Publications
231 results found
Allouba M, Walsh R, Afify A, et al., 2022, Homozygosity predominantly affects hypertrophic cardiomyopathy minor genes in an Egyptian clinical cohort, Publisher: OXFORD UNIV PRESS, Pages: 2880-2880, ISSN: 0195-668X
Lota A, Hazebroek M, Theotokis P, et al., 2022, Genetic architecture of acute myocarditis and the overlap with inherited cardiomyopathy, Circulation, Vol: 146, Pages: 1123-1134, ISSN: 0009-7322
Background: Acute myocarditis is an inflammatory condition that may herald the onset of dilated (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. Methods: Population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA-sequencing for well-characterised cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. Results: Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared to <1% of healthy controls (p=0.0097). In the London cohort (n=230; median age 33years; 84% men), patients were representative of national myocarditis admissions (median age 32years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% cases vs 0.4% controls; odds ratio 8.2; p=0.001). This was driven predominantly by desmoplakin (DSP)-tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age 54years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly TTN-tv found in 7% (all with LVEF<50%) compared to 1% in controls (OR 3.6; p=0.0116). Across both cohorts over a median of 5.0 years (IQR 3.9-7.8), all-cause mortality was 5.4%. Two thirds of deaths were cardiovascular, due to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype negative patients versus 11.1% for genotype positive patients (Padjusted=0.08). Conclusions: We identified DCM- or ACM-associated genetic variants in 8% of patients wit
Dixon PH, Levine AP, Cebola I, et al., 2022, GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements, Nature Communications, Vol: 13, ISSN: 2041-1723
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1,138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility.
Reichart D, Lindberg EL, Maatz H, et al., 2022, Pathogenic variants damage cell composition and single-cell transcription in cardiomyopathies, Science, Vol: 377, Pages: 1-13, ISSN: 0036-8075
INTRODUCTIONHuman heart failure is a highly morbid condition that affects 23 million individuals worldwide. It emerges in the setting of an array of different cardiovascular disorders, which has propelled the notion that diverse stimuli converge on a common final pathway. Consistent with this, initiating etiologies do not direct heart failure treatments, which are often inadequate and necessitate mechanical interventions and cardiac transplantation.The recent application of single-nucleus RNA sequencing (snRNAseq) transcriptional analyses to characterize the cellular composition and molecular states in the healthy adult human heart provides an emerging benchmark by which disease-related changes can be assessed. Moreover, the discovery of human pathogenic variants that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM), disorders associated with high rates of heart failure, provides direct opportunities to evaluate whether genotype influences heart failure pathways.RATIONALEA systematic identification of shared and distinct molecules and pathways involved in heart failure is lacking, and knowledge of these fundamental data could propel the development of more effective treatments. To enable these discoveries, we performed snRNAseq of explanted ventricular tissues from 18 healthy donors and 61 heart failure patients. By focusing analyses on multiple samples with pathogenic variants in DCM genes (LMNA, RBM20, and TTN), ACM genes (PKP2), or pathogenic variant–negative (PV negative) samples, we characterized genotype-stratified and common heart failure responses.RESULTSFrom 881,081 nuclei isolated from left and right diseased and healthy ventricles, we identified 10 major cell types and 71 distinct transcriptional states. DCM and ACM tissues showed significant depletion of cardiomyocytes and increased endothelial and immune cells. Fibrosis was expanded in disease hearts, but, unexpectedly, fibroblasts were not increased, and instead showed a
Francis C, Futschik M, Huang J, et al., 2022, Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities, Nature Communications, Vol: 13, ISSN: 2041-1723
Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.
Wilde AAM, Semsarian C, Márquez MF, et al., 2022, European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases, Europace, Vol: 38, Pages: 491-553, ISSN: 1099-5129
DiStefano MT, Goehringer S, Babb L, et al., 2022, The Gene Curation Coalition: a global effort to harmonize gene-disease evidence resources, Genetics in Medicine, Vol: 24, Pages: 1732-1742, ISSN: 1098-3600
Purpose:Several groups and resources provide information that pertains to the validity of gene–disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed.Methods:The GenCC drafted harmonized definitions for differing levels of gene–disease validity on the basis of existing resources, and performed a modified Delphi survey with 3 rounds to narrow the list of terms. The GenCC also developed a unified database to display curated gene–disease validity assertions from its members.Results:On the basis of 241 survey responses from the genetics community, a consensus term set was chosen for grading gene–disease validity and database submissions. As of December 2021, the database contained 15,241 gene–disease assertions on 4569 unique genes from 12 submitters. When comparing submissions to the database from distinct sources, conflicts in assertions of gene–disease validity ranged from 5.3% to 13.4%.Conclusion:Terminology standardization, sharing of gene–disease validity classifications, and resolution of curation conflicts will facilitate collaborations across international curation efforts and in turn, improve consistency in genetic testing and variant interpretation.
Wilde AAM, Semsarian C, Márquez MF, et al., 2022, European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases., Journal of Arrhythmia, Vol: 38, Pages: 491-553, ISSN: 1880-4276
McGurk KA, Kasapi M, Ware JS, 2022, Effect of taurine administration on symptoms, severity, or clinical outcome of dilated cardiomyopathy and heart failure in humans: a systematic review., Wellcome open research, Vol: 7, Pages: 1-15, ISSN: 2398-502X
Background: Taurine, 2-aminoethanesulfonic acid, is an amino acid found in animal products. Taurine is produced for human consumption as a supplement and ingredient in beverages. Supplementation is a safe, inexpensive, and effective treatment for dilated cardiomyopathy (DCM) in domestic mammals, however it is currently unlicensed in Europe and the United States for human medical treatment. Recent genome-wide association studies of DCM have identified the locus of the taurine transporter ( SLC6A6). To assess whether taurine supplementation may be a novel therapeutic option for DCM, we undertook a systematic review. Methods: Four electronic databases (PubMed, Cochrane Central Register, Web of Science, Biomed Central) were searched until 11/03/21. Included studies of human participants reported measured phenotypes or symptoms for cardiomyopathy, heart failure (HF), or altered left ventricle structure or function, administering taurine in any formulation, by any method. Non-English articles were excluded. Meta-analysis was completed in R software (version 3.6.0). The Newcastle-Ottawa Scale quality assessment score (NOQAS) tool was used to assess bias. Results: 285 articles were identified, of which eleven met our criteria for inclusion. Only one paper was deemed "high quality" using the NOQAS tool. Taurine supplementation varied across studies; by dose (500 mg to 6g per day), frequency (once to thrice daily), delivery method (tablet, capsule, drink, powder), and duration (2 to 48 weeks). Patient inclusion was all-cause HF patients with ejection fraction (EF) <50% and no study was specific to DCM. While improvements in diastolic and systolic function, exercise capacity, and haemodynamic parameters were described, only EF and stroke volume were measured in enough studies to complete a meta-analysis; the association was not significant with all-cause HF (P<0.05). No significant safety concerns were reported. Conclusions: A formal clinical trial is needed to
McGurk K, Kasapi M, Ware J, 2022, Effect of taurine administration on symptoms, severity, or clinical outcome of dilated cardiomyopathy and heart failure in humans: a systematic review [version ; peer review: 2 approved], Wellcome Open Research, Vol: 7, Pages: 1-17, ISSN: 2398-502X
Background: Taurine, 2-aminoethanesulfonic acid, is an amino acid found in animal products. Taurine is produced for human consumption as a supplement and ingredient in beverages. Supplementation is a safe, inexpensive, and effective treatment for dilated cardiomyopathy (DCM) in domestic mammals, however it is currently unlicensed in Europe and the United States for human medical treatment. Recent genome-wide association studies of DCM have identified the locus of the taurine transporter (SLC6A6). To assess whether taurine supplementation may be a novel therapeutic option for DCM, we undertook a systematic review.Methods: Four electronic databases (PubMed, Cochrane Central Register, Web of Science, Biomed Central) were searched until 11/03/21. Included studies of human participants reported measured phenotypes or symptoms for cardiomyopathy, heart failure (HF), or altered left ventricle structure or function, administering taurine in any formulation, by any method. Non-English articles were excluded. Meta-analysis was completed in R software (version 3.6.0). The Newcastle-Ottawa Scale quality assessment score (NOQAS) tool was used to assess bias.Results: 285 articles were identified, of which eleven met our criteria for inclusion. Only one paper was deemed “high quality” using the NOQAS tool. Taurine supplementation varied across studies; by dose (500 mg to 6g per day), frequency (once to thrice daily), delivery method (tablet, capsule, drink, powder), and duration (2 to 48 weeks). Patient inclusion was all-cause HF patients with ejection fraction (EF) <50% and no study was specific to DCM. While improvements in diastolic and systolic function, exercise capacity, and haemodynamic parameters were described, only EF and stroke volume were measured in enough studies to complete a meta-analysis; the association was not significant with all-cause HF (P<0.05). No significant safety concerns were reported.Conclusions: A formal clinical trial is needed to a
Wilde AAM, Semsarian C, Márquez MF, et al., 2022, European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus statement on the state of genetic testing for cardiac diseases, Heart Rhythm, Vol: 19, Pages: e1-e60, ISSN: 1547-5271
Genetic testing has advanced significantly since the publication of the 2011 HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies.1 In addition to single-gene testing, there is now the ability to perform whole-exome sequencing (WES) and whole-genome sequencing (WGS). There is growing appreciation of oligogenic disorders,2,3 the role of modifier genes,2 and the use of genetic testing for risk stratification, even in common cardiac diseases such as coronary artery disease or atrial fibrillation (AFib), including a proposal for a score awaiting validation.4 This document reviews the state of genetic testing at the present time, and addresses the questions of what tests to perform and when to perform them. It should be noted that, as articulated in a 1999 Task Force Document by the European Society of Cardiology (ESC) on the legal value of medical guidelines,5 ‘The guidelines from an international organization, such as the ESC, have no specific legal territory and have no legally enforcing character. Nonetheless, in so far as they represent the state-of-the-art, they may be used as indicating deviation from evidence-based medicine in cases of questioned liability’. In the case of potentially lethal and treatable conditions such as catecholaminergic polymorphic ventricular tachycardia (CPVT) or long QT syndrome (LQTS), it is the responsibility of the physician, preferably in conjunction with an expert genetics team, to communicate to the patient/family the critical importance of family screening, whether this be facilitated by cascade genetic testing or by broader clinical family screening
Patel K, li X, xu X, et al., 2022, Increasing adiposity is associated with QTc interval prolongation and increased ventricular arrhythmic risk in the context of metabolic dysfunction: results from the UK Biobank, Frontiers in Cardiovascular Medicine, Vol: 9, Pages: 1-11, ISSN: 2297-055X
Background: Small-scale studies have linked obesity (Ob) and metabolic ill-health with proarrhythmic repolarisation abnormalities. Whether these are observed at a population-scale, modulated by individuals’ genetics and confer higher risks of ventricular arrhythmias (VA) are not known. Methods and Results: Firstly, using the UK Biobank, the association between adiposity and QTc interval was assessed in participants with resting 12-lead ECG (n=23,683), and a polygenic risk score was developed to investigate any modulatory effect of genetics. Participants were also categorised into four phenotypes according to presence (+) or absence (-) of Ob, and if they were metabolically unhealthy (MU+) or not (MU-). QTc was positively associated with body mass index, body fat, waist:hip ratio, and hip and waist girths. Individuals’ genetics had no significant modulatory effect on QTc-prolonging effects of increasing adiposity. QTc was comparably longer in those with metabolic perturbationwithout obesity (Ob-MU+) and obesity alone (Ob+MU-) compared to individuals with neither (Ob-MU-), and their co-existence (Ob+MU+) had an additive effect on QTc interval. Secondly, for 502,536 participants in the UK Biobank, odds ratios (OR) for ventricular arrhythmias (VA) were computed for the four clinical phenotypes above using their past medical records. Referenced to Ob-MU-, ORs for VA in Ob-MU+ males and females were 5.96 (95%CI: 4.70-7.55) and 5.10 (95%CI: 3.34-7.80), respectively. OR for Ob+MU+ were 6.99 (95%CI: 5.72-8.54) and 3.56 (95%CI: 2.66-4.77) in males and females, respectively. Conclusion: Adiposity and metabolic perturbation increase QTc to a similar degree, and their co-existence exerts an additive effect. These effects are not modulated by individuals’ genetics. Metabolic ill-health is associated with higher OR for VA than obesity.
Tayal U, Verdonschot JAJ, Hazebroek MR, et al., 2022, Precision phenotyping of dilated cardiomyopathy using multidimensional data., Journal of the American College of Cardiology, Vol: 79, Pages: 2219-2232, ISSN: 0735-1097
BACKGROUND: Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction. OBJECTIVES: The purpose of this study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification. METHODS: Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years). RESULTS: In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005). CONCLUSIONS: Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to trad
Patel K, Bajaj N, Statton B, et al., 2022, Bariatric surgery reverses ventricular repolarisation heterogeneity – mechanistic insights into fat-related arrhythmic risk, British Cardiovascular Society Annual Conference, ‘100 years of Cardiology’, 6–8 June 2022, Publisher: BMJ Publishing Group, Pages: A60-A61, ISSN: 1355-6037
Tayal U, 2022, Exposure to elevated nitrogen dioxide concentrations and cardiac remodelling in patients with dilated cardiomyopathy, Journal of Cardiac Failure, Vol: 28, Pages: 924-934, ISSN: 1071-9164
Rationale: Empirical evidence suggests a strong link between exposure to air pollution and heart failure incidence, hospitalisations and mortality, but the biological basis of this remains unclear. Objective: To determine the relationship between differential air pollution levels and changes in cardiac structure and function in patients with dilated cardiomyopathy. Methods and Results: We undertook a prospective longitudinal observational cohort study of patients in England with dilated cardiomyopathy (enrollment 2009-2015; n=716, 66% male, 85% Caucasian) and conducted cross sectional analysis at the time of study enrollment. Annual average air pollution exposure estimates for nitrogen dioxide (NO2) and particulate matter with diameter ≤ 2.5µm (PM2.5) at enrolment were assigned to each residential postcode (on average 12 households). The relationship between air pollution and cardiac morphology was assessed using linear regression modelling. Greater ambient exposure to NO2 was associated with higher indexed left ventricular mass (4.3 g/m2 increase per interquartile range (IQR) increase in NO2, 95% CI 1.9 to 7.0 g/m2) and lower left ventricular ejection fraction (-1.5% decrease per IQR increase in NO2, 95% CI -2.7 to -0.2%), independent of age, sex, socio-economic status and clinical covariates. The associations were robust to adjustment for smoking status and geographical clustering by postcode area. The effect of air pollution on left ventricular mass was greatest in women. These effects were specific to NO2 exposure. Conclusion: Exposure to air pollution is associated with raised left ventricular mass and lower left ventricular ejection fraction, with the strongest effect in women. Whilst epidemiological associations between air pollution and heart failure have been established and supported by pre-clinical studies, our findings provide novel empirical evidence of cardiac remodelling and exposure to air pollution with important clinical and public health
Mahmood A, Morris-Rosendahl D, Edwards M, et al., 2022, DISEASE PENETRANCE IN ASYMPTOMATIC CARRIERS OF FAMILIAL CARDIOMYOPATHY VARIANTS, Annual Conference of the British-Cardiovascular-Society - 100 Years of Cardiology, Publisher: BMJ PUBLISHING GROUP, Pages: A9-A9, ISSN: 1355-6037
Thanaj M, Mielke J, McGurk K, et al., 2022, Genetic and environmental determinants of diastolic heart function, Nature Cardiovascular Research, Vol: 1, Pages: 361-371, ISSN: 2731-0590
Diastole is the sequence of physiological events that occur in the heart during ventricular filling and principally depends onmyocardial relaxation and chamber stiffness. Abnormal diastolic function is related to many cardiovascular disease processesand is predictive of health outcomes, but its genetic architecture is largely unknown. Here, we use machine learning cardiacmotion analysis to measure diastolic functional traits in 39,559 participants of the UK Biobank and perform a genome-wideassociation study. We identified 9 significant, independent loci near genes that are associated with maintaining sarcomericfunction under biomechanical stress and genes implicated in the development of cardiomyopathy. Age, sex and diabetes wereindependent predictors of diastolic function and we found a causal relationship between genetically-determined ventricularstiffness and incident heart failure. Our results provide insights into the genetic and environmental factors influencing diastolicfunction that are relevant for identifying causal relationships and potential tractable targets.
Stroeks SLVMSLVM, Hellebrekers DMEI, Krapels IPC, et al., 2022, Clinical impact of re-evaluating genes and variants implicated in dilated cardiomyopathy, Publisher: SPRINGERNATURE, Pages: 189-189, ISSN: 1018-4813
Tayal U, gregson J, Buchan R, et al., 2022, Moderate excess alcohol consumption and adverse cardiac remodelling in dilated cardiomyopathy, Heart, Vol: 108, Pages: 619-625, ISSN: 1355-6037
Objective The effect of moderate excess alcohol consumption is widely debated and has not been well defined in dilated cardiomyopathy (DCM). There is need for a greater evidence base to help advise patients. We sought to evaluate the effect of moderate excess alcohol consumption on cardiovascular structure, function and outcomes in DCM. Methods Prospective longitudinal observational cohort study. Patients with DCM (n=604) were evaluated for a history of moderate excess alcohol consumption (UK government guidelines; >14 units/week for women, >21 units/week for men) at cohort enrollment, had cardiovascular magnetic resonance and were followed up for the composite endpoint of cardiovascular death, heart failure and arrhythmic events. Patients meeting criteria for alcoholic cardiomyopathy were not recruited. ResultsDCM patients with a history of moderate excess alcohol consumption (n=98, 16%) had lower biventricular function and increased chamber dilatation of the left ventricle, right ventricle and left atrium, as well as increased left ventricular hypertrophy compared to patients without moderate alcohol consumption. They were more likely to be male (alcohol excess group– n =92, 94% vs n =306, 61%, p=<0.001). After adjustment for biological sex, moderate excess alcohol was not associated with adverse cardiac structure. There was no difference in mid-wall myocardial fibrosis between groups. Prior moderate excess alcohol consumption did not affect prognosis (HR 1.29, 0.73 to 2.26, p=0.38) during median follow up of 3.9 years. ConclusionDilated cardiomyopathy patients with moderate excess alcohol consumption have adverse cardiac structure and function at presentation but this is largely due to biological sex. Alcohol may contribute to sex-specific phenotypic differences in DCM. These findings help to inform lifestyle discussions for patients with dilated cardiomyopathy.
Loong L, Cubuk C, Choi S, et al., 2022, Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants, Genetics in Medicine, Vol: 24, Pages: 552-563, ISSN: 1098-3600
PURPOSE: Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice. METHODS: We used as a truthset 7541 dichotomous functional classifications of BRCA1 and MSH2, spanning 311 codons of BRCA1 and 918 codons of MSH2, generated from large-scale functional assays that have been shown to correlate excellently with clinical classifications. We assessed PM5 at 5 stringencies with incorporation of 8 in silico tools. For each analysis, we quantified a positive likelihood ratio (pLR, true positive rate/false positive rate), the predictive value of PM5-lookup in ClinVar compared with the functional truthset. RESULTS: pLR was 16.3 (10.6-24.9) for variants for which there was exactly 1 additional colocated deleterious variant on ClinVar, and the variant under examination was equally or more damaging when analyzed using BLOSUM62. pLR was 71.5 (37.8-135.3) for variants for which there were 2 or more colocated deleterious ClinVar variants, and the variant under examination was equally or more damaging than at least 1 colocated variant when analyzed using BLOSUM62. CONCLUSION: These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met.
McGurk KA, Zheng SL, Henry A, et al., 2022, Correspondence on "ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)" by Miller et al, Genetics in Medicine, Vol: 24, Pages: 744-746, ISSN: 1098-3600
Zhang X, Theotokis PI, Li N, et al., 2022, Genetic constraint at single amino acid resolution improves missense variant prioritisation and gene discovery
<jats:title>Abstract</jats:title><jats:p>The clinical impact of most germline missense variants in humans remains unknown. Genetic constraint identifies genomic regions under negative selection, where variations likely have functional impacts, but the spatial resolution of existing constraint metrics is limited. Here we present the Homologous Missense Constraint (HMC) score, which measures genetic constraint at quasi single amino-acid resolution by aggregating signals across protein homologues. We identify one million possible missense variants under strong negative selection. HMC precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising <jats:italic>de novo</jats:italic> mutations from probands with developmental disorders (DD), and is orthogonal to these, adding power when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly-significant associated with DD that could act through an altered-function mechanism. Overall, HMC is a novel and strong predictor to improve missense variant interpretation.</jats:p>
Hammersley D, Buchan R, Lota A, et al., 2022, Direct and indirect effect of the COVID-19 pandemic on patients with cardiomyopathy, Open Heart, Vol: 9, Pages: 1-9, ISSN: 2053-3624
Objectives: (i) To evaluate the prevalence and hospitalisation rate of COVID-19 infections amongst patients with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) in the Royal Brompton & Harefield Hospital Cardiovascular Research Centre (RBHH CRC) Biobank. (ii) To evaluate the indirect impact of the pandemic on patients with cardiomyopathy through the Heart Hive COVID-19 study. (iii) To assess the impact of the pandemic on national cardiomyopathy-related hospital admissions.Methods: (i) 1,236 patients (703 DCM, 533 HCM) in the RBHH CRC Biobank were assessed for COVID-19 infections and hospitalisations; ii) 207 subjects (131 cardiomyopathy, 76 without heart disease) in the Heart Hive COVID-19 study completed online surveys evaluating physical health, psychological wellbeing, and behavioural adaptations during the pandemic; (iii) 11,447 cardiomyopathy-related hospital admissions across NHS England were studied from NHS Digital Hospital Episode Statistics over 2019-2020. Results: A comparable proportion of patients with cardiomyopathy in the RBHH CRC Biobank had tested positive for COVID-19 compared with the UK population (1.1% vs 1.6%, p=0.14), but a higher proportion of those infected were hospitalised (53.8% vs 16.5%, p=0.002). In the Heart Hive COVID-19 study, more patients with cardiomyopathy felt their physical health had deteriorated due to the pandemic than subjects without heart disease (32.3% vs 13.2%, p=0.004) despite only 4.6% of the cardiomyopathy cohort reporting COVID-19 symptoms. A 17.9% year-on-year reduction in national cardiomyopathy-related hospital admissions was observed in 2020.Conclusion: Patients with cardiomyopathy had similar reported rates of testing positive for COVID-19 to the background population, but those with test-proven infection were hospitalised more frequently. Deterioration in physical health amongst patients could not be explained by COVID-19 symptoms, inferring a significant contribution of the indirect con
DiStefano MT, Goehringer S, Babb L, et al., 2022, The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources
<jats:sec><jats:title>PURPOSE</jats:title><jats:p>Several groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease, and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>The GenCC drafted harmonized definitions for differing levels of gene-disease validity based on existing resources, and performed a modified Delphi survey with three rounds to narrow the list of terms. The GenCC also developed a unified database to display curated gene-disease validity assertions from its members.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Based on 241 survey responses from the genetics community, a consensus term set was chosen for grading gene-disease validity and database submissions. As of December 2021, the database contains 15,241 gene-disease assertions on 4,569 unique genes from 12 submitters. When comparing submissions to the database from distinct sources, conflicts in assertions of gene-disease validity ranged from 5.3% to 13.4%.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p>Terminology standardization, sharing of gene-disease validity classifications, and resolution of curation conflicts will facilitate collaborations across international curation efforts and in turn, improve consistency in genetic testing and variant interpretation.</jats:p></jats:sec>
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.
Lota AS, Tsao A, Owen R, et al., 2021, Prognostic significance of non-ischaemic patterns of myocardial fibrosis in patients with normal left ventricular volumes and ejection fraction – the FINALIZE study, JACC: Cardiovascular Imaging, Vol: 14, Pages: 2353-2365, ISSN: 1876-7591
Background: Non-ischaemic patterns of late gadolinium enhancement (LGE) with normal left ventricular volumes and ejection fraction are increasingly detected on cardiovascular magnetic resonance (CMR) but their prognostic significance, and consequently management, is uncertain. Objectives: To investigate the prognostic significance of LGE in patients without coronary artery disease and with normal range LV volumes and ejection fraction. Methods: Patients with mid-wall/subepicardial LGE and normal LV volumes, wall thickness and ejection fraction on CMR were enrolled and compared to a control group without LGE.57 The primary outcome was actual or aborted sudden cardiac death (SCD). Results: Of 748 patients enrolled, 401 had LGE and 347 did not. Median age was 50 years (IQR 38-61), LV ejection fraction 66% (IQR 62-70) and 287 (38%) were women. Scan indications included chest pain (40%), palpitation (33%) and breathlessness (13%). Nopatient experienced SCD and only one LGE+ patient (0.13%) had an aborted SCD in the 11th follow-up year. Over a median of 4.3years, thirty patients (4.0%) died. All-cause mortality was similar for LGE+/- patients (3.7% vs 4.3%; p=0.71) and was associated with age (H 2.04 per 10-years; 95%CI 1.46-2.79; p<0.001). Twenty-one LGE+ and 4 LGE- patients had an unplanned CV hospitalisation (HR 7.22; 95%CI 4.26-21.17; p<0.0001). Conclusion: There was a low SCD risk during long-term follow-up in patients with LGE but otherwise normal LV volumes and ejection fraction. Mortality was driven by age and not LGE presence, location or extent, although the latter was associated with greater CV hospitalisation for suspected myocarditis and symptomatic ventricular tachycardia.
Lampert R, Ackerman MJ, Marino BS, et al., 2021, Physical Activity in Individuals With Hypertrophic Cardiomyopathy: Baseline Data From the Prospective "Lifestyle and Exercise in Hcm" (live-hcm) Study, Annual Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Tayal U, Owen R, Buchan R, et al., 2021, Biological Sex as a Modifier of the Natural History of Dilated Cardiomyopathy, Annual Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Lota AS, Meena D, Halliday B, et al., 2021, Impact of Covid-19 on Acute Myocarditis Hospital Admissions in the National Health Service of England, Uk (2019-2020), Annual Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Lota AS, Hazebroek M, Theotokis P, et al., 2021, Genetic Overlap of Acute Myocarditis and Inherited Cardiomyopathy, Annual Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
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