Publications
57 results found
Lipov A, Jurgens SJ, Mazzarotto F, et al., 2023, Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies, Nature Cardiovascular Research, Vol: 2, Pages: 1078-1094
Discrete categorization of Mendelian disease genes into dominant and recessive models often oversimplifies their underlying genetic architecture. Cardiomyopathies (CMs) are genetic diseases with complex etiologies for which an increasing number of recessive associations have recently been proposed. Here, we comprehensively analyze all published evidence pertaining to biallelic variation associated with CM phenotypes to identify high-confidence recessive genes and explore the spectrum of monoallelic and biallelic variant effects in established recessive and dominant disease genes. We classify 18 genes with robust recessive association with CMs, largely characterized by dilated phenotypes, early disease onset and severe outcomes. Several of these genes have monoallelic association with disease outcomes and cardiac traits in the UK Biobank, including LMOD2 and ALPK3 with dilated and hypertrophic CM, respectively. Our data provide insights into the complex spectrum of dominance and recessiveness in genetic heart disease and demonstrate how such approaches enable the discovery of unexplored genetic associations.
Beltrami M, Fedele E, Fumagalli C, et al., 2023, Long-Term Prevalence of Systolic Dysfunction in MYBPC3 Versus MYH7-Related Hypertrophic Cardiomyopathy, CIRCULATION-GENOMIC AND PRECISION MEDICINE, Vol: 16, Pages: 363-371, ISSN: 2574-8300
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- Citations: 1
Pioner JM, Santini L, Palandri C, et al., 2023, Calcium handling maturation and adaptation to increased substrate stiffness in human iPSC-derived cardiomyocytes: the impact of full-length dystrophin deficiency (Vol 13, 1030920, 2022), FRONTIERS IN PHYSIOLOGY, Vol: 14
Mazzarotto F, Argiro A, Zampieri M, et al., 2023, Investigation on the high recurrence of the ATTRv-causing transthyretin variant Val142Ile in central Italy, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 31, Pages: 541-547, ISSN: 1018-4813
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- Citations: 5
Pioner JM, Vitale G, Steczina S, et al., 2023, Slower Calcium Handling Balances Faster Cross-Bridge Cycling in Human <i>MYBPC3</i> HCM, CIRCULATION RESEARCH, Vol: 132, Pages: 628-644, ISSN: 0009-7330
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- Citations: 2
Tadros R, Zheng SL, Grace C, et al., 2023, Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy., medRxiv
Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.
Cappelli F, Argiro' A, Zampieri M, et al., 2022, INVESTIGATION ON THE HIGH INCIDENCE OF THE ATTRV-CAUSING TRANSTHYRETIN VARIANT VAL142ILE IN CENTRAL ITALY, Publisher: OXFORD UNIV PRESS, ISSN: 1520-765X
Pioner JM, Santini L, Palandri C, et al., 2022, Calcium handling maturation and adaptation to increased substrate stiffness in human iPSC-derived cardiomyocytes: The impact of full-length dystrophin deficiency, FRONTIERS IN PHYSIOLOGY, Vol: 13
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- Citations: 3
Piculin M, Smole T, Zunkovic B, et al., 2022, Disease Progression of Hypertrophic Cardiomyopathy: Modeling Using Machine Learning, JMIR MEDICAL INFORMATICS, Vol: 10
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- Citations: 6
Garrett A, Loveday C, King L, et al., 2022, Quantifying evidence toward pathogenicity for rare phenotypes: the case of succinate dehydrogenase genes, SDHB and SDHD, Genetics in Medicine, Vol: 24, Pages: 41-50, ISSN: 1098-3600
PURPOSE: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain. METHODS: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features. RESULTS: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ɑɑ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ɑɑ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD). CONCLUSION: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity.
Walsh R, Adler A, Amin AS, et al., 2021, Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death, European Heart Journal, Vol: 00, Pages: 1-12, ISSN: 0195-668X
AimsCatecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene–disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes.Methods and resultsThree teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3).ConclusionsSeven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.
Simoes Monteiro de Marvao A, McGurk K, Zheng S, et al., 2021, Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy, Journal of the American College of Cardiology, Vol: 78, Pages: 1097-1110, ISSN: 0735-1097
Background: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomereencoding genes, but little is known about the clinical significance of these variants in thegeneral population.Objectives: To compare lifetime outcomes and cardiovascular phenotypes according to thepresence of rare variants in sarcomere-encoding genes amongst middle-aged adults.Methods: We analysed whole exome sequencing and cardiac magnetic resonance (CMR)imaging in UK Biobank participants stratified by sarcomere-encoding variant status.Results: The prevalence of rare variants (allele frequency <0.00004) in HCM-associatedsarcomere-encoding genes in 200,584 participants was 2.9% (n=5,712; 1 in 35), and theprevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was0.25% (n=493, 1 in 407). SARC-HCM-P/LP variants were associated with increased risk ofdeath or major adverse cardiac events compared to controls (HR 1.69, 95% CI 1.38 to 2.07,p<0.001), mainly due to heart failure endpoints (HR 4.23, 95% CI 3.07 to 5.83, p<0.001). In21,322 participants with CMR, SARC-HCM-P/LP were associated with asymmetric increasein left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p<0.001) buthypertrophy (≥13mm) was only present in 18.4% (n=9/49, 95% CI 9 to 32%). SARC-HCMP/LP were still associated with heart failure after adjustment for wall thickness (HR 6.74,95% CI 2.43 to 18.7, p<0.001).Conclusions: In this population of middle-aged adults, SARC-HCM-P/LP variants have lowaggregate penetrance for overt HCM but are associated with increased risk of adversecardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absoluteevent rates are low, identification of these variants may enhance risk stratification beyondfamilial disease.
Smole T, Zunkovic B, Piculin M, et al., 2021, A machine learning-based risk stratification model for ventricular tachycardia and heart failure in hypertrophic cardiomyopathy, COMPUTERS IN BIOLOGY AND MEDICINE, Vol: 135, ISSN: 0010-4825
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- Citations: 18
Jordan E, Peterson L, Ai T, et al., 2021, An evidence-based assessment of genes in dilated cardiomyopathy, Circulation, Vol: 144, Pages: 7-19, ISSN: 0009-7322
Background: The cardiomyopathies, classically categorized as hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular (ARVC), each have a signature genetic theme. HCM and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning more than 10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted.Methods: An international Panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The Panel utilized the ClinGen semi-quantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories based on the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated.Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from eight gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%) (ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including two additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, six were similarly classified for HCM and three for ARVC. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence.Conclusions: In the curation of 51 genes, 19 had high evidence (12 definitive/strong; seven m
Thompson AD, Helms AS, Kannan A, et al., 2021, Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation, Genetics in Medicine, Vol: 23, Pages: 1281-1287, ISSN: 1098-3600
Purpose: Variants in MYBPC3 causing loss of function are the most common cause of hypertrophic cardiomyopathy (HCM). However, a substantial number of patients carry missense variants of uncertain significance (VUS) in MYBPC3. We hypothesize that a structural-based algorithm, STRUM, which estimates the effect of missense variants on protein folding, will identify a subgroup of HCM patients with a MYBPC3 VUS associated with increased clinical risk.Methods: Among 7,963 patients in the multicenter Sarcomeric Human Cardiomyopathy Registry (SHaRe), 120 unique missense VUS in MYBPC3 were identified. Variants were evaluated for their effect on subdomain folding and a stratified time-to-event analysis for an overall composite endpoint (first occurrence of ventricular arrhythmia, heart failure, all-cause mortality, atrial fibrillation, and stroke) was performed for patients with HCM and a MYBPC3 missense VUS.Results: We demonstrated that patients carrying a MYBPC3 VUS predicted to cause subdomain misfolding (STRUM+, ΔΔG ≤ −1.2 kcal/mol) exhibited a higher rate of adverse events compared with those with a STRUM- VUS (hazard ratio = 2.29, P = 0.0282). In silico saturation mutagenesis of MYBPC3 identified 4,943/23,427 (21%) missense variants that were predicted to cause subdomain misfolding.Conclusion: STRUM identifies patients with HCM and a MYBPC3 VUS who may be at higher clinical risk and provides supportive evidence for pathogenicity.
Finocchiaro G, Sheikh N, Leone O, et al., 2021, Arrhythmogenic potential of myocardial disarray in hypertrophic cardiomyopathy: genetic basis, functional consequences and relation to sudden cardiac death, EUROPACE, Vol: 23, Pages: 985-995, ISSN: 1099-5129
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- Citations: 7
Mazzarotto F, Hawley MH, Beltrami M, et al., 2021, Systematic large-scale assessment of the genetic architecture of left ventricular non-compaction reveals diverse aetiologies, Genetics in Medicine, Vol: 23, Pages: 856-864, ISSN: 1098-3600
Purpose: To characterise the genetic architecture of left ventricular non-compaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases.Methods: We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Results: We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants (TV) in MYH7, ACTN2 and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC aetiology. In particular, MYH7 TV, generally considered non-pathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7 TV heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater non-compaction compared to matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes.Conclusions: LVNC is characterised by substantial genetic overlap with DCM/HCM but is also associated with distinct non-compaction and arrhythmia aetiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological non-compaction.
de Marvao A, McGurk KA, Zheng SL, et al., 2021, Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We compared outcomes and cardiovascular phenotypes in UK Biobank participants with whole exome sequencing stratified by sarcomere-encoding variant status.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n=5,727; 1 in 35), of which 0.24% (n=474, 1 in 423) were pathogenic or likely pathogenic variants (SARC-P/LP). SARC-P/LP variants were associated with increased risk of death or major adverse cardiac events compared to controls (HR 1.68, 95% CI 1.37-2.06, p<0.001), mainly due to heart failure (HR 4.40, 95% CI 3.22-6.02, p<0.001) and arrhythmia (HR 1.55, 95% CI 1.18-2.03, p=0.002). In 21,322 participants with cardiac magnetic resonance imaging, SARC-P/LP were associated with increased left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p<0.001) and concentric remodelling (mass/volume ratio: 0.63±0.12 vs 0.58±0.09 g/mL, p<0.001), but hypertrophy (≥13mm) was only present in 16% (n=7/43, 95% CI 7-31%). Other rare sarcomere-encoding variants had a weak effect on wall thickness (9.5±1.7 vs 9.4±1.6 mm, p=0.002) with no combined excess cardiovascular risk (HR 1.00 95% CI 0.92-1.08, p=0.9).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>In the general population, SARC-P/LP variants have low aggregate penetrance for overt HCM bu
Ware J, Tadros R, Francis C, et al., 2021, Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect, Nature Genetics, Vol: 53, Pages: 128-134, ISSN: 1061-4036
The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young otherwise healthy individuals. We conducted genome-wide association studies (GWAS) and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases), and nine left ventricular (LV) traits in 19,260 UK Biobank participants with structurally-normal hearts. We identified 16 loci associated with HCM, 13 with DCM, and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased contractility with HCM risk. A polygenic risk score (PRS) explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that PRS may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
Zhang X, Walsh R, Whiffin N, et al., 2021, Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions, Genetics in Medicine, Vol: 23, Pages: 69-79, ISSN: 1098-3600
Background: Accurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning tools are useful for genome-wide variant prioritisation but remain imprecise. Since the relationship between molecular consequence and likelihood of pathogenicity varies between genes with distinct molecular mechanisms, we hypothesised that a disease-specific classifier may outperform existing genome-wide tools. Methods: We present a novel disease-specific variant classification tool, CardioBoost, that estimates the probability of pathogenicity for rare missense variants in inherited cardiomyopathies and arrhythmias, trained with variants of known clinical effect. To benchmark against state-of-the-art genome-wide pathogenicity classification tools, we assessed classification of hold-out test variants using both overall performance metrics, and metrics of high-confidence (>90%) classifications relevant to variant interpretation. We further evaluated the prioritisation of variants associated with disease and patient clinical outcomes, providing validations that are robust to potential mis-classification in gold-standard reference datasets.Results: CardioBoost has higher discriminating power than published genome-wide variant classification tools in distinguishing between pathogenic and benign variants based on overall classification performance measures with the highest area under the Precision-Recall Curve as 91% for cardiomyopathies and as 96% for inherited arrhythmias. When assessed at high-confidence (>90%) classification thresholds, prediction accuracy is improved by at least 120% over existing tools for both cardiomyopathies and arrhythmias, with significantly improved sensitivity and specificity. Finally, CardioBoost improves prioritisation of variants significantly associated with disease, and stratifies survival of patients with cardiomyopathies, confirming biologically relevant vari
Walsh R, Lahrouchi N, Glinge C, et al., 2020, Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of 5182 cases from long QT syndrome and Brugada syndrome consortia cohorts and gnomAD population controls, Publisher: SPRINGERNATURE, Pages: 63-63, ISSN: 1018-4813
Thompson AD, Helms AS, Kannan A, et al., 2020, Computational Prediction of Protein Subdomain Stability as a Novel Approach to Cardiac Myosin Binding ProteinC Variant Adjudication and Clinical Risk Stratification in Hypertrophic Cardiomyopathy, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Walsh R, Mazzarotto F, Hawley 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, European-Society-of-Cardiology (ESC) Congress, Publisher: OXFORD UNIV PRESS, Pages: 3715-3715, ISSN: 0195-668X
Walsh R, Lahrouchi N, Glinge C, et al., 2020, Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of 5182 cases from long QT syndrome and Brugada syndrome consortia cohorts and gnomAD population controls, European-Society-of-Cardiology (ESC) Congress, Publisher: OXFORD UNIV PRESS, Pages: 3686-3686, ISSN: 0195-668X
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- Citations: 1
Canepa M, Fumagalli C, Tini G, et al., 2020, Temporal trend of age at diagnosis in hypertrophic cardiomyopathy: an analysis of the international SHaRe Registry, Circulation, Vol: 13, Pages: 376-381, ISSN: 0009-7322
BACKGROUNDOver the last 50 years, the epidemiology of hypertrophic cardiomyopathy (HCM) has changed dueto increased awareness and availability of advanced diagnostic tools. We aim to describe thetemporal trends in age, gender and clinical characteristics at HCM diagnosis over >4 decades.METHODSWe retrospectively analyzed records from the ongoing multinational SHaRe registry. Overall, 7,286HCM patients diagnosed at an age ≥18 years between 1961 and 2019 were included in the analysisand divided into three eras of diagnosis (<2000, 2000-2010, >2010).RESULTSAge at diagnosis increased markedly over time (40±14 vs. 47±15 vs. 51±16 years, p<0.001), both inUS and non-US sites, with a stable male-to-female ratio of about 3:2. Frequency of familial HCMdeclined over time (38.8% vs. 34.3% vs. 32.7%, p<0.001), as well as heart failure symptoms atpresentation (NYHA III/IV: 18.1% vs. 15.8% vs. 12.6%, p<0.001). Left ventricular hypertrophybecame less marked over time (maximum wall thickness: 20±6 vs. 18±5 vs. 17±5 mm, p<0.001),while prevalence of obstructive HCM was greater in recent cohorts (peak gradient >30 mmHg:31.9% vs. 39.3% vs. 39.0%, p=0.001). Consistent with decreasing phenotypic severity, yield ofpathogenic/likely-pathogenic variants at genetic testing decreased over time (57.7% vs. 45.6% vs.38.4%, p<0.001).CONCLUSIONSEvolving HCM populations include progressively greater representation of older patients withsporadic disease, mild phenotypes and genotype-negative status. Such trend suggests a prominentrole of imaging over genetic testing in promoting HCM diagnoses and urges efforts to understandgenotype-negative disease eluding the classic monogenic paradigm
Ware J, Mazzarotto F, 2020, Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls, Genetics in Medicine, Vol: 23, Pages: 47-58, ISSN: 1098-3600
PURPOSE:Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS:We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS:Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION:Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
Helms AS, Thompson AD, Glazier AA, et al., 2020, Spatial and functional distribution of MYBPC3 pathogenic variants and clinical outcomes in patients with hypertrophic cardiomyopathy, Circulation: Genomic and Precision Medicine, Vol: 13, Pages: 396-405, ISSN: 2574-8300
Background - Pathogenic variants in MYBPC3, encoding cardiac MyBP-C, are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped HCM cohorts have precluded detailed genotype-phenotype correlations.Methods - Patients with HCM and MYBPC3 variants were identified from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Variant types and locations were analyzed, morphologic severity was assessed, and time-event analysis was performed (composite clinical outcome of sudden death, class III/IV heart failure, LVAD/transplant, atrial fibrillation). For selected missense variants falling in enriched domains, myofilament localization and degradation rates were measured in vitro.Results - Among 4,756 genotyped HCM patients in SHaRe, 1,316 patients were identified with adjudicated pathogenic truncating (N=234 unique variants, 1047 patients) or non-truncating (N=22 unique variants, 191 patients) variants in MYBPC3. Truncating variants were evenly dispersed throughout the gene, and hypertrophy severity and outcomes were not associated with variant location (grouped by 5' - 3' quartiles or by founder variant subgroup). Non-truncating pathogenic variants clustered in the C3, C6, and C10 domains (18 of 22, 82%, p<0.001 vs. gnomAD common variants) and were associated with similar hypertrophy severity and adverse event rates as observed with truncating variants. MyBP-C with variants in the C3, C6, and C10 domains was expressed in rat ventricular myocytes. C10 mutant MyBP-C failed to incorporate into myofilaments and degradation rates were accelerated by ~90%, while C3 and C6 mutant MyBP-C incorporated normally with degradation rate similar to wild-type.Conclusions - Truncating variants account for 91% of MYBPC3 pathogenic variants and cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function. Non-truncating MYBPC3 pathogenic variants are regi
Mazzarotto F, Olivotto I, Boschi B, et al., 2020, Contemporary insights into the genetics of hypertrophic cardiomyopathy: towards a new era in clinical testing?, Journal of the American Heart Association, Vol: 21, Pages: 1-22, ISSN: 2047-9980
Genetic testing for hypertrophic cardiomyopathy (HCM) is an established clinical technique, supported by30 years of research into its genetic aetiology. Although pathogenic variants are often detected in patientsand used to identify at-risk relatives, the effectiveness of genetic testing has been hampered by ambiguousgenetic associations (yielding uncertain and potentially false-positive results), difficulties in classifyingvariants and uncertainty about genotype-negative patients. Recent case-control studies on rare variation,improved data sharing and meta-analysis of case cohorts contributed to new insights into the genetic basisof HCM. In particular, while research into new genes and mechanisms remains essential, re-assessment ofMendelian genetic associations in HCM argues that current clinical genetic testing should be limited to asmall number of validated disease genes that yield informative and interpretable results. Accurate andconsistent variant interpretation has benefitted from new standardised variant interpretation guidelines andinnovative approaches to improve classification. Most cases lacking a pathogenic variant are now believedto indicate non-Mendelian HCM, with more benign prognosis and minimal risk to relatives.Here, we discuss recent advances in the genetics of HCM and their application to clinical genetic testingtogether with practical issues regarding implementation. While this review focuses on HCM, many of theissues discussed are also relevant to other inherited cardiac diseases.
Mazzarotto F, Olivotto I, Walsh R, 2020, Advantages and perils of clinical whole-exome and whole-genome sequencing in cardiomyopathy., Cardiovascular Drugs and Therapy, Vol: 34, Pages: 241-253, ISSN: 0920-3206
As the price of next-generation sequencing keeps decreasing, cost is becoming a less important discriminator for diagnostic laboratories in choosing the preferred type of approach to genetic testing. Genome-wide sequencing strategies will plausibly become the standard first-tier tools for genetic testing, with the potential for deeper understanding of the genetic architecture of cardiomyopathies and discovery of the underlying aetiology in the many patients in whom the genetic cause remains elusive. Routine usage of extended sequencing assays will also enable "genetic-first diagnostics", particularly for those patients affected with syndromic conditions of unclear genetic origin, often resulting in costly and distressing diagnostic odysseys before reaching a diagnosis. However, access to genome-wide data for all patients will need to be managed with rigour and caution by (cardiovascular) genetic professionals to avoid erroneous variant pathogenicity assertions and over-reporting uncertain findings, both damaging scenarios to patients and their family members. Researchers will also be required to adopt robust methods to demonstrate novel genetic associations with disease, given the high "narrative potential" of such large datasets and the dangers of generating further false positive associations (that have previously blighted the field of cardiac genetics). Here, we discuss advantages and dangers associated with the routine adoption of whole-exome (and whole-genome) sequencing in diagnostic facilities and in the research setting in the context of cardiomyopathies but relevant to several other conditions.
Mazzarotto F, Tayal U, Buchan RJ, et al., 2020, Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy, Circulation, Vol: 141, Pages: 387-398, ISSN: 0009-7322
Background: Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes 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 in 2538 patients with DCM across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60 706 individuals to identify clinically interpretable genes robustly associated with dominant monogenic DCM. Methods: We used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 patients with DCM and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 patients with DCM sequenced in diagnostic laboratories and the Exome Aggregation Consortium database for replication and meta-analysis. Results: Truncating variants in TTN and DSP were associated with DCM in all comparisons. Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1, and VCL were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM. Overall, rare variants in these 12 genes potentially explained 17% of cases in the outpatient clinic cohort representing a broad range of adult patients with DCM and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM. Although the absence of a significant excess in other genes cannot preclude a limited role in disease, such genes have limited diagnostic value because novel variants will be uninterpretable and their diagnostic yield is minimal. Conclusions: In the largest sequenced DCM cohort yet described, we observe robust disease association with 12 genes, highlighting their importance in DCM and translating into high
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