience utilizing precision medicine over the past ten years. Based on our experience using pharmacogenetic (PGx)-informed prescribing, we implemented a five-step precision medicine protocol (5SPM) that includes the assessment of the biological–clinical characteristics of the patient, current and past prescription history, and the patient’s PGx test results. To illustrate our approach, we present cases highlighting the clinical relevance of precision medicine with a focus on patients with a complex history and polypharmacy.

Precision medicine applied to psychiatry provides new insight into the promising field of precision psychiatry. Psychotic disorders are heterogeneous, complex, chronic, and severe mental disorders. Not only does the prognosis and the course of the disease vary among patients suffering from psychotic disorders, but the treatment response varies as well. Although antipsychotic drugs are the cornerstone of the treatment of schizophrenia, many patients only partially respond to these drugs. Furthermore, patients often experience adverse events which can lead to poor treatment adherence. Interindividual variability in drug response could be related to age, gender, ethnicity, lifestyle factors, pharmacological interactions, obesity, and genetics, all of which influence the process of drug metabolism. Commonly prescribed antipsychotics are metabolized by cytochrome P450 (CYP450) enzymes, and CYP450 genes are highly polymorphic. Pharmacogenetic testing is increasingly being used to predict a patient's drug response and could help to find the most appropriate therapy for an individual patient. In this report, we describe a psychotic patient who did not receive adequate clinical follow-up and subsequently presented adverse events, which could be explained by his pharmacogenetic profile and the drug interactions resulting from the polypharmacy prescribed.

Se han descrito previamente variantes genéticas del gen HCN4 con el fenotipo combinado de síndrome del seno enfermo (SSE) y miocardiopatía no compactada del ventrículo izquierdo (MCNC). Actualmente hay pocos casos en los que se haya probado esta relación y ningún caso previo se ha relacionado con dilatación de la aurícula izquierda (DAi). El objetivo es estudiar un trastorno familiar caracterizado por SSE, DAi e hipertrabeculación/fenotipo de MCNC para identificar las bases genéticas y electrofisiológicas subyacentes. Se realizó una evaluación clínica, genética y electrofisiológica de una familia con SSE y MCNC. Se practicaron electrocardiograma, Holter, ecocardiografía y ergometría, así como resonancia magnética en los casos patológicos. Se realizaron pruebas genéticas con técnicas next-generation-sequencing (NGS) y un estudio funcional de la variante genética candidata en células de ovario de hámster chino. Se observó bradicardia sinusal en 12 familiares, asociada con criterios diagnósticos de MCNC en 4, hipertrabeculación en 6 y DAi en 9. Se detectó la variante genética HCN4 c.1123C > T (p.Arg375Cys) en heterocigosis en todos los pacientes afectados y ausente en individuos normales. Los análisis electrofisiológicos mostraron que la amplitud y las densidades de las corrientes de HCN4 (I HCN4 ) generadas por canales HCN4 con la variante genética p.R375C eran significativamente menores que las generadas por canales no mutados. El fenotipo combinado de SSE, DAi y fenotipo de MCNC está asociado con la variante genética de HCN4 c.1123C > T (p.Arg375Cys). El gen HCN4 debería incluirse en el diagnóstico genético de la MCNC y en formas familiares de SSE, pero también en individuos con bradicardia sinusal y DAi. HCN4 variants have been reported to cause combined sick sinus syndrome (SSS) and left ventricular noncompaction (LVNC) cardiomyopathy. This relationship has been proven in few cases and no previous patients have associated left atrial dilatation (LAD). Our objective was to study a familial disorder characterized by SSS, LAD, and hypertrabeculation/LVNC and to identify the underlying genetic and electrophysiological characteristics. A family with SSS and LVNC underwent a clinical, genetic, and electrophysiological assessment. They were studied via electrocardiography, Holter recording, echocardiography, and exercise stress tests; cardiac magnetic resonance imaging was additionally performed in affected individuals. Genetic testing was undertaken with targeted next-generation sequencing, as well as a functional study of the candidate variant in Chinese hamster ovary cells. Twelve members of the family had sinus bradycardia, associated with complete criteria of LVNC in 4 members and hypertrabeculation in 6 others, as well as LAD in 9 members. A HCN4 c.1123C >T;(p.R375C) variant was present in heterozygosis in all affected patients and absent in unaffected individuals. Electrophysiological analyses showed that the amplitude and densities of the HCN4 currents (I HCN4 ) generated by mutant p.R375C HCN4 channels were significantly lower than those generated by wild-type channels. The combined phenotype of SSS, LAD, and LVNC is associated with the heritable HCN4 c.1123C >T;(p.R375C) variant. HCN4 variants should be included in the genetic diagnosis of LVNC cardiomyopathy and of patients with familial forms of SSS, as well as of individuals with sinus bradycardia and LAD.

BACKGROUND:Schizophrenia is a severe mental disorder that often manifests within the first three decades of life. Its prognosis is uncertain and may result in a prolonged treatment that could extend throughout the entire lifespan of the patient. Antipsychotic drugs are characterized by a high interindividual variability when considering therapeutic effect and emergence of adverse effects. Such interindividual variability is thought to be associated primarily with pharmacokinetic matters. OBJECTIVE:The objective of this study was to evaluate the economic impact of the application of the 5-Step Precision Medicine model (5SPM), an approach based on the pharmacogenetic analysis of the primary genes involved in the metabolism of the therapy for each patient, restructuring treatment as necessary. PATIENTS AND METHODS:One hundred eighty-eight psychiatry patients were analysed for single nucleotide polymorphisms on genes CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5 and ABCB1. Information on patients' diagnosis, pharmacotherapy, and hospitalizations was collected. RESULTS:We achieved a cost-benefit ratio of 3.31-3.59 with a reduction of direct cost (hospitalizations plus pharmacotherapy) with a reduction of total cost in 67% of the patients who underwent the clinical intervention. CONCLUSION:A rational Precision Medicine-based approach to psychiatric patients could result in a reduction on number of drugs required to control exacerbations, and the underlying pathologies, reducing the risk of adverse effects and improving adherence to treatment, leading to a potential decrease in direct costs. This methodology has been shown to be cost-dominant and, being based on a pharmacogenetic analysis, it has a lifelong nature, as the data obtained can be applied to other medical disciplines.

Antipsychotics are the keystone of the treatment of severe and prolonged mental disorders. However, there are many risks associated with these drugs and not all patients undergo full therapeutic profit from them. The application of the 5 Step Precision Medicine model(5SPM), based on the analysis of the pharmacogenetic profile of each patient, could be a helpful tool to solve many of the problematics traditionally associated with the neuroleptic treatment. In order to solve this question, a cohort of psychotic patients that showed poor clinical evolution was analyzed. After evaluating the relationship between the prescribed treatment and pharmacogenetic profile of each patient, a great number of pharmacological interactions and pharmacogenetical conflicts were found. After reconsidering the treatment of the conflictive cases, patients showed a substantial reduction on mean daily doses and polytherapy cases, which may cause less risk of adverse effects, greater adherence, and a reduction on economic costs.

Introduction and objectives: HCN4 variants have been reported to cause combined sick sinus syndrome (SSS) and left ventricular noncompaction (LVNC) cardiomyopathy. This relationship has been proven in few cases and no previous patients have associated left atrial dilatation (LAD). Our objective was to study a familial disorder characterized by SSS, LAD, and hypertrabeculation/LVNC and to identify the underlying genetic and electrophysiological characteristics. Methods: A family with SSS and LVNC underwent a clinical, genetic, and electrophysiological assessment. They were studied via electrocardiography, Holter recording, echocardiography, and exercise stress tests; cardiac magnetic resonance imaging was additionally performed in affected individuals. Genetic testing was undertaken with targeted next-generation sequencing, as well as a functional study of the candidate variant in Chinese hamster ovary cells. Results: Twelve members of the family had sinus bradycardia, associated with complete criteria of LVNC in 4 members and hypertrabeculation in 6 others, as well as LAD in 9 members. A HCN4 c.1123C >T;(p.R375C) variant was present in heterozygosis in all affected patients and absent in unaffected individuals. Electrophysiological analyses showed that the amplitude and densities of the HCN4 currents (I-HCN4) generated by mutant p.R375C HCN4 channels were significantly lower than those generated by wild-type channels. Conclusions: The combined phenotype of SSS, LAD, and LVNC is associated with the heritable HCN4 c.1123C >T;(p.R375C) variant. HCN4 variants should be included in the genetic diagnosis of LVNC cardiomyopathy and of patients with familial forms of SSS, as well as of individuals with sinus bradycardia and LAD. (C) 2020 Sociedad Espanola de Cardiologica. Published by Elsevier Espana, S.L.U. All rights reserved.

There are many factors involved in the effectiveness and efficiency of psychiatric drug treatment. One of them is psychotropic drug metabolism, which takes place mostly in the liver through the P450 enzyme system. However, there are genotypic variants of this system's enzymes that can directly affect both the efficacy and the onset of side effects of a given therapeutic regimen. These genotypic changes could partly explain the lack of efficacy of treatment in certain patients. We report the case of a patient diagnosed with bipolar type I disorder that presented multiple and frequent manic episodes in which the efficacy and tolerability of several pharmacological regimens with mood stabilizers and antipsychotics was scarce. The choice of medical treatment should be based on its efficacy and side effect profile. This decision can be made more accurately using the information provided by pharmacogenetic analysis. This case illustrates the importance of pharmacogenetic studies in clinical practice. The results of pharmacogenetic analysis helped to decide on a better treatment plan to achieve clinical improvement and reduce drug-induced adverse effects.

El principal objetivo de la farmacogenómica (PGx) es definir un tratamiento farmacológico individualizado basado en el perfil genético de cada paciente, convirtiendo el paradigma clásico de tratamiento clínico centrado en la enfermedad en un nuevo enfoque, la medicina personalizada. Los polimorfismos genéticos pueden modificar la expresión y la función de las enzimas y las proteínas involucradas en la farmacocinética y la farmacodinámica de los fármacos. Así, la presencia de variantes alélicas permite predecir la respuesta farmacológica para garantizar la eficacia y la seguridad del tratamiento. Para la aplicación clínica de la PGx mediante la identificación de dichas variantes existen actualmente 2 planteamientos diferentes: el análisis de genes candidatos y los estudios de asociación genómica. La implementación clínica de la PGx mejora la eficacia, la seguridad y la relación costo-efectividad de los tratamientos; sin embargo, se ha ralentizado debido a una serie de barreras que se revisarán en este trabajo, así como sus posibles soluciones.