Francesco Mazzarotto
A5076368396- Cardiomyopathy and Myosin Studies
- Congenital heart defects research
- Cardiovascular Function and Risk Factors
- Cardiovascular Effects of Exercise
- Genomics and Rare Diseases
- Genetic Associations and Epidemiology
- RNA Research and Splicing
- Viral Infections and Immunology Research
- Williams Syndrome Research
- Muscle Physiology and Disorders
- RNA and protein synthesis mechanisms
- Cardiac electrophysiology and arrhythmias
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Cardiac Structural Anomalies and Repair
- Cardiovascular Issues in Pregnancy
- Firm Innovation and Growth
- Cellular transport and secretion
- RNA modifications and cancer
- Genetics, Bioinformatics, and Biomedical Research
- Signaling Pathways in Disease
- Genetics and Neurodevelopmental Disorders
- Trypanosoma species research and implications
- Peptidase Inhibition and Analysis
- Studies on Chitinases and Chitosanases
- Phosphodiesterase function and regulation
University of Brescia
2022-2025
Imperial College London
2016-2025
University of Florence
2017-2022
National Health Service
2015-2021
Royal Brompton & Harefield NHS Foundation Trust
2014-2021
Azienda Ospedaliero-Universitaria Careggi
2017-2021
Harefield Hospital
2020-2021
MRC London Institute of Medical Sciences
2021
National Institute for Health Research
2015-2020
NIHR Royal Brompton Cardiovascular Biomedical Research Unit
2016-2020
The accurate interpretation of variation in Mendelian disease genes has lagged behind data generation as sequencing become increasingly accessible. Ongoing large efforts present huge interpretive challenges, but they also provide an invaluable opportunity to characterize the spectrum and importance rare variation.We analyzed sequence from 7,855 clinical cardiomyopathy cases 60,706 Exome Aggregation Consortium (ExAC) reference samples obtain a better understanding genetic representative...
Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin.
The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization this opportunity has been hindered by the burden TTN-truncating variants (TTNtv) general population uncertainty about their consequences health or disease. To elucidate effects TTNtv, we coupled...
Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular has a signature genetic theme. Hypertrophic are largely understood diseases sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing complex diverse architecture. To clarify this, systematic curation evidence to establish relationship with DCM was conducted.
Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation 2538 patients DCM across protein-coding regions 56 commonly and compare this to both 912 confirmed healthy controls a reference 60 706 individuals identify clinically interpretable...
International guidelines for variant interpretation in Mendelian disease set stringent criteria to report a as (likely) pathogenic, prioritising control of false-positive rate over test sensitivity and diagnostic yield. Genetic testing is also more likely informative individuals with well-characterised variants from extensively studied European-ancestry populations. Inherited cardiomyopathies are relatively common diseases that allow empirical calibration assessment this framework. We...
Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to these conditions, but evidence supporting gene-disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT SQTS patients, we applied an evidence-based reappraisal previously genes.Three teams independently curated all published 11 9 implicated using...
BACKGROUND Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little known about the clinical significance of these general population.OBJECTIVES The goal this study was to compare lifetime outcomes and cardiovascular phenotypes according presence genes among middle-aged adults.METHODS This analyzed whole exome sequencing cardiac magnetic resonance imaging UK Biobank participants stratified variant status. RESULTSThe prevalence (allele frequency...
PurposeTo characterize the genetic architecture of left ventricular noncompaction (LVNC) and investigate extent to which it may represent a distinct pathology or secondary phenotype associated with other cardiac diseases.MethodsWe performed rare variant association analysis 840 LVNC cases 125,748 gnomAD population controls, compared results similar analyses on dilated cardiomyopathy (DCM) hypertrophic (HCM).ResultsWe observed substantial overlap indicating that often represents phenotypic...
Abstract Background Atrial fibrillation (AF) is a common heart rhythm disorder that associated with an increased risk of stroke and failure (HF). Initially, association between AF ion channel dysfunction was identified, classifying the pathology as predominantly electrical disease. More recently it has been recognized fibrosis structural atrial remodeling play driving role in development this arrhythmia also these cases. Purpose Understanding genetic determined could be important to better...
Pathogenic variants in MYBPC3, encoding cardiac MyBP-C (myosin binding protein C), are the most common cause of familial hypertrophic cardiomyopathy. A large number unique MYBPC3 and relatively small genotyped cardiomyopathy cohorts have precluded detailed genotype-phenotype correlations.Patients with were identified from Sarcomeric Human Cardiomyopathy Registry. Variant types locations analyzed, morphological severity was assessed, time-event analysis performed (composite clinical outcome...
Background: Over the last 50 years, epidemiology of hypertrophic cardiomyopathy (HCM) has changed because increased awareness and availability advanced diagnostic tools. We aim to describe temporal trends in age, sex, clinical characteristics at HCM diagnosis over >4 decades. Methods: retrospectively analyzed records from ongoing multinational Sarcomeric Human Cardiomyopathy Registry. Overall, 7286 patients with diagnosed an age ≥18 years between 1961 2019 were included analysis divided...
Genetic testing in hypertrophic cardiomyopathy (HCM) has long relied on Sanger sequencing of sarcomeric genes. The advent next-generation (NGS) catalyzed routine additional genes dubious HCM-causing potential. We used 19 years genetic results to define a reliable set implicated Mendelian HCM and assess the value expanded NGS panels.We dissected from 1,198 single-center probands devised widely applicable score identify which yield effective diagnostic setting.Compared with early panels...
Abstract The accurate interpretation of variation in Mendelian disease genes has lagged behind data generation as sequencing become increasingly accessible. Ongoing large efforts present huge interpretive challenges, but also provide an invaluable opportunity to characterize the spectrum and importance rare variation. Here we analyze sequence from 7,855 clinical cardiomyopathy cases 60,706 ExAC reference samples better understand genetic a representative autosomal dominant disorder. We show...
PurposeAccurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning variant prioritization tools are imprecise ignore important parameters defining gene–disease relationships, e.g., distinct consequences gain-of-function versus loss-of-function variants. We hypothesized that incorporating disease-specific information would improve tool performance.MethodsWe developed classifier, CardioBoost, estimates...
Stringent variant interpretation guidelines can lead to high rates of variants uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada (BrS). Quantitative disease-specific customization American College Medical Genetics Genomics/Association Molecular Pathology (ACMG/AMP) address this false negative rate.We compared rare frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) 3335 BrS (SCN5A) cases the International LQTS/BrS Consortia...
Machine learning (ML) and artificial intelligence are emerging as important components of precision medicine that enhance diagnosis risk stratification. Risk stratification tools for hypertrophic cardiomyopathy (HCM) exist, but they based on traditional statistical methods. The aim was to develop a novel machine tool the prediction 5-year in HCM. goal determine if its predictive accuracy is higher than state-of-the-art tools. Data from total 2302 patients were used. data comprised...
Background: The pathogenesis of MYBPC3 -associated hypertrophic cardiomyopathy (HCM) is still unresolved. In our HCM patient cohort, a large and well-characterized population carrying the :c772G>A variant (p.Glu258Lys, E258K) provides unique opportunity to study basic mechanisms -HCM with comprehensive translational approach. Methods: We collected clinical genetic data from 93 patients variant. Functional perturbations were investigated using different biophysical techniques in left...
Abstract Background Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation 2538 DCM patients across protein-coding regions 56 commonly and compare this to both 912 confirmed healthy controls a reference 60,706 individuals. Purpose To...