Publications
32 results found
Roberts AM, DiStefano MT, Riggs ER, et al., 2024, Toward robust clinical genome interpretation: Developing a consistent terminology to characterize Mendelian disease-gene relationships-allelic requirement, inheritance modes, and disease mechanisms., Genet Med, Vol: 26
PURPOSE: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here, we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation and to support variant classification within the ACMG/AMP framework. METHODS: Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated. RESULTS: We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both Sequence Ontology (SO) and Human Phenotype Ontology (HPO) ontologies. Gene Curation Coalition member groups intend to use or map to these terms in their respective resources. CONCLUSION: The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.
Owen R, Buchan R, Frenneaux M, et al., 2024, Sex differences in the clinical presentation and natural history of dilated cardiomyopathy, JACC: Heart Failure, Vol: 12, Pages: 352-363, ISSN: 2213-1787
Background: Biological sex has a diverse impact on the cardiovascular system. Its influence on dilated cardiomyopathy (DCM) remains unresolved.Objective: To investigate sex-specific differences in DCM presentation, natural history, and prognostic factors.Methods We conducted a prospective observational cohort study of DCM patients, assessing baseline characteristics, CMR-imaging, biomarkers and genotype. The composite outcome was cardiovascular mortality or major heart-failure (HF) events. Results: Overall, 206 females and 398 males with DCM were followed for a median of 3.9 years. At baseline female patients had higher left ventricular ejection fraction (LVEF), smaller left ventricular volumes, less prevalent mid-wall myocardial fibrosis (23% vs 42%) and lower high sensitivity cardiac troponin (hs-cTnI) than males (all p<0.05), with no difference in time from diagnosis, age at enrollment, NT-proBNP levels, pathogenic DCM genetic variants, myocardial fibrosis extent or medications used for HF. Despite a more favourable profile, the risk of the primary outcome at 2 years was higher in females than males (8.6% vs 4.4%, adjusted hazard ratio 3.14, 95% CI 1.55 to 6.35, p=0.001). Between 2-5 years, the effect of sex as a prognostic modifier attenuated. Age, mid-wall myocardial fibrosis, LVEF, left atrial volume, NT-proBNP, hs-cTnI, left bundle branch block and NYHA class were not sex specific prognostic factors. Conclusions: We identify a novel paradox in prognosis for females with DCM. Female DCM patients have a paradoxical early increase in major HF events despite less prevalent myocardial fibrosis and a milder phenotype at presentation. Future studies should interrogate the mechanistic basis for these sex differences.
Gargano MA, Matentzoglu N, Coleman B, et al., 2024, The Human Phenotype Ontology in 2024: phenotypes around the world, Nucleic Acids Research, Vol: 52, Pages: D1333-D1346, ISSN: 0305-1048
The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs.
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.
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.
Brunet-Garcia L, Odori A, Fell H, et al., 2022, Noncompaction Cardiomyopathy, Sick Sinus Disease, and Aortic Dilatation: Too Much for a Single Diagnosis?, JACC Case Rep, Vol: 4, Pages: 287-293
HCN4 mutations have been reported in association with sick sinus syndrome. A more complex phenotype, including noncompaction cardiomyopathy and aortic dilatation, has recently emerged. We report 3 family members with the pathogenic p.Gly482Arg variant, emphasizing the importance of considering HCN4 mutations when this combination of features is encountered in clinical practice. (Level of Difficulty: Advanced.).
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
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>
Whiffin N, Karczewski KJ, Zhang X, et al., 2021, Characterising the loss-of-function impact of 5 ' untranslated region variants in 15,708 individuals (vol 11, 2523, 2020), Nature Communications, Vol: 12, Pages: 1-1, ISSN: 2041-1723
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.
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
Lopez-Sainz A, Dominguez F, Rocha Lopes L, et al., 2020, Clinical features and natural history of PRKAG2 variant cardiac glycogenosis, Journal of the American College of Cardiology, Vol: 76, Pages: 186-197, ISSN: 0735-1097
BackgroundPRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood.ObjectivesThe aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort.MethodsClinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied.ResultsAt first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died.ConclusionsPRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.
Whiffin N, Karczewski KJ, Zhang X, et al., 2020, Characterising the loss-of-function impact of 5' untranslated region variants in 15,708 individuals, Nature Communications, Vol: 11, Pages: 1-12, ISSN: 2041-1723
Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes.
Mazzarotto F, Tayal U, Buchan RJ, et al., 2020, Re-evaluating 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 DCM patients 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 in order 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 DCM patients and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 DCM patients sequenced in diagnostic laboratories and the ExAC 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 DCM patients and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM. Whilst the absence of a significant excess in other genes cannot preclude a limited role in disease, such genes have limited diagnostic value since novel variants will be uninterpretable and their diagnostic yield is minimal.Conclusion: 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 interpretability in diagnostic testing. The
Mazzarotto F, Hawley M, Beltrami M, et al., 2020, The genetic architecture of left ventricular non-compaction reveals both substantial overlap with other cardiomyopathies and a distinct aetiology in a subset of cases, Publisher: bioRxiv
Rationale: Left ventricular non-compaction (LVNC) is a condition characterised by trabeculations in the myocardial wall and is the subject of considerable conjecture as to whether it represents a distinct pathology or a secondary phenotype associated with other cardiac diseases, particularly cardiomyopathies. Objective: To investigate the genetic architecture of LVNC by identifying genes and variant classes robustly associated with disease and comparing these to other genetically characterised cardiomyopathies. Methods and Results: We performed rare variant association analysis using six different LVNC cohorts comprising 840 cases together with 125,748 gnomAD population controls and compared results to similar analyses with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) cases. We observed substantial overlap in genes and variant classes enriched in LVNC and DCM/HCM, indicating that in many cases LVNC belongs to a spectrum of more established cardiomyopathies, with non-compaction representing a phenotypic variation in patients with DCM- or HCM-causing variants. In contrast, five variant classes were uniquely enriched in LVNC cases, of which truncating variants in MYH7, ACTN2 and PRDM16 may represent a distinct LVNC aetiology. MYH7 truncating variants are generally considered as non-pathogenic but were detected in 2% of LVNC cases compared to 0.1% of controls, including a cluster of variants around a single splice region. Additionally, structural variants (exon deletions) in RYR2 and missense variants in the transmembrane region of HCN4 were enriched in LVNC cases, confirming prior reports regarding the association of these variant classes with combined LVNC and arrhythmia phenotypes. Conclusions: We demonstrated that genetic association analysis can clarify the relationship between LVNC and established cardiomyopathies, highlighted substantial overlap with DCM/HCM but also identified variant classes associated with distinct LVNC and with joint LVN
Whiffin N, Roberts AM, Minikel E, et al., 2019, Using high-resolution variant frequencies empowers clinical genome interpretation and enables investigation of genetic architecture, American Journal of Human Genetics, Vol: 104, Pages: 187-190, ISSN: 0002-9297
Horvat C, Johnson R, Lam L, et al., 2019, A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy, Genetics in Medicine, Vol: 21, Pages: 133-143, ISSN: 1098-3600
PurposeWe evaluated strategies for identifying disease-causing variants in genetic testing for dilated cardiomyopathy (DCM).MethodsCardiomyopathy gene panel testing was performed in 532 DCM patients and 527 healthy control subjects. Rare variants in 41 genes were stratified using variant-level and gene-level characteristics.ResultsA majority of DCM cases and controls carried rare protein-altering cardiomyopathy gene variants. Variant-level characteristics alone had limited discriminative value. Differentiation between groups was substantially improved by addition of gene-level information that incorporated ranking of genes based on literature evidence for disease association. The odds of DCM were increased to nearly 9-fold for truncating variants or high-impact missense variants in the subset of 14 genes that had the strongest biological links to DCM (P <0.0001). For some of these genes, DCM-associated variants appeared to be clustered in key protein functional domains. Multiple rare variants were present in many family probands, however, there was generally only one “driver” pathogenic variant that cosegregated with disease.ConclusionRare variants in cardiomyopathy genes can be effectively stratified by combining variant-level and gene-level information. Prioritization of genes based on their a priori likelihood of disease causation is a key factor in identifying clinically actionable variants in cardiac genetic testing.
Whiffin N, Roberts A, Minikel E, et al., 2018, Response to Shah <i>et al</i>: Using high-resolution variant frequencies empowers clinical genome interpretation and enables investigation of genetic architecture
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.
Kalman LV, Agúndez J, Appell ML, et al., 2016, Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting., Clin Pharmacol Ther, Vol: 99, Pages: 172-185
This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.
Fatkin D, Lam L, Herman DS, et al., 2016, Titin truncating mutations: a rare cause of dilated cardiomyopathy in the young, Progress in Pediatric Cardiology, Vol: 40, Pages: 41-45, ISSN: 1058-9813
Truncating mutations in the TTN gene are the most common genetic cause of dilated cardiomyopathy in adults but their role in young patients is unknown. We studied 82 young dilated cardiomyopathy subjects and found that the prevalence of truncating TTN mutations in adolescents was similar to adults, but surprisingly few truncating TTN mutations were identified in affected children, including one confirmed de novo variant. In several cases, truncating TTN mutations in children with dilated cardiomyopathy had evidence of additional clinical or genetic risk factors. These findings have implications for genetic testing and suggest that single truncating TTN mutations are insufficient alone to cause pediatric-onset dilated cardiomyopathy.
Roberts AM, Ware JS, Herman DS, et al., 2015, Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease, Science Translational Medicine, Vol: 7, Pages: 270ra6-270ra6, ISSN: 1946-6234
The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http://cardiodb.org/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings.
Baksi AJ, Roberts AM, Ware JS, et al., 2014, Titin: a phenotype-genotype descriptive comparison of dilated cardiomyopathy, ISSN: 1097-6647
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Keenan NG, Varkey S, Buchan RJ, et al., 2014, Genotype positive hypertrophic cardiomyopathy is associated with myocardial perfusion abnormalities, Journal of Cardiovascular Magnetic Resonance, Vol: 16, Pages: P342-P342, ISSN: 1097-6647
Barber JCK, Hall V, Maloney VK, et al., 2013, 16p11.2-p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 21, Pages: 182-189, ISSN: 1018-4813
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Ware JS, John S, Roberts AM, et al., 2013, Next Generation Diagnostics in Inherited Arrhythmia Syndromes, JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH, Vol: 6, Pages: 94-103, ISSN: 1937-5387
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Ware JS, Roberts AM, Cook SA, 2012, Republished review: Next generation sequencing for clinical diagnostics and personalised medicine: implications for the next generation cardiologist, POSTGRADUATE MEDICAL JOURNAL, Vol: 88, Pages: 234-239, ISSN: 0032-5473
Ware JS, Roberts AM, Cook SA, 2012, Next generation sequencing for clinical diagnostics and personalised medicine: implications for the next generation cardiologist, HEART, Vol: 98, Pages: 276-281, ISSN: 1355-6037
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Villard E, Perret C, Gary F, et al., 2011, A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy, EUROPEAN HEART JOURNAL, Vol: 32, Pages: 1065-1076, ISSN: 0195-668X
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- Citations: 240
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