Pub Date : 2024-06-01Epub Date: 2024-06-07DOI: 10.1161/CIRCGEN.123.004448
Gabriella Captur, Ivan Doykov, Sheng-Chia Chung, Ella Field, Annabelle Barnes, Enpei Zhang, Imogen Heenan, Gabrielle Norrish, James C Moon, Perry M Elliott, Wendy E Heywood, Kevin Mills, Juan Pablo Kaski
Background: Hypertrophic cardiomyopathy (HCM) is defined clinically by pathological left ventricular hypertrophy. We have previously developed a plasma proteomics biomarker panel that correlates with clinical markers of disease severity and sudden cardiac death risk in adult patients with HCM. The aim of this study was to investigate the utility of adult biomarkers and perform new discoveries in proteomics for childhood-onset HCM.
Methods: Fifty-nine protein biomarkers were identified from an exploratory plasma proteomics screen in children with HCM and augmented into our existing multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay. The association of these biomarkers with clinical phenotypes and outcomes was prospectively tested in plasma collected from 148 children with HCM and 50 healthy controls. Machine learning techniques were used to develop novel pediatric plasma proteomic biomarker panels.
Results: Four previously identified adult HCM markers (aldolase fructose-bisphosphate A, complement C3a, talin-1, and thrombospondin 1) and 3 new markers (glycogen phosphorylase B, lipoprotein a and profilin 1) were elevated in pediatric HCM. Using supervised machine learning applied to training (n=137) and validation cohorts (n=61), this 7-biomarker panel differentiated HCM from healthy controls with an area under the curve of 1.0 in the training data set (sensitivity 100% [95% CI, 95-100]; specificity 100% [95% CI, 96-100]) and 0.82 in the validation data set (sensitivity 75% [95% CI, 59-86]; specificity 88% [95% CI, 75-94]). Reduced circulating levels of 4 other peptides (apolipoprotein L1, complement 5b, immunoglobulin heavy constant epsilon, and serum amyloid A4) found in children with high sudden cardiac death risk provided complete separation from the low and intermediate risk groups and predicted mortality and adverse arrhythmic outcomes (hazard ratio, 2.04 [95% CI, 1.0-4.2]; P=0.044).
Conclusions: In children, a 7-biomarker proteomics panel can distinguish HCM from controls with high sensitivity and specificity, and another 4-biomarker panel identifies those at high risk of adverse arrhythmic outcomes, including sudden cardiac death.
{"title":"Novel Multiplexed Plasma Biomarker Panel Has Diagnostic and Prognostic Potential in Children With Hypertrophic Cardiomyopathy.","authors":"Gabriella Captur, Ivan Doykov, Sheng-Chia Chung, Ella Field, Annabelle Barnes, Enpei Zhang, Imogen Heenan, Gabrielle Norrish, James C Moon, Perry M Elliott, Wendy E Heywood, Kevin Mills, Juan Pablo Kaski","doi":"10.1161/CIRCGEN.123.004448","DOIUrl":"10.1161/CIRCGEN.123.004448","url":null,"abstract":"<p><strong>Background: </strong>Hypertrophic cardiomyopathy (HCM) is defined clinically by pathological left ventricular hypertrophy. We have previously developed a plasma proteomics biomarker panel that correlates with clinical markers of disease severity and sudden cardiac death risk in adult patients with HCM. The aim of this study was to investigate the utility of adult biomarkers and perform new discoveries in proteomics for childhood-onset HCM.</p><p><strong>Methods: </strong>Fifty-nine protein biomarkers were identified from an exploratory plasma proteomics screen in children with HCM and augmented into our existing multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay. The association of these biomarkers with clinical phenotypes and outcomes was prospectively tested in plasma collected from 148 children with HCM and 50 healthy controls. Machine learning techniques were used to develop novel pediatric plasma proteomic biomarker panels.</p><p><strong>Results: </strong>Four previously identified adult HCM markers (aldolase fructose-bisphosphate A, complement C3a, talin-1, and thrombospondin 1) and 3 new markers (glycogen phosphorylase B, lipoprotein a and profilin 1) were elevated in pediatric HCM. Using supervised machine learning applied to training (n=137) and validation cohorts (n=61), this 7-biomarker panel differentiated HCM from healthy controls with an area under the curve of 1.0 in the training data set (sensitivity 100% [95% CI, 95-100]; specificity 100% [95% CI, 96-100]) and 0.82 in the validation data set (sensitivity 75% [95% CI, 59-86]; specificity 88% [95% CI, 75-94]). Reduced circulating levels of 4 other peptides (apolipoprotein L1, complement 5b, immunoglobulin heavy constant epsilon, and serum amyloid A4) found in children with high sudden cardiac death risk provided complete separation from the low and intermediate risk groups and predicted mortality and adverse arrhythmic outcomes (hazard ratio, 2.04 [95% CI, 1.0-4.2]; <i>P</i>=0.044).</p><p><strong>Conclusions: </strong>In children, a 7-biomarker proteomics panel can distinguish HCM from controls with high sensitivity and specificity, and another 4-biomarker panel identifies those at high risk of adverse arrhythmic outcomes, including sudden cardiac death.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004448"},"PeriodicalIF":6.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11188636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-05-28DOI: 10.1161/CIRCGEN.123.004320
Lu-Chen Weng, Shaan Khurshid, Amelia Weber Hall, Victor Nauffal, Valerie N Morrill, Yan V Sun, Joel T Rämö, Dominik Beer, Simon Lee, Girish Nadkarni, Renee Johnson, Laura Andreasen, Anne Clayton, Clive R Pullinger, Zachary T Yoneda, Daniel J Friedman, Matthew C Hyman, Renae L Judy, Allan C Skanes, Kate M Orland, Paloma Jordà, Timothy M Treu, Matthew T Oetjens, Rajesh Subbiah, Jacob P Hartmann, Heidi T May, John P Kane, Tariq Z Issa, Navid A Nafissi, Peter Leong-Sit, Marie-Pierre Dubé, Carolina Roselli, Seung Hoan Choi, Jean-Claude Tardif, Habib R Khan, Stacey Knight, Jesper H Svendsen, Bruce Walker, Richard Karlsson Linnér, J Michael Gaziano, Rafik Tadros, Diane Fatkin, Daniel J Rader, Svati H Shah, Dan M Roden, Gregory M Marcus, Ruth J F Loos, Scott M Damrauer, Christopher M Haggerty, Kelly Cho, Aarno Palotie, Morten S Olesen, Lee L Eckhardt, Jason D Roberts, Michael J Cutler, M Benjamin Shoemaker, Peter W F Wilson, Patrick T Ellinor, Steven A Lubitz
Background: Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT).
Methods: We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies.
Results: Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate SCN5A, SCN10A, and TTN/CCDC141. Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals.
Conclusions: Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.
{"title":"Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias.","authors":"Lu-Chen Weng, Shaan Khurshid, Amelia Weber Hall, Victor Nauffal, Valerie N Morrill, Yan V Sun, Joel T Rämö, Dominik Beer, Simon Lee, Girish Nadkarni, Renee Johnson, Laura Andreasen, Anne Clayton, Clive R Pullinger, Zachary T Yoneda, Daniel J Friedman, Matthew C Hyman, Renae L Judy, Allan C Skanes, Kate M Orland, Paloma Jordà, Timothy M Treu, Matthew T Oetjens, Rajesh Subbiah, Jacob P Hartmann, Heidi T May, John P Kane, Tariq Z Issa, Navid A Nafissi, Peter Leong-Sit, Marie-Pierre Dubé, Carolina Roselli, Seung Hoan Choi, Jean-Claude Tardif, Habib R Khan, Stacey Knight, Jesper H Svendsen, Bruce Walker, Richard Karlsson Linnér, J Michael Gaziano, Rafik Tadros, Diane Fatkin, Daniel J Rader, Svati H Shah, Dan M Roden, Gregory M Marcus, Ruth J F Loos, Scott M Damrauer, Christopher M Haggerty, Kelly Cho, Aarno Palotie, Morten S Olesen, Lee L Eckhardt, Jason D Roberts, Michael J Cutler, M Benjamin Shoemaker, Peter W F Wilson, Patrick T Ellinor, Steven A Lubitz","doi":"10.1161/CIRCGEN.123.004320","DOIUrl":"10.1161/CIRCGEN.123.004320","url":null,"abstract":"<p><strong>Background: </strong>Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT).</p><p><strong>Methods: </strong>We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies.</p><p><strong>Results: </strong>Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate <i>NKX2-5</i> and <i>TTN</i> as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of <i>NKX2-5</i> and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate <i>SCN5A</i>, <i>SCN10A</i>, and <i>TTN/CCDC141</i>. Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals.</p><p><strong>Conclusions: </strong>Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004320"},"PeriodicalIF":6.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11187659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-16DOI: 10.1161/circgen.122.003978
Serwet Demirdas, Lisa M. van den Bersselaar, Rosan Lechner, Jessica Bos, Suzanne I.M. Alsters, Marieke J.H. Baars, Annette F. Baas, Özlem Baysal, Saskia N. van der Crabben, Eelco Dulfer, Noor A.A. Giesbertz, Apollonia T.J.M. Helderman-van den Enden, Yvonne Hilhorst-Hofstee, Marlies J.E. Kempers, Fenne L. Komdeur, Bart Loeys, Daniëlle Majoor-Krakauer, Charlotte W. Ockeloen, Eline Overwater, Peter J. van Tintelen, Marsha Voorendt, Vivian de Waard, Alessandra Maugeri, Hennie T. Brüggenwirth, Ingrid M.B.H. van de Laar, Arjan C. Houweling
BACKGROUND:Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1. The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease.METHODS:Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination.RESULTS:A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent (P=0.90), but occurred at a younger age (P=0.01). A major event occurred more often and at a younger age in men compared with women (P<0.001 and P=0.004, respectively). Aortic aneurysms (P=0.003) and pneumothoraces (P=0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a COL3A1 variant in the first quarter of the collagen helical domain (P=0.03).CONCLUSIONS:Male sex, type and location of the COL3A1 variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and/or early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS.
{"title":"Vascular Ehlers-Danlos Syndrome: A Comprehensive Natural History Study in a Dutch National Cohort of 142 Patients","authors":"Serwet Demirdas, Lisa M. van den Bersselaar, Rosan Lechner, Jessica Bos, Suzanne I.M. Alsters, Marieke J.H. Baars, Annette F. Baas, Özlem Baysal, Saskia N. van der Crabben, Eelco Dulfer, Noor A.A. Giesbertz, Apollonia T.J.M. Helderman-van den Enden, Yvonne Hilhorst-Hofstee, Marlies J.E. Kempers, Fenne L. Komdeur, Bart Loeys, Daniëlle Majoor-Krakauer, Charlotte W. Ockeloen, Eline Overwater, Peter J. van Tintelen, Marsha Voorendt, Vivian de Waard, Alessandra Maugeri, Hennie T. Brüggenwirth, Ingrid M.B.H. van de Laar, Arjan C. Houweling","doi":"10.1161/circgen.122.003978","DOIUrl":"https://doi.org/10.1161/circgen.122.003978","url":null,"abstract":"BACKGROUND:Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in <i>COL3A1</i>. The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease.METHODS:Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination.RESULTS:A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent (<i>P</i>=0.90), but occurred at a younger age (<i>P</i>=0.01). A major event occurred more often and at a younger age in men compared with women (<i>P</i><0.001 and <i>P</i>=0.004, respectively). Aortic aneurysms (<i>P</i>=0.003) and pneumothoraces (<i>P</i>=0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a <i>COL3A1</i> variant in the first quarter of the collagen helical domain (<i>P</i>=0.03).CONCLUSIONS:Male sex, type and location of the <i>COL3A1</i> variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and/or early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS.","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":"81 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140610815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-02-08DOI: 10.1161/CIRCGEN.124.004572
Juan Mundisugih, Eddy Kizana
{"title":"Crossing the Threshold of Therapeutic Hope for Patients With PKP2 Arrhythmogenic Cardiomyopathy.","authors":"Juan Mundisugih, Eddy Kizana","doi":"10.1161/CIRCGEN.124.004572","DOIUrl":"10.1161/CIRCGEN.124.004572","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004572"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139702040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-03-18DOI: 10.1161/CIRCGEN.124.004598
Yuchen Chang, Mathias Francois, Richard D Bagnall
{"title":"Transcription Factors Leave Their Mark on the Heart.","authors":"Yuchen Chang, Mathias Francois, Richard D Bagnall","doi":"10.1161/CIRCGEN.124.004598","DOIUrl":"10.1161/CIRCGEN.124.004598","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004598"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140142911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-02-19DOI: 10.1161/CIRCGEN.123.004218
Wenjian Lv, Apoorva Babu, Michael P Morley, Kiran Musunuru, Marie A Guerraty
{"title":"Resource of Gene Expression Data From a Multiethnic Population Cohort of Induced Pluripotent Stem Cell-Derived Cardiomyocytes.","authors":"Wenjian Lv, Apoorva Babu, Michael P Morley, Kiran Musunuru, Marie A Guerraty","doi":"10.1161/CIRCGEN.123.004218","DOIUrl":"10.1161/CIRCGEN.123.004218","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004218"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11021142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-02-13DOI: 10.1161/CIRCGEN.124.004571
Anne K Bozack, Ana Navas-Acien, Andres Cardenas
{"title":"DNA Methylation-Based Biomarkers of Protein Levels and Cardiovascular Disease Risk: Opportunities and Challenges for Precision Cardiology.","authors":"Anne K Bozack, Ana Navas-Acien, Andres Cardenas","doi":"10.1161/CIRCGEN.124.004571","DOIUrl":"10.1161/CIRCGEN.124.004571","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004571"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11021153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139721858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-02-14DOI: 10.1161/CIRCGEN.123.004404
Almudena Amor-Salamanca, Alfredo Santana Rodríguez, Hazhee Rasoul, José F Rodríguez-Palomares, Oana Moldovan, Thomas Morris Hey, María Gallego Delgado, David López Cuenca, Daniel de Castro Campos, María Teresa Basurte-Elorz, Rosa Macías-Ruiz, María Eugenia Fuentes Cañamero, Joseph Galvin, Raquel Bilbao Quesada, Luis de la Higuera Romero, Juan Pablo Trujillo-Quintero, Loida María García-Cruz, Ivonne Cárdenas-Reyes, Juan Jiménez-Jáimez, Soledad García-Hernández, María Valverde-Gómez, Iria Gómez-Díaz, Javier Limeres Freire, José M García-Pinilla, Juan R Gimeno-Blanes, Konstantinos Savattis, Pablo García-Pavía, Juan Pablo Ochoa
Background: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC.
Methods: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers.
Results: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P<0.0001) and 99.76 (95% CI, 34.60-287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias.
Conclusions: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.
{"title":"Role of <i>TBX20</i> Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction.","authors":"Almudena Amor-Salamanca, Alfredo Santana Rodríguez, Hazhee Rasoul, José F Rodríguez-Palomares, Oana Moldovan, Thomas Morris Hey, María Gallego Delgado, David López Cuenca, Daniel de Castro Campos, María Teresa Basurte-Elorz, Rosa Macías-Ruiz, María Eugenia Fuentes Cañamero, Joseph Galvin, Raquel Bilbao Quesada, Luis de la Higuera Romero, Juan Pablo Trujillo-Quintero, Loida María García-Cruz, Ivonne Cárdenas-Reyes, Juan Jiménez-Jáimez, Soledad García-Hernández, María Valverde-Gómez, Iria Gómez-Díaz, Javier Limeres Freire, José M García-Pinilla, Juan R Gimeno-Blanes, Konstantinos Savattis, Pablo García-Pavía, Juan Pablo Ochoa","doi":"10.1161/CIRCGEN.123.004404","DOIUrl":"10.1161/CIRCGEN.123.004404","url":null,"abstract":"<p><strong>Background: </strong>Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. <i>TBX20</i> has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the <i>TBX20</i> truncating variant (<i>TBX20tv</i>) and DCM/LVNC.</p><p><strong>Methods: </strong><i>TBX20</i> was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of <i>TBX20tv</i> in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers.</p><p><strong>Results: </strong><i>TBX20tv</i> was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; <i>P</i><0.0001) and 99.76 (95% CI, 34.60-287.62; <i>P</i><0.0001), respectively. <i>TBX20tv</i> was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with <i>TBX20tv</i> (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias.</p><p><strong>Conclusions: </strong><i>TBX20tv</i> is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. <i>TBX20tv</i>-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. <i>TBX20</i> should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004404"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11019988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139729140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-02-14DOI: 10.1161/CIRCGEN.123.004271
Rahul Chaudhary, Adam C Straub, Felix E Y Aggor, Ifeoluwa Onasanya, Jordan Richardson, Patrick J Strollo, Steven E Reis, Oladipupo Olafiranye
{"title":"CYB5R3 T117S Genetic Mutation Is Associated With Major Adverse Cardiovascular and Cerebrovascular Events in Black Adults.","authors":"Rahul Chaudhary, Adam C Straub, Felix E Y Aggor, Ifeoluwa Onasanya, Jordan Richardson, Patrick J Strollo, Steven E Reis, Oladipupo Olafiranye","doi":"10.1161/CIRCGEN.123.004271","DOIUrl":"10.1161/CIRCGEN.123.004271","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004271"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11021138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139729139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}