Publications
57 results found
Mazzarotto F, Hawley M, Beltrami M, et al., 2020, The genetic architecture of left ventricular non-compaction reveals both substantial overlap with other cardiomyopathies and a distinct aetiology in a subset of cases, Publisher: bioRxiv
Rationale: Left ventricular non-compaction (LVNC) is a condition characterised by trabeculations in the myocardial wall and is the subject of considerable conjecture as to whether it represents a distinct pathology or a secondary phenotype associated with other cardiac diseases, particularly cardiomyopathies. Objective: To investigate the genetic architecture of LVNC by identifying genes and variant classes robustly associated with disease and comparing these to other genetically characterised cardiomyopathies. Methods and Results: We performed rare variant association analysis using six different LVNC cohorts comprising 840 cases together with 125,748 gnomAD population controls and compared results to similar analyses with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) cases. We observed substantial overlap in genes and variant classes enriched in LVNC and DCM/HCM, indicating that in many cases LVNC belongs to a spectrum of more established cardiomyopathies, with non-compaction representing a phenotypic variation in patients with DCM- or HCM-causing variants. In contrast, five variant classes were uniquely enriched in LVNC cases, of which truncating variants in MYH7, ACTN2 and PRDM16 may represent a distinct LVNC aetiology. MYH7 truncating variants are generally considered as non-pathogenic but were detected in 2% of LVNC cases compared to 0.1% of controls, including a cluster of variants around a single splice region. Additionally, structural variants (exon deletions) in RYR2 and missense variants in the transmembrane region of HCN4 were enriched in LVNC cases, confirming prior reports regarding the association of these variant classes with combined LVNC and arrhythmia phenotypes. Conclusions: We demonstrated that genetic association analysis can clarify the relationship between LVNC and established cardiomyopathies, highlighted substantial overlap with DCM/HCM but also identified variant classes associated with distinct LVNC and with joint LVN
Canepa M, Fumagalli C, Tini G, et al., 2019, Temporal trend in age at diagnosis of hypertrophic cardiomyopathy: an analysis of the share registry, 80th SIC National Congress, Publisher: OXFORD UNIV PRESS, Pages: J181-J182, ISSN: 1520-765X
Canepa M, Fumagalli C, Tini G, et al., 2019, Temporal Trend in Age at Diagnosis of Hypertrophic Cardiomyopathy: An Analysis of the Share Registry, Scientific Sessions of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Ghiselli L, Marchi A, Fumagalli C, et al., 2019, Sex-related differences in exercise performance and outcome of patients with hypertrophic cardiomyopathy., Eur J Prev Cardiol, Pages: 2047487319886961-2047487319886961
AIMS: Exercise performance is known to predict outcome in hypertrophic cardiomyopathy (HCM), but whether sex-related differences exist is unresolved. We explored whether functional impairment, assessed by exercise echocardiography, has comparable predictive accuracy in females and males with HCM. METHODS: We retrospectively evaluated 292 HCM patients (46 ± 16 years, 72% males), consecutively referred for exercise echocardiography; 242 were followed for 5.9 ± 4.2 years. RESULTS: Peak exercise capacity was 6.5 ± 1.6 metabolic equivalents (METs). Sixty patients (21%) showed impaired exercise capacity (≤5 METs). Exercise performance was reduced in females, compared with males (5.6 ± 1.6 vs 6.9 ± 1.5 METs, p < 0.001; peak METs ≤ 5 in 40% vs 13%, p < 0.001), largely driven by a worse performance in women >50 years of age. At multivariable analysis, female sex was independently associated with impaired exercise capacity (odds ratio: 4.67; 95% confidence interval (CI): 1.83-11.90; p = 0.001). During follow-up, 24 patients (10%) met the primary endpoint (a combination of cardiac death, heart failure requiring hospitalization, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator discharge, resuscitated sudden cardiac death and cardioembolic stroke). Event-free survival was reduced in females (p = 0.035 vs males). Peak METs were inversely related to outcome in males (hazard ratio (HR) per unit increase: 0.57; 95% CI: 0.39-0.84; p = 0.004) but not in females (HR: 1.22; 95% CI: 0.66-2.24; p = 0.53). CONCLUSIONS: Female patients with HCM showed significant age-related impairment in functional capacity compared with males, particularly evident in post-menopausal age groups. While women were at greater risk of HCM-related complications
Walsh R, Mazzarotto F, Whiffin N, et al., 2019, Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases, 52nd Conference of the European-Society-of-Human-Genetics (ESHG), Publisher: NATURE PUBLISHING GROUP, Pages: 1720-1720, ISSN: 1018-4813
Fumagalli C, Fedele E, Beltrami M, et al., 2019, Comparison of long-term clinical course and outcome of MYBPC3-versus MYH7-related hypertrophic cardiomyopathy, Congress of the European-Society-of-Cardiology (ESC) / World Congress of Cardiology, Publisher: OXFORD UNIV PRESS, Pages: 699-699, ISSN: 0195-668X
Cappelli F, Mazzarotto F, Frusconi S, et al., 2019, Genetic ancestry analysis of the Italian founder population carrying the cardiac amyloidosis-causing variant Val122Ile in the transthyretin gene, Congress of the European-Society-of-Cardiology (ESC) / World Congress of Cardiology, Publisher: OXFORD UNIV PRESS, Pages: 1682-1682, ISSN: 0195-668X
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Mazzarotto F, Tayal P, Buchan R, et al., 2019, RE-EVALUATING THE GENETIC CONTRIBUTION OF MONOGENIC DILATED CARDIOMYOPATHY, Annual Conference of the British-Cardiovascular-Society (BCS) - Digital Health Revolution, Publisher: BMJ PUBLISHING GROUP, Pages: A100-A100, ISSN: 1355-6037
Mazzarotto F, Girolami F, Boschi B, et al., 2019, Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center, Genetics in Medicine, Vol: 21, Pages: 284-292, ISSN: 1098-3600
PurposeGenetic testing in hypertrophic cardiomyopathy (HCM) has long relied on Sanger sequencing of sarcomeric genes. The advent of next-generation sequencing (NGS) has catalyzed routine testing of additional genes of dubious HCM-causing potential. We used 19 years of genetic testing results to define a reliable set of genes implicated in Mendelian HCM and assess the value of expanded NGS panels.MethodsWe dissected genetic testing results from 1,198 single-center HCM probands and devised a widely applicable score to identify which genes yield effective results in the diagnostic setting.ResultsCompared with early panels targeting only fully validated sarcomeric HCM genes, expanded NGS panels allow the prompt recognition of probands with HCM-mimicking diseases. Scoring by “diagnostic effectiveness” highlighted that PLN should also be routinely screened besides historically validated genes for HCM and its mimics.ConclusionThe additive value of expanded panels in HCM genetic testing lies in the systematic screening of genes associated with HCM mimics, requiring different patient management. Only variants in a limited set of genes are highly actionable and interpretable in the clinic, suggesting that larger panels offer limited additional sensitivity. A score estimating the relative effectiveness of a given gene’s inclusion in diagnostic panels is proposed.
Walsh R, Mazzarotto F, Whiffin N, et al., 2019, Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: The case of hypertrophic cardiomyopathy, Genome Medicine, Vol: 11, ISSN: 1756-994X
BackgroundInternational guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false-positive rate over test sensitivity and diagnostic yield. Genetic testing is also more likely informative in individuals with well-characterised variants from extensively studied European-ancestry populations. Inherited cardiomyopathies are relatively common Mendelian diseases that allow empirical calibration and assessment of this framework.MethodsWe compared rare variants in large hypertrophic cardiomyopathy (HCM) cohorts (up to 6179 cases) to reference populations to identify variant classes with high prior likelihoods of pathogenicity, as defined by etiological fraction (EF). We analysed the distribution of variants using a bespoke unsupervised clustering algorithm to identify gene regions in which variants are significantly clustered in cases.ResultsAnalysis of variant distribution identified regions in which variants are significantly enriched in cases and variant location was a better discriminator of pathogenicity than generic computational functional prediction algorithms. Non-truncating variant classes with an EF ≥ 0.95 were identified in five established HCM genes. Applying this approach leads to an estimated 14–20% increase in cases with actionable HCM variants, i.e. variants classified as pathogenic/likely pathogenic that might be used for predictive testing in probands’ relatives.ConclusionsWhen found in a patient confirmed to have disease, novel variants in some genes and regions are empirically shown to have a sufficiently high probability of pathogenicity to support a “likely pathogenic” classification, even without additional segregation or functional data. This could increase the yield of high confidence actionable variants, consistent with the framework and recommendations of current guidelines. The techniques outlined offer a consisten
Horvat C, Johnson R, Lam L, et al., 2019, A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy, Genetics in Medicine, Vol: 21, Pages: 133-143, ISSN: 1098-3600
PurposeWe evaluated strategies for identifying disease-causing variants in genetic testing for dilated cardiomyopathy (DCM).MethodsCardiomyopathy gene panel testing was performed in 532 DCM patients and 527 healthy control subjects. Rare variants in 41 genes were stratified using variant-level and gene-level characteristics.ResultsA majority of DCM cases and controls carried rare protein-altering cardiomyopathy gene variants. Variant-level characteristics alone had limited discriminative value. Differentiation between groups was substantially improved by addition of gene-level information that incorporated ranking of genes based on literature evidence for disease association. The odds of DCM were increased to nearly 9-fold for truncating variants or high-impact missense variants in the subset of 14 genes that had the strongest biological links to DCM (P <0.0001). For some of these genes, DCM-associated variants appeared to be clustered in key protein functional domains. Multiple rare variants were present in many family probands, however, there was generally only one “driver” pathogenic variant that cosegregated with disease.ConclusionRare variants in cardiomyopathy genes can be effectively stratified by combining variant-level and gene-level information. Prioritization of genes based on their a priori likelihood of disease causation is a key factor in identifying clinically actionable variants in cardiac genetic testing.
Fornaro A, Olivotto I, Rigacci L, et al., 2018, Comparison of long-term outcome in anthracycline-related versus idiopathic dilated cardiomyopathy: a single centre experience, European Journal of Heart Failure, Vol: 20, Pages: 898-906, ISSN: 1388-9842
AimsCardiac dysfunction is a severe complication of anthracycline‐containing anticancer therapy. The outcome of anthracycline‐induced cardiomyopathy (AICM) compared with other non‐ischaemic causes of heart failure (HF), such as idiopathic dilated cardiomyopathy (IDCM), is unresolved. The aim of this study was to compare the survival of AICM patients with an IDCM cohort followed at our centre from 1990 to 2016.Methods and resultsWe included 67 patients (67% female, 50 ± 15 years) with AICM, defined as onset of otherwise unexplained left ventricular ejection fraction (LVEF) ≤50% following anthracycline therapy, and 488 IDCM patients (28% female, 55 ± 12 years). Patients were followed with constantly optimized HF therapy, for 7.6 ± 5.5 and 8.1 ± 5.5 years, respectively. In both cohorts, 25% of patients reached the combined endpoint of death/heart transplantation. Overall survival rates at 5 and 10 years were similar (AICM: 86% and 61%, IDCM: 88% and 75%; P = 0.61), and so was cardiovascular survival (AICM: 91% and 76%, IDCM: 91% and 80%; P = 0.373), also after 1:1 propensity matching (P = 0.27) and adjusting for age, LVEF and left ventricular size. A trend toward higher all‐cause mortality was present in AICM patients [hazard ratio (HR) 1.67, 95% confidence interval (CI) 0.95–2.92, P = 0.076]. No differences were observed between AICM and IDCM with regard to pharmacological HF therapy, but AICM patients were less likely to receive devices (13% vs. 41.8% in IDCM, P < 0.001).ConclusionCardiovascular mortality in patients with AICM did not differ from that of a matched IDCM cohort, despite cancer‐related morbidity and less prevalent use of devices. These data suggest that patients with AICM should be treated with appropriate guideline‐directed medical therapies similar to other non
Mazzarotto F, Girolami F, Boschi B, et al., 2018, Two decades of genetic testing in hypertrophic cardiomyopathy in a single center: The additive value of extended next-generation sequencing panels lies in the early diagnosis of metabolic mimics, XXI Congress of the Italian Society of Cardiovascular Research, Publisher: ELSEVIER SCIENCE INC, Pages: 63-63, ISSN: 1537-1891
Schafer S, de Marvao A, Adami E, et al., 2017, Titin-truncating variants affect heart function in disease cohorts and the general population, Nature Genetics, Vol: 49, Pages: 46-53, ISSN: 1546-1718
Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ~1% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-learning-based analysis of high-resolution cardiac imaging showed TTNtv to be associated with eccentric cardiac remodeling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease.
Walsh R, Thomson KL, Ware JS, et al., 2016, Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples, Genetics in Medicine, Vol: 19, Pages: 192-203, ISSN: 1530-0366
PURPOSE: The accurate interpretation of variation in Mendelian disease genes has lagged behind data generation as sequencing has become increasingly accessible. Ongoing large sequencing efforts present huge interpretive challenges, but they also provide an invaluable opportunity to characterize the spectrum and importance of rare variation. METHODS: We analyzed sequence data from 7,855 clinical cardiomyopathy cases and 60,706 Exome Aggregation Consortium (ExAC) reference samples to obtain a better understanding of genetic variation in a representative autosomal dominant disorder. RESULTS: We found that in some genes previously reported as important causes of a given cardiomyopathy, rare variation is not clinically informative because there is an unacceptably high likelihood of false-positive interpretation. By contrast, in other genes, we find that diagnostic laboratories may be overly conservative when assessing variant pathogenicity. CONCLUSIONS: We outline improved analytical approaches that evaluate which genes and variant classes are interpretable and propose that these will increase the clinical utility of testing across a range of Mendelian diseases.Genet Med advance online publication 17 August 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.90.
Tayal U, Buchan RJ, Whiffin N, et al., 2016, Clinical and Genetic Characteristics of Familial Dilated Cardiomyopathy in a Large UK Prospective Cohort, Annual Conference of the British Cardiovascular Society (BCS) on Prediction and Prevention, Publisher: BMJ Publishing Group, Pages: A103-A103, ISSN: 1355-6037
Tayal U, Buchan RJ, Whiffin N, et al., 2016, Effects of Truncating Variants in Titin on Cardiac Phenotype and Left Ventricular Remodelling in Dilated Cardiomyopathy, Annual Conference of the British Cardiovascular Society (BCS) on Prediction and Prevention, Publisher: BMJ Publishing Group, Pages: A102-A103, ISSN: 1355-6037
Ware JS, Li J, Mazaika E, et al., 2016, Shared genetic etiology of peripartum and dilated cardiomyopathies, New England Journal of Medicine, Vol: 374, Pages: 233-241, ISSN: 1533-4406
Background: Peripartum cardiomyopathy (PPCM) shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in over 40 genes, including TTN, which encodes the sarcomere protein titin.Methods: We sequenced 43 genes, with variants that have been associated with dilated cardiomyopathy, in 172 women with peripartum cardiomyopathy. We compared the prevalence of different types of variant (nonsense, frameshift, and splicing) in these women with the prevalence of these variants in persons with dilated cardiomyopathy and population controls.Results: We identified 26 distinct rare truncating variants in eight genes in women with PPCM. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than in a reference population of 60,706 individuals (4.7%, P=1.3x10-7), but was similar to a cohort of 332 dilated cardiomyopathy cases (55 in 332 [17%], P=0.81). Two thirds of identified truncating variants were in TTN ([10%], P=2.7x10-10 versus 1.4% in reference population), almost all located in the titin A-band. Seven of the TTN truncating variants were previously reported in cases of idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of women with PPCM (n=83), the presence of TTN truncating variants correlated with lower ejection fraction at one-year follow-up (P=0.005). Conclusions: The distribution of truncating variants in a large series of women with PPCM is remarkably similar to that found in idiopathic dilated cardiomyopathy. TTN truncating variants are the most prevalent genetic predisposition of each disorder.
Tayal U, Mazzarotto F, Buchan R, et al., 2015, Comprehensive Assessment of Rare Genetic Variation in Dilated Cardiomyopathy Genes in Patients and Controls (vol 101, pg A41, 2015), HEART, Vol: 101, ISSN: 1355-6037
Mazzarotto F, Walsh R, Buchan RJ, et al., 2015, Comprehensive sequencing of dilated cardiomyopathy genes reveals additive effects of multiple genes on disease risk and severity, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 523-523, ISSN: 0195-668X
Buyandelger B, Mansfield C, Kostin S, et al., 2015, ZBTB17 (MIZ1) Is Important for the Cardiac Stress Response and a Novel Candidate Gene for Cardiomyopathy and Heart Failure., Circulation. Cardiovascular Genetics, Vol: 8, Pages: 643-652, ISSN: 1942-3268
BACKGROUND: -Mutations in sarcomeric and cytoskeletal proteins are a major cause of hereditary cardiomyopathies, but our knowledge remains incomplete as to how the genetic defects execute their effects. METHODS AND RESULTS: -We used cysteine and glycine-rich protein 3 (CSRP3), a known cardiomyopathy gene, in a yeast two-hybrid screen and identified zinc finger and BTB domain containing protein 17 (ZBTB17) as a novel interacting partner. ZBTB17 is a transcription factor that contains the peak association signal (rs10927875) at the replicated 1p36 cardiomyopathy locus. ZBTB17 expression protected cardiac myocytes from apoptosis in vitro and in a mouse model with cardiac myocyte-specific deletion of Zbtb17, which develops cardiomyopathy and fibrosis after biomechanical stress. ZBTB17 also regulated cardiac myocyte hypertrophy in vitro and in vivo in a calcineurin-dependent manner. CONCLUSIONS: -We revealed new functions for ZBTB17 in the heart, a transcription factor which may play a role as a novel cardiomyopathy gene.
Tayal U, Mazzarotto F, Buchan R, et al., 2015, COMPREHENSIVE ASSESSMENT OF RARE GENETIC VARIATION IN DILATED CARDIOMYOPATHY GENES IN PATIENTS AND CONTROLS, British-Cardiac-Society (BCS) Annual Conference on Hearts and Genes, Publisher: BMJ PUBLISHING GROUP, Pages: A41-A42, ISSN: 1355-6037
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Roberts A, Ware J, Herman D, et al., 2015, INTEGRATED ALLELIC, TRANSCRIPTIONAL, AND PHENOTYPIC DISSECTION OF THE CARDIAC EFFECTS OF TITIN VARIATION IN HEALTH AND DISEASE, British-Cardiac-Society (BCS) Annual Conference on Hearts and Genes, Publisher: BMJ PUBLISHING GROUP, Pages: A93-A93, ISSN: 1355-6037
Roberts AM, Ware J, Herman D, et al., 2015, INTEGRATED ALLELIC, TRANSCRIPTIONAL, AND PHENOTYPIC DISSECTION OF THE CARDIAC EFFECTS OF TITIN VARIATION IN HEALTH AND DISEASER, British-Cardiac-Society (BCS) Annual Conference on Hearts and Genes, Publisher: BMJ PUBLISHING GROUP, Pages: A126-A126, ISSN: 1355-6037
Roberts AM, Ware JS, Herman DS, et al., 2015, Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease, Science Translational Medicine, Vol: 7, Pages: 270ra6-270ra6, ISSN: 1946-6234
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 of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http://cardiodb.org/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings.
Roberts AM, Ware JS, Herman DS, et al., 2015, What Happens When Titins Are Trimmed?, SCIENCE TRANSLATIONAL MEDICINE, Vol: 7, ISSN: 1946-6234
Gatto A, Torroja-Fungairino C, Mazzarotto F, et al., 2014, FineSplice, enhanced splice junction detection and quantification: a novel pipeline based on the assessment of diverse RNA-Seq alignment solutions, Nucleic Acids Research, Vol: 42, Pages: 1-11, ISSN: 0305-1048
Alternative splicing is the main mechanism governing protein diversity. The recent developments in RNA-Seq technology have enabled the study of the global impact and regulation of this biological process. However, the lack of standardized protocols constitutes a major bottleneck in the analysis of alternative splicing. This is particularly important for the identification of exon–exon junctions, which is a critical step in any analysis workflow. Here we performed a systematic benchmarking of alignment tools to dissect the impact of design and method on the mapping, detection and quantification of splice junctions from multi-exon reads. Accordingly, we devised a novel pipeline based on TopHat2 combined with a splice junction detection algorithm, which we have named FineSplice. FineSplice allows effective elimination of spurious junction hits arising from artefactual alignments, achieving up to 99% precision in both real and simulated data sets and yielding superior F1 scores under most tested conditions. The proposed strategy conjugates an efficient mapping solution with a semi-supervised anomaly detection scheme to filter out false positives and allows reliable estimation of expressed junctions from the alignment output. Ultimately this provides more accurate information to identify meaningful splicing patterns. FineSplice is freely available at https://sourceforge.net/p/finesplice/.
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