Browsing by Subject "Cardiovascular genetics"

Now showing 1 - 8 of 8
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    A multicenter cross-sectional study in infants with congenital heart defects demonstrates high diagnostic yield of genetic testing but variable evaluation practices
    (Elsevier, 2023-04-29) Durbin, Matthew D.; Helvaty, Lindsey R.; Li, Ming; Border, William; Fitzgerald-Butt, Sara; Garg, Vidu; Geddes, Gabrielle C.; Helm, Benjamin M.; Lalani, Seema R.; McBride, Kim L.; McEntire, Alexis; Mitchell, Dana K.; Murali, Chaya N.; Wechsler, Stephanie B.; Landis, Benjamin J.; Ware, Stephanie M.; Pediatrics, School of Medicine
    Purpose: For patients with congenital heart disease (CHD), the most common birth defect, genetic evaluation is not universally accepted, and current practices are anecdotal. Here, we analyzed genetic evaluation practices across centers, determined diagnostic yield of testing, and identified phenotypic features associated with abnormal results. Methods: This is a multicenter cross-sectional study of 5 large children's hospitals, including 2899 children ≤14 months undergoing surgical repair for CHD from 2013 to 2016, followed by multivariate logistics regression analysis. Results: Genetic testing occurred in 1607 of 2899 patients (55%). Testing rates differed highly between institutions (42%-78%, P < .001). Choice of testing modality also differed across institutions (ie, chromosomal microarray, 26%-67%, P < .001). Genetic testing was abnormal in 702 of 1607 patients (44%), and no major phenotypic feature drove diagnostic yield. Only 849 patients were seen by geneticists (29%), ranging across centers (15%-52%, P < .001). Geneticist consultation associated with increased genetic testing yield (odds ratio: 5.7, 95% CI 4.33-7.58, P < .001). Conclusion: Genetics evaluation in CHD is diagnostically important but underused and highly variable, with high diagnostic rates across patient types, including in infants with presumed isolated CHD. These findings support recommendations for comprehensive testing and standardization of care.
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    A non-coding GWAS variant impacts anthracycline-induced cardiotoxic phenotypes in human iPSC-derived cardiomyocytes
    (Springer Nature, 2022-11-22) Wu, Xi; Shen, Fei; Jiang, Guanglong; Xue, Gloria; Philips, Santosh; Gardner, Laura; Cunningham, Geneva; Bales, Casey; Cantor, Erica; Schneider, Bryan Paul; Medicine, School of Medicine
    Anthracyclines, widely used to treat breast cancer, have the potential for cardiotoxicity. We have previously identified and validated a germline single nucleotide polymorphism, rs28714259, associated with an increased risk of anthracycline-induced heart failure. We now provide insights into the mechanism by which rs28714259 might confer increased risk of cardiac damage. Using hiPSC-derived cardiomyocyte cell lines with either intrinsic polymorphism or CRISPR-Cas9-mediated deletion of rs28714259 locus, we demonstrate that glucocorticoid receptor signaling activated by dexamethasone pretreatment prior to doxorubicin exposure preserves cardiomyocyte viability and contractility in cardiomyocytes containing the major allele. Homozygous loss of the rs28714259 major allele diminishes dexamethasone’s protective effect. We further demonstrate that the risk allele of rs28714259 disrupts glucocorticoid receptor and rs28714259 binding affinity. Finally, we highlight the activation of genes and pathways involved in cardiac hypertrophy signaling that are blocked by the risk allele, suggesting a decreased adaptive survival response to doxorubicin-related stress.
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    Clinical exome sequencing efficacy and phenotypic expansions involving anomalous pulmonary venous return
    (Springer Nature, 2023) Huth, Emily A.; Zhao, Xiaonan; Owen, Nichole; Luna, Pamela N.; Vogel, Ida; Dorf, Inger L. H.; Joss, Shelagh; Clayton-Smith, Jill; Parker, Michael J.; Louw, Jacoba J.; Gewillig, Marc; Breckpot, Jeroen; Kraus, Alison; Sasaki, Erina; Kini, Usha; Burgess, Trent; Tan, Tiong Y.; Armstrong, Ruth; Neas, Katherine; Ferrero, Giovanni B.; Brusco, Alfredo; Kerstjens-Frederikse, Wihelmina S.; Rankin, Julia; Helvaty, Lindsey R.; Landis, Benjamin J.; Geddes, Gabrielle C.; McBride, Kim L.; Ware, Stephanie M.; Shaw, Chad A.; Lalani, Seema R.; Rosenfeld, Jill A.; Scott, Daryl A.; Medical and Molecular Genetics, School of Medicine
    Anomalous pulmonary venous return (APVR) frequently occurs with other congenital heart defects (CHDs) or extra-cardiac anomalies. While some genetic causes have been identified, the optimal approach to genetic testing in individuals with APVR remains uncertain, and the etiology of most cases of APVR is unclear. Here, we analyzed molecular data from 49 individuals to determine the diagnostic yield of clinical exome sequencing (ES) for non-isolated APVR. A definitive or probable diagnosis was made for 8 of those individuals yielding a diagnostic efficacy rate of 16.3%. We then analyzed molecular data from 62 individuals with APVR accrued from three databases to identify novel APVR genes. Based on data from this analysis, published case reports, mouse models, and/or similarity to known APVR genes as revealed by a machine learning algorithm, we identified 3 genes-EFTUD2, NAA15, and NKX2-1-for which there is sufficient evidence to support phenotypic expansion to include APVR. We also provide evidence that 3 recurrent copy number variants contribute to the development of APVR: proximal 1q21.1 microdeletions involving RBM8A and PDZK1, recurrent BP1-BP2 15q11.2 deletions, and central 22q11.2 deletions involving CRKL. Our results suggest that ES and chromosomal microarray analysis (or genome sequencing) should be considered for individuals with non-isolated APVR for whom a genetic etiology has not been identified, and that genetic testing to identify an independent genetic etiology of APVR is not warranted in individuals with EFTUD2-, NAA15-, and NKX2-1-related disorders.
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    A Comprehensive Clinical Genetics Approach to Critical Congenital Heart Disease in Infancy
    (Elsevier, 2020-12) Shikany, Amy R.; Landis, Benjamin J.; Parrott, Ashley; Miller, Erin M.; Coyan, Alyxis; Walters, Lauren; Hinton, Robert B.; Goldenberg, Paula; Ware, Stephanie M.; Medical and Molecular Genetics, School of Medicine
    Objective: To investigate the frequency of genetic diagnoses among infants with critical congenital heart disease (CHD) using a comprehensive cardiovascular genetics approach and to identify genotype-phenotype correlations. Study design: A retrospective chart review of patients evaluated by cardiovascular genetics in a pediatric cardiac intensive care unit from 2010 to 2015 was performed. Infants with CHD who were <1 month of age were included. CHD was classified using structured phenotype definitions. Cardiac and noncardiac phenotypes were tested for associations with abnormal genetic testing using χ1 and Fisher exact tests. Results: Genetic evaluation was completed in 293 infants with CHD, of whom 213 had isolated congenital heart disease (iCHD) and 80 had multiple congenital anomalies. Overall, the yield of abnormal genetic testing was 26%. The multiple congenital anomalies cohort had a greater yield of genetic testing (39%) than the iCHD cohort (20%) (OR 2.7). Using a non-hierarchical CHD classification and excluding 22q11.2 deletion and common aneuploidies, right ventricular obstructive defects were associated with abnormal genetic testing (P = .0005). Extracardiac features associated with abnormal genetic testing included ear, nose, and throat (P = .003) and brain (P = .0001) abnormalities. A diagnosis of small for gestational age or intrauterine growth retardation also was associated with abnormal genetic testing (P = .0061), as was presence of dysmorphic features (P = .0033, OR 3.5). Infants without dysmorphia with iCHD or multiple congenital anomalies had similar frequencies of abnormal genetic testing. Conclusions: The present study provides evidence to support a comprehensive cardiovascular genetics approach in evaluating infants with critical CHD while also identifying important genotype-phenotype considerations.
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    Genetic Testing Guidelines Impact Care in Newborns with Congenital Heart Defects
    (Elsevier, 2023) Durbin, Matthew D.; Fairman, Korre; Helvaty, Lindsey R.; Huang, Manyan; Li, Ming; Abreu, Daniel; Geddes, Gabrielle C.; Helm, Benjamin M.; Landis, Benjamin J.; McEntire, Alexis; Mitchell, Dana K.; Ware, Stephanie M.; Pediatrics, School of Medicine
    Objective: To evaluate genetic evaluation practices in newborns with the most common birth defect, congenital heart defects (CHD), we determined the prevalence and the yield of genetic evaluation across time and across patient subtypes, before and after implementation of institutional genetic testing guidelines. Study design: This was a retrospective, cross-sectional study of 664 hospitalized newborns with CHD using multivariate analyses of genetic evaluation practices across time and patient subtypes. Results: Genetic testing guidelines for hospitalized newborns with CHD were implemented in 2014, and subsequently genetic testing increased (40% in 2013 and 75% in 2018, OR 5.02, 95% CI 2.84-8.88, P < .001) as did medical geneticists' involvement (24% in 2013 and 64% in 2018, P < .001). In 2018, there was an increased use of chromosomal microarray (P < .001), gene panels (P = .016), and exome sequencing (P = .001). The testing yield was high (42%) and consistent across years and patient subtypes analyzed. Increased testing prevalence (P < .001) concomitant with consistent testing yield (P = .139) added an estimated 10 additional genetic diagnoses per year, reflecting a 29% increase. Conclusions: In patients with CHD, yield of genetic testing was high. After implementing guidelines, genetic testing increased significantly and shifted to newer sequence-based methods. Increased use of genetic testing identified more patients with clinically important results with potential to impact patient care.
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    Genome sequencing unveils a regulatory landscape of platelet reactivity
    (Springer Nature, 2021-06-15) Keramati, Ali R.; Chen, Ming-Huei; Rodriguez, Benjamin A. T.; Yanek, Lisa R.; Bhan, Arunoday; Gaynor, Brady J.; Ryan, Kathleen; Brody, Jennifer A.; Zhong, Xue; Wei, Qiang; NHLBI Trans-Omics for Precision (TOPMed) Consortium; Kammers, Kai; Kanchan, Kanika; Iyer, Kruthika; Kowalski, Madeline H.; Pitsillides, Achilleas N.; Cupples, L. Adrienne; Li, Bingshan; Schlaeger, Thorsten M.; Shuldiner, Alan R.; O’Connell, Jeffrey R.; Ruczinski, Ingo; Mitchell, Braxton D.; Faraday, Nauder; Taub, Margaret A.; Becker, Lewis C.; Lewis, Joshua P.; Mathias, Rasika A.; Johnson, Andrew D.; Medicine, School of Medicine
    Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes.
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    Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure
    (Springer Nature, 2019-06-24) Cordero, Pablo; Parikh, Victoria N.; Chin, Elizabeth T.; Erbilgin, Ayca; Gloudemans, Michael J.; Shang, Ching; Huang, Yong; Chang, Alex C.; Smith, Kevin S.; Dewey, Frederick; Zaleta, Kathia; Morley, Michael; Brandimarto, Jeff; Glazer, Nicole; Waggott, Daryl; Pavlovic, Aleksandra; Zhao, Mingming; Moravec, Christine S.; Tang, W. H. Wilson; Skreen, Jamie; Malloy, Christine; Hannenhalli, Sridhar; Li, Hongzhe; Ritter, Scott; Li, Mingyao; Bernstein, Daniel; Connolly, Andrew; Hakonarson, Hakon; Lusis, Aldons J.; Margulies, Kenneth B.; Depaoli-Roach, Anna A.; Montgomery, Stephen B.; Wheeler, Matthew T.; Cappola, Thomas; Ashley, Euan A.; Biochemistry and Molecular Biology, School of Medicine
    Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.
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    The Role of MCTP2 in Health and Disease
    (2021-01) Alkhouli, Mohammed A.; Ware, Stephanie M.; Firulli, Anthony B.; Payne, R. Mark; Wek, Ronald C.
    MCTP2 (multiple C2 domain transmembrane containing protein 2) encodes a protein with poorly understood roles in lipid metabolism and lipid droplet biogenesis. Genetic studies previously identified variations in MCTP2 in conjunction with left ventricular outflow tract obstructive forms of congenital heart disease (CHD). This dissertation research aimed to delineate the biomedical significance of Mctp2 by investigating its expression and consequences of its genetic deletion in mouse models. Temporal and spatial expression of Mctp2 was investigated by RT-PCR and in-situ hybridization. A novel isoform, designated as isoform 2 in mice, results from alternative pre-mRNA splicing. Similar levels of Mctp2 isoforms 1 and 2 are present in embryonic tissues, whereas isoform 1 is preferentially expressed in adult tissues with high lipid metabolism. During mouse embryonic development, in-situ hybridization suggests expression of Mctp2 at the gut tube, liver bud and near the pharyngeal arches from E8.5 – E10.5. Given association of MCTP2 with CHD, the biological significance of Mctp2 was addressed using gene trap (GT) and conditional mouse models. Survival of Mctp2 GT mice was dependent on the genetic background strain, suggesting a role for strain-specific modifiers. Conditional knockout of Mctp2 in cardiac progenitor cells displayed no effect on survival. The role of Mctp2 in cardiac development remains to be delineated. The role of Mctp2 in cardiac function was addressed in both mouse models. Initial findings suggest Mctp2 allele dosage effects on the development of heart failure. GT mice lacking one, or both, copies of Mctp2 display cardiac systolic dysfunction, with upregulation of heart failure markers at 50 weeks of age in heterozygotes and increases in cardiac fibrosis in homozygotes. Systemic conditional deletion of Mctp2 did not show heart failure phenotypes using the strain protective from lethality. However, cardiac specific deletion of Mctp2 using the Nkx2.5-Cre driver, a line that is sensitized for cardiac dysfunction, led to decreased ejection fraction and fractional shortening in mice with conditional deletion of both copies of Mctp2 as well as Mctp2 dosage dependent penetrance of cardiac dilation. These studies of knockout mice suggest a role for Mctp2 in maintenance of cardiac function and possible genetic interaction with Nkx2.5.