Publications
79 results found
Corden B, Jarman J, Whiffin N, et al., 2019, Association between titin truncating variants and life-threatening cardiac arrhythmias in patients with dilated cardiomyopathy and implantable defibrillator, JAMA Network Open, Vol: 2, Pages: 1-12, ISSN: 2574-3805
Importance There is a need for better arrhythmic risk stratification in nonischemic dilated cardiomyopathy (DCM). Titin-truncating variants (TTNtvs) in the TTN gene are the most common genetic cause of DCM and may be associated with higher risk of arrhythmias in patients with DCM.Objective To determine if TTNtv status is associated with the development of life-threatening ventricular arrhythmia and new persistent atrial fibrillation in patients with DCM and implanted cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) devices.Design, Setting, and Participants This retrospective, multicenter cohort study recruited 148 patients with or without TTNtvs who had nonischemic DCM and ICD or CRT-D devices from secondary and tertiary cardiology clinics in the United Kingdom from February 1, 2011, to June 30, 2016, with a median (interquartile range) follow-up of 4.2 (2.1-6.5) years. Exclusion criteria were ischemic cardiomyopathy, primary valve disease, congenital heart disease, or a known or likely pathogenic variant in the lamin A/C gene. Analyses were performed February 1, 2017, to May 31, 2017.Main Outcome and Measures The primary outcome was time to first device-treated ventricular tachycardia of more than 200 beats/min or first device-treated ventricular fibrillation. Secondary outcome measures included time to first development of persistent atrial fibrillation.Results Of 148 patients recruited, 117 adult patients with nonischemic DCM and an ICD or CRT-D device (mean [SD] age, 56.9 [12.5] years; 76 [65.0%] men; 106 patients [90.6%] with primary prevention indications) were included. Having a TTNtv was associated with a higher risk of receiving appropriate ICD therapy (shock or antitachycardia pacing) for ventricular tachycardia or fibrillation (hazard ratio [HR], 4.9; 95% CI, 2.2-10.7; P < .001). This association was independent of all covariates, including midwall fibrosis measured by late gadolinium enhanc
Wei W, Tuna S, Keogh MJ, et al., 2019, Germline selection shapes human mitochondrial DNA diversity, Science, Vol: 364, ISSN: 0036-8075
INTRODUCTIONOnly 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear.Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans.RATIONALETo determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals.RESULTSPreviously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between
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
Rhodes CJ, Batai K, Bleda M, et al., 2019, Genetic determinants of risk in pulmonary arterial hypertension: international case-control studies and meta-analysis, Lancet Respiratory Medicine, Vol: 7, Pages: 227-238, ISSN: 2213-2600
BackgroundRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.MethodsWe did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.FindingsA locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-media
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
Ware JS, Amor-Salamanca A, Tayal U, et al., 2018, A genetic etiology for alcohol-induced cardiac toxicity, Journal of the American College of Cardiology, Vol: 71, Pages: 2293-2302, ISSN: 0735-1097
Background: Alcoholic cardiomyopathy (ACM) is defined by a dilated and impaired left ventricle due to chronic excess alcohol consumption. It is largely unknown what factors determine cardiac toxicity on exposure to alcohol.Objectives: We sought to evaluate the role of variation in cardiomyopathy-associated genes in the pathophysiology of ACM, and to examine the effects of alcohol intake and genotype on DCM severity.Methods: We characterized 141 ACM cases, 716 dilated cardiomyopathy (DCM) cases and 445 healthy volunteers. We compared the prevalence of rare, protein-altering variants in 9 genes associated with inherited DCM. We evaluated the effect of genotype and alcohol-consumption on phenotype in DCM.Results: Variants in well-characterized DCM-causing genes were more prevalent in patients with ACM than controls (13.5% vs 2.9%; P=1.2e-05), but similar between patients with ACM and DCM (19.4%; P=0.12) and with a predominant burden of Titin-truncating variants (TTNtv, 9.9%). Separately, we identified an interaction between TTN genotype and excess alcohol consumption in a cohort of DCM patients not meeting ACM criteria. On multivariate analysis, DCM patients with a TTNtv who consumed excess alcohol had an 8.7% absolute reduction in ejection fraction (95% CI -2.3 to -15.1, P<0.007) compared with those without TTNtv and excess alcohol consumption. The presence of TTNtv did not predict phenotype, outcome or functional recovery on treatment in ACM patients. Conclusions: TTNtv represent a prevalent genetic predisposition for ACM, and are also associated with a worse LVEF in DCM patients who consume alcohol above recommended levels. Familial evaluation and genetic testing should be considered in patients presenting with ACM.
de Marvao A, Biffi C, Walsh R, et al., 2018, Defining The Effects Of Genetic Variation Using Machine Learning Analysis Of CMRs: A Study In Hypertrophic Cardiomyopathy And In A Healthy Population, Joint Meeting of the British-Society-of-Cardiovascular-Imaging/British-Society-of-Cardiovascular-CT, British-Society-of-Cardiovascular-Magnetic-Resonance and British-Nuclear-Cardiac-Society on British Cardiovascular Imaging, Publisher: BMJ PUBLISHING GROUP, Pages: A7-A8, ISSN: 1355-6037
Whiffin N, walsh R, Govind R, et al., 2018, CardioClassifier: disease- and gene-specific computational decision support for clinical genome interpretation, Genetics in Medicine, Vol: 20, Pages: 1246-1254, ISSN: 1098-3600
PurposeInternationally adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier (http://www.cardioclassifier.org), a semiautomated decision-support tool for inherited cardiac conditions (ICCs).MethodsCardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support variant interpretation. Combining disease- and gene-specific knowledge with variant observations in large cohorts of cases and controls, we refined 14 computational ACMG criteria and created three ICC-specific rules.ResultsWe benchmarked CardioClassifier on 57 expertly curated variants and show full retrieval of all computational data, concordantly activating 87.3% of rules. A generic annotation tool identified fewer than half as many clinically actionable variants (64/219 vs. 156/219, Fisher’s P = 1.1 × 10−18), with important false positives, illustrating the critical importance of disease and gene-specific annotations. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data.ConclusionCardioClassifier is an ICC-specific decision-support tool that integrates expertly curated computational annotations with case-specific data to generate fast, reproducible, and interactive variant pathogenicity reports, according to best practice guidelines.
Walsh R, Buchan R, Wilk A, et al., 2017, Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes, European Heart Journal, Vol: 38, Pages: 3461-3468, ISSN: 1522-9645
Aim: Hypertrophic cardiomyopathy (HCM)exhibits genetic heterogeneity that is dominated by variation in eight sarcomericgenes.Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM.Methods and results: We sequenced known and putative HCM genes ina new large prospective HCM cohort (n=804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n=6179), previously published HCM cohorts and reference population samples from the Exome Aggregation Consortium (ExAC, n=60,706) to assess variation in 31 genes implicated in HCM. We foundno significant excess of rare (minor allele frequency < 1:10,000 in ExAC)protein-alteringvariants over controls for most genes tested and conclude that novel variantsin these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, weintegratedHCM gene sequencedata with aggregatedpedigreeand functional data and suggest ameans of assessing genepathogenicity in HCMusing this evidence. Conclusions: We show that genetic variation in the majority of non-sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority ofpatients.
Corden B, Jarman J, Whiffin N, et al., 2017, Titin Truncating Variants Predict Life-threatening Arrhythmias in Patients With Dilated Cardiomyopathy, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Corden B, Jarman J, Whiffin N, et al., 2017, Titin Truncating Variants Predict Life-threatening Arrhythmias in Patients With Dilated Cardiomyopathy, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: American Heart Association, Pages: E96-E96, ISSN: 0009-7322
Introduction: There is an urgent need for better arrhythmic risk stratification in non-ischaemic dilated cardiomyopathy (DCM), where the benefit of ICD implantation is unclear. Titin truncating variants (TTNtv) are the commonest genetic cause of DCM and are associated with early onset non-sustained ventricular tachycardia (NSVT) and atrial fibrillation (AF) in these patients.Hypothesis: We hypothesize that TTNtv status can predict potentially life threatening ventricular tachycardia (VT) or fibrillation (VF) and development of new persistent AF in DCM patients with CRT-D or ICD devices.Methods: We studied 117 DCM patients with an ICD or CRT-D and documented device-recorded arrhythmia over a median period of 4.2 years. Patients were stratified by TTN genotype (28 positive for a TTNtv, 89 negative). The primary outcome was time to first device-treated VT >200bpm or VF. Secondary outcome measures included time to first development of persistent AF.Results: TTNtv predicted the risk of receiving an appropriate ICD therapy for VT/VF (hazard ratio [HR] = 4.9, 95% confidence interval [CI]=2.3-10.7, P<0.0001). This association was independent of all covariates, including replacement fibrosis measured by late-gadolinium enhancement (LGE), (adjusted HR = 8.2, 95% CI 1.9-36.5, P=0.005). Individuals with both a TTNtv and fibrosis had a markedly greater risk for appropriate device therapy than those with neither (HR = 16.6, CI 3.5-79.3, P<0.0001). TTNtv were also a risk factor for developing new persistent AF (HR = 4.4, 95% CI = 1.45-13.1, P=0.006).Conclusion: TTNtv status is an important risk factor for clinically significant arrhythmia in patients with DCM and CRT-D or ICD devices. TTNtv status alone, or more powerfully in combination with fibrosis imaging by MRI, may provide an effective approach for risk stratifying the need for ICD therapy in DCM patients.
Tayal U, Newsome S, Buchan R, et al., 2017, Phenotype and clinical outcomes of titin cardiomyopathy, Journal of the American College of Cardiology, Vol: 70, Pages: 2264-2274, ISSN: 0735-1097
Background Improved understanding of dilated cardiomyopathy (DCM) due to titin truncation (TTNtv) may help guide patient stratification.Objectives The purpose of this study was to establish relationships among TTNtv genotype, cardiac phenotype, and outcomes in DCM.Methods In this prospective, observational cohort study, DCM patients underwent clinical evaluation, late gadolinium enhancement cardiovascular magnetic resonance, TTN sequencing, and adjudicated follow-up blinded to genotype for the primary composite endpoint of cardiovascular death, and major arrhythmic and major heart failure events.Results Of 716 subjects recruited (mean age 53.5 ± 14.3 years; 469 men [65.5%]; 577 [80.6%] New York Heart Association function class I/II), 83 (11.6%) had TTNtv. Patients with TTNtv were younger at enrollment (49.0 years vs. 54.1 years; p = 0.002) and had lower indexed left ventricular mass (5.1 g/m2 reduction; padjusted = 0.03) compared with patients without TTNtv. There was no difference in biventricular ejection fraction between TTNtv+/− groups. Overall, 78 of 604 patients (12.9%) met the primary endpoint (median follow-up 3.9 years; interquartile range: 2.0 to 5.8 years), including 9 of 71 patients with TTNtv (12.7%) and 69 of 533 (12.9%) without. There was no difference in the composite primary outcome of cardiovascular death, heart failure, or arrhythmic events, for patients with or without TTNtv (hazard ratio adjusted for primary endpoint: 0.92 [95% confidence interval: 0.45 to 1.87]; p = 0.82).Conclusions In this large, prospective, genotype-phenotype study of ambulatory DCM patients, we show that prognostic factors for all-cause DCM also predict outcome in TTNtv DCM, and that TTNtv DCM does not appear to be associated with worse medium-term prognosis.
Kassem HS, Walsh R, Barton PJ, et al., 2017, A comparative study of mutation screening of sarcomeric genes ( MYBPC3 , MYH7 , TNNT2 ) using single gene approach versus targeted gene panel next generation sequencing in a cohort of HCM patients in Egypt, Egyptian Journal of Medical Human Genetics, Vol: 18, Pages: 381-387, ISSN: 1110-8630
BackgroundNGS enables simultaneous sequencing of large numbers of associated genes in genetic heterogeneous disorders, in a more rapid and cost-effective manner than traditional technologies. However there have been limited direct comparisons between NGS and more established technologies to assess the sensitivity and false negative rates of this new approach. The scope of the present manuscript is to compare variants detected in MYBPC3, MYH7 and TNNT2 genes using the stepwise dHPLC/Sanger versus targeted NGS.MethodsIn this study, we have analysed a group of 150 samples of patients from the Bibliotheca Alexandrina-Aswan Heart Centre National HCM program. The genetic testing was simultaneously undertaken by high throughput denaturing high-performance liquid chromatography (dHPLC) followed by Sanger based sequencing and targeted next generation deep sequencing using panel of inherited cardiac genes (ICC). The panel included over 100 genes including the 3 sarcomeric genes. Analysis of the sequencing data of the 3 genes was undertaken in a double blinded strategy.ResultsNGS analysis detected all pathogenic and likely pathogenic variants identified by dHPLC (50 in total, some samples had double hits). There was a 0% false negative rate for NGS based analysis. Nineteen variants were missed by dHPLC and detected by NGS, thus increasing the diagnostic yield in this co- analysed cohort from 22.0% (33/150) to 31.3% (47/150).Of interest to note that the mutation spectrum in this Egyptian HCM population revealed a high rate of homozygosity in MYBPC3 and MYH7 genes in comparison to other population studies (6/150, 4%). None of the homozygous samples were detected by dHPLC analysis.ConclusionNGS provides a useful and rapid tool to allow panoramic screening of several genes simultaneously with a high sensitivity rate amongst genes of known etiologic role allowing high throughput analysis of HCM patients and relevant control series in a less characterised population.
Rossi R, Scotton C, Barton P, et al., 2017, <i>POPDC1</i> gene mutation screening in patients with LGMD and heart disturbances: a mutation load effect?, 22nd International Annual Congress of the World-Muscle-Society (WMS), Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: S140-S140, ISSN: 0960-8966
Biffi C, Simoes Monteiro de Marvao A, Attard M, et al., 2017, Three-dimensional Cardiovascular Imaging-Genetics: A Mass Univariate Framework, Bioinformatics, ISSN: 1367-4803
Motivation: Left ventricular (LV) hypertrophy is a strong predictor of cardiovascular outcomes, but its genetic regulation remains largely unexplained. Conventional phenotyping relies on manual calculation of LV mass and wall thickness, but advanced cardiac image analysis presents an opportunity for highthroughput mapping of genotype-phenotype associations in three dimensions (3D).Results: High-resolution cardiac magnetic resonance images were automatically segmented in 1,124 healthy volunteers to create a 3D shape model of the heart. Mass univariate regression was used to plot a 3D effect-size map for the association between wall thickness and a set of predictors at each vertex in the mesh. The vertices where a significant effect exists were determined by applying threshold-free cluster enhancement to boost areas of signal with spatial contiguity. Experiments on simulated phenotypic signals and SNP replication show that this approach offers a substantial gain in statistical power for cardiac genotype-phenotype associations while providing good control of the false discovery rate. This framework models the effects of genetic variation throughout the heart and can be automatically applied to large population cohorts.Availability: The proposed approach has been coded in an R package freely available at https://doi.org/10.5281/zenodo.834610 together with the clinical data used in this work.
Whiffin N, Walsh R, Govind R, et al., 2017, CardioClassifier – demonstrating the power of disease- and gene-specific computational decision support for clinical genome interpretation
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Purpose</jats:title><jats:p>Internationally-adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.cardioclassifier.org">www.cardioclassifier.org</jats:ext-link>), a semi-automated decision-support tool for inherited cardiac conditions (ICCs).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>CardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support varian interpretation. Combining disease- and gene-specific knowledge with variant observations in large cohorts of cases and controls, we refined 14 computational ACMG criteria and created three ICC-specific rules.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We benchmarked CardioClassifier on 57 expertly-curated variants and show full retrieval of all computational data, concordantly activating 87.3% of rules. A generic annotation tool identified fewer than half as many clinically-actionable variants (64/219 vs 156/219, Fisher’s <jats:bold>P</jats:bold>=1.1x10-18), with important false positives; illustrating the critical importance of disease and gene-specific annotations. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually-curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data.</jats:p></jats:sec><jats:sec><jat
Tayal U, Newsome S, Walsh R, et al., 2017, Defining the genetic architecture of dilated cardiomyopathy- insights from population genetic variation and the role of titin, Publisher: OXFORD UNIV PRESS, Pages: 821-822, ISSN: 0195-668X
Tayal U, Buchan R, Whiffin N, et al., 2017, EVALUATION OF TITIN CARDIOMYOPATHY IN PATIENTS WITH DILATED CARDIOMYOPATHY REVEALS A BLUNTED HYPERTROPHIC RESPONSE, AN EARLY ARRHYTHMIC RISK AND A SIGNIFICANT INTERACTION WITH ALCOHOL, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, Pages: A95-A95, ISSN: 1355-6037
Tayal U, Newsome S, Buchan R, et al., 2017, Truncating variants in titin independently predict early arrhythmias in patients with dilated cardiomyopathy, Journal of the American College of Cardiology, Vol: 69, Pages: 2466-2468, ISSN: 1558-3597
Tayal U, Newsome S, Voges I, et al., 2017, MULTIMODALITY ASSESSMENT OF RISK IN DILATED CARDIOMYOPATHY-THE IMPORTANCE OF CMR, 12th Annual Meeting of the British-Society-of-Cardiovascular-Magnetic-Resonance (BSCMR), Publisher: BMJ PUBLISHING GROUP, Pages: A4-A4, ISSN: 1355-6037
Tayal U, Newsome S, Whiffin N, et al., 2017, PRECISE PHENOTYPING WITH CMR IDENTIFIES MODERATE ALCOHOL CONSUMPTION AS AN IMPORTANT PHENOTYPIC MODIFIER OF TITIN CARDIOMYOPATHY, 12th Annual Meeting of the British-Society-of-Cardiovascular-Magnetic-Resonance (BSCMR), Publisher: BMJ PUBLISHING GROUP, Pages: A2-A3, ISSN: 1355-6037
Tayal U, Buchan R, Whiffin N, et al., 2017, INTEGRATED ANALYSIS OF THE CLINICAL MANIFESTATIONS AND PHENOTYPIC DRIVERS OF TITIN CARDIOMYOPATHY, 66th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC), Publisher: ELSEVIER SCIENCE INC, Pages: 2563-2563, ISSN: 0735-1097
rea G, Homfray T, Till J, et al., 2016, Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11, Cold Spring Harbor Molecular Case Studies, Vol: 3, ISSN: 2373-2873
Variants in NDUFB11, which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in NDUFB11 (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome. The case we describe here lacked the diagnostic features of MLS syndrome, but a detailed clinical comparison of the two cases revealed significant phenotypic overlap. Heterozygous variants in HCCS (which encodes an important mitochondrially targeted protein) and COX7B, which, like NDUFB11, encodes a protein of the MRC, have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and histiocytoid CM. However, a systematic review of WES data from previously published histiocytoid CM cases, alongside four additional cases presented here for the first time, did not identify any variants in these genes. We conclude that NDUFB11 variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related).
Tayal U, Newsome S, Buchan R, et al., 2016, Defining titin cardiomyopathy: genotype- phenotype correlations in a large prospective cohort of dilated cardiomyopathy patients, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 365-365, ISSN: 0195-668X
Tayal U, Newsome S, Buchan R, et al., 2016, Genetic determinants of arrhythmia in dilated cardiomyopathy, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 206-206, ISSN: 0195-668X
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
Rea G, Homfray T, Till J, et al., 2016, Whole Exome Sequencing Identifies Genetic Cause of Histiocytoid Cardiomyopathy, Annual Conference of the British-Cardiovascular-Society (BCS) on Prediction and Prevention, Publisher: BMJ Publishing Group, Pages: A138-A139, ISSN: 1468-201X
Histiocytoid cardiomyopathy (CM) is a rare, distinctive form of cardiomyopathy, characterised by malignant arrhythmias and associated sudden death. ~90% of cases present in females <2 years of age. We undertook whole exome sequencing (WES) in five unrelated affected females, including one with parental samples available. In the family trio we identified a de novo nonsense mutation in NDUFB11 (c.262C>T; p. Arg88*), located on the X chromosome and encoding a component of the mitochondrial respiratory chain (MRC). Mutations in NDUFB11, including one identical to the one we describe here, have been reported to cause microphthalmia and linear skin defects syndrome (MLS). During the course of our studies, additional mutations in NDUFB11 were associated with Histiocytoid CM by another group. Four of the affected individuals in our study did not carry variants in NDUFB11. Heterozygous mutations in HCCS (which encodes an important mitochondrially-targeted protein) and COX7B (which, like NDUFB11, encodes a protein of the MRC) have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and Histiocytoid CM. However, a systematic review of WES data from previously published cases, alongside the four additional cases presented here, did not identify any further mutations in these genes in Histiocytoid CM. We conclude thattruncating variants in NDUFB11 link the distinct phenotypes of Histiocytoid CM and MLS syndrome. Screening for malignant arrhythmias and cardiomyopathy would be appropriate in individuals with MLS syndrome. Additional nuclear encoded mitochondrial or mitochondrial DNA genes are good candidates for further causes of both Histiocytoid CM and MLS syndrome.
Tayal U, Newsome S, Buchan R, et al., 2016, The presence of a truncating mutation in titin independently associates with arrhythmic burden in patients with dilated cardiomyopathy, Heart Failure 2016 Conference, Publisher: Wiley, Pages: 156-156, ISSN: 1879-0844
Rea G, Ware JS, Homfray T, et al., 2016, HISTIOCYTOID CARDIOMYOPATHY AND MICROPHTHALMIA WITH LINEAR SKIN DEFECTS SYNDROME: PHENOTYPES LINKED BY TRUNCATING VARIANTS IN <i>NDUFB11</i>, Annual Meeting of the British-Congenital-Cardiac-Association, Publisher: BMJ PUBLISHING GROUP, Pages: A18-A18, ISSN: 1355-6037
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