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Christine seidman

Christine Dehlendorf, Reiley Reed, Edith Fox, Dominika Seidman, Cara Hall, Jody Steinauer
No abstract text is available yet for this article.
March 12, 2018: Contraception
Kathryn B Manheimer, Nihir Patel, Felix Richter, Joshua Gorham, Angela C Tai, Jason Homsy, Marko T Boskovski, Michael Parfenov, Elizabeth Goldmuntz, Wendy K Chung, Martina Brueckner, Martin Tristani-Firouzi, Deepak Srivastava, Jonathan G Seidman, Christine E Seidman, Bruce D Gelb, Andrew J Sharp
Multiple tools have been developed to identify copy number variants (CNVs) from whole exome (WES) and whole genome sequencing (WGS) data. Current tools such as XHMM for WES and CNVnator for WGS identify CNVs based on changes in read depth. For WGS, other methods to identify CNVs include utilizing discordant read pairs and split reads and genome-wide local assembly with tools such as Lumpy and SvABA, respectively. Here, we introduce a new method to identify deletion CNVs from WES and WGS trio data based on the clustering of Mendelian errors (MEs)...
March 11, 2018: Human Mutation
Amanda C Garfinkel, Jonathan G Seidman, Christine E Seidman
Sarcomere cardiomyopathies are genetic diseases that perturb contractile function and lead to hypertrophic or dilated myocardial remodeling. Identification of preclinical mutation carriers has yielded insights into the earliest biomechanical defects that link pathogenic variants to cardiac dysfunction. Understanding this early molecular pathophysiology can illuminate modifiable pathways to reduce the emergence of overt cardiomyopathy and curb adverse outcomes. Here, the authors review current understandings of how human hypertrophic cardiomyopathy- and hypertrophic dilated cardiomyopathy-linked mutations disrupt the normal structure and function of the sarcomere...
April 2018: Heart Failure Clinics
Kathryn B Manheimer, Felix Richter, Lisa J Edelmann, Sunita L D'Souza, Lisong Shi, Yufeng Shen, Jason Homsy, Marko T Boskovski, Angela C Tai, Joshua Gorham, Christopher Yasso, Elizabeth Goldmuntz, Martina Brueckner, Richard P Lifton, Wendy K Chung, Christine E Seidman, J G Seidman, Bruce D Gelb
Mosaicism due to somatic mutations can cause multiple diseases including cancer, developmental and overgrowth syndromes, neurodevelopmental disorders, autoinflammatory diseases, and atrial fibrillation. With the increased use of next generation sequencing technology, multiple tools have been developed to identify low-frequency variants, specifically from matched tumor-normal tissues in cancer studies. To investigate whether mosaic variants are implicated in congenital heart disease (CHD), we developed a pipeline using the cancer somatic variant caller MuTect to identify mosaic variants in whole-exome sequencing (WES) data from a cohort of parent/affected child trios (n = 715) and a cohort of healthy individuals (n = 416)...
February 7, 2018: Human Genetics
Arun Sharma, Christopher N Toepfer, Manuel Schmid, Amanda C Garfinkel, Christine E Seidman
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent a powerful cellular platform for illuminating mechanisms of human cardiovascular disease and for pharmacological screening. Recent advances in CRISPR/Cas9-mediated genome editing technology underlie this profound utility. We have generated hiPSC-CMs harboring fluorescently-tagged sarcomeric proteins, which provide a tool to non-invasively study human sarcomere function and dysfunction. In this unit, we illustrate methods for conducting high-efficiency, small molecule-mediated differentiation of hiPSCs into cardiomyocytes, and for performing non-invasive contractile analysis through direct sarcomere tracking of GFP-sarcomere reporter hiPSC-CMs...
January 24, 2018: Current Protocols in Human Genetics
Arun Sharma, Christopher N Toepfer, Tarsha Ward, Lauren Wasson, Radhika Agarwal, David A Conner, Johnny H Hu, Christine E Seidman
Human induced pluripotent stem cells (hiPSCs) can be used to mass produce surrogates of human tissues, enabling new advances in drug screening, disease modeling, and cell therapy. Recent developments in clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing technology use homology-directed repair (HDR) to efficiently generate custom hiPSC lines harboring a variety of genomic insertions and deletions. Thus, hiPSCs that encode an endogenous protein fused to a fluorescent reporter protein can be rapidly created by employing CRISPR/Cas9 genome editing, enhancing HDR efficiency and optimizing homology arm length...
January 24, 2018: Current Protocols in Human Genetics
Spyros Chalkias, Joshua M Gorham, Erica Mazaika, Michael Parfenov, Xin Dang, Steve DePalma, David McKean, Christine E Seidman, Jonathan G Seidman, Igor J Koralnik
Deep nucleotide sequencing enables the unbiased, broad-spectrum detection of viruses in clinical samples without requiring an a priori hypothesis for the source of infection. However, its use in clinical research applications is limited by low cost-effectiveness given that most of the sequencing information from clinical samples is related to the human genome, which renders the analysis of viral genomes challenging. To overcome this limitation we developed ViroFind, an in-solution target-enrichment platform for virus detection and discovery in clinical samples...
2018: PloS One
Anant Chopra, Matthew L Kutys, Kehan Zhang, William J Polacheck, Calvin C Sheng, Rebeccah J Luu, Jeroen Eyckmans, J Travis Hinson, Jonathan G Seidman, Christine E Seidman, Christopher S Chen
Truncating mutations in the sarcomere protein titin cause dilated cardiomyopathy due to sarcomere insufficiency. However, it remains mechanistically unclear how these mutations decrease sarcomere content in cardiomyocytes. Utilizing human induced pluripotent stem cell-derived cardiomyocytes, CRISPR/Cas9, and live microscopy, we characterize the fundamental mechanisms of human cardiac sarcomere formation. We observe that sarcomerogenesis initiates at protocostameres, sites of cell-extracellular matrix adhesion, where nucleation and centripetal assembly of α-actinin-2-containing fibers provide a template for the fusion of Z-disk precursors, Z bodies, and subsequent striation...
January 8, 2018: Developmental Cell
Xin Sun, Swetansu K Hota, Yu-Qing Zhou, Stefanie Novak, Dario Miguel-Perez, Danos Christodoulou, Christine E Seidman, J G Seidman, Carol C Gregorio, R Mark Henkelman, Janet Rossant, Benoit G Bruneau
How chromatin-remodeling complexes modulate gene networks to control organ-specific properties is not well understood. For example, Baf60c ( Smarcd3 ) encodes a cardiac-enriched subunit of the SWI/SNF-like BAF chromatin complex, but its role in heart development is not fully understood. We found that constitutive loss of Baf60c leads to embryonic cardiac hypoplasia and pronounced cardiac dysfunction. Conditional deletion of Baf60c in cardiomyocytes resulted in postnatal dilated cardiomyopathy with impaired contractile function...
January 5, 2018: Biology Open
Sebastian Schafer, Sivakumar Viswanathan, Anissa A Widjaja, Wei-Wen Lim, Aida Moreno-Moral, Daniel M DeLaughter, Benjamin Ng, Giannino Patone, Kingsley Chow, Ester Khin, Jessie Tan, Sonia P Chothani, Lei Ye, Owen J L Rackham, Nicole S J Ko, Norliza E Sahib, Chee Jian Pua, Nicole T G Zhen, Chen Xie, Mao Wang, Henrike Maatz, Shiqi Lim, Kathrin Saar, Susanne Blachut, Enrico Petretto, Sabine Schmidt, Tracy Putoczki, Nuno Guimarães-Camboa, Hiroko Wakimoto, Sebastiaan van Heesch, Kristmundur Sigmundsson, See L Lim, Jia L Soon, Victor T T Chao, Yeow L Chua, Teing E Tan, Sylvia M Evans, Yee J Loh, Muhammad H Jamal, Kim K Ong, Kim C Chua, Boon-Hean Ong, Mathew J Chakaramakkil, Jonathan G Seidman, Christine E Seidman, Norbert Hubner, Kenny Y K Sin, Stuart A Cook
Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect...
December 7, 2017: Nature
Alexander G Bick, Hiroko Wakimoto, Kimberli J Kamer, Yasemin Sancak, Olga Goldberger, Anna Axelsson, Daniel M DeLaughter, Joshua M Gorham, Vamsi K Mootha, J G Seidman, Christine E Seidman
Comparative analyses of transcriptional profiles from humans and mice with cardiovascular pathologies revealed consistently elevated expression of MICU2 , a regulatory subunit of the mitochondrial calcium uniporter complex. To determine if MICU2 expression was cardioprotective, we produced and characterized Micu2 -/- mice. Mutant mice had left atrial enlargement and Micu2 -/- cardiomyocytes had delayed sarcomere relaxation and cytosolic calcium reuptake kinetics, indicating diastolic dysfunction. RNA sequencing (RNA-seq) of Micu2 -/- ventricular tissues revealed markedly reduced transcripts encoding the apelin receptor ( Micu2 -/- vs...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
Calum A MacRae, Christine E Seidman
No abstract text is available yet for this article.
October 17, 2017: Circulation
Allison L Cirino, Neal K Lakdawala, Barbara McDonough, Lauren Conner, Dale Adler, Mark Weinfeld, Patrick O'Gara, Heidi L Rehm, Kalotina Machini, Matthew Lebo, Carrie Blout, Robert C Green, Calum A MacRae, Christine E Seidman, Carolyn Y Ho
BACKGROUND: As DNA sequencing costs decline, genetic testing options have expanded. Whole exome sequencing and whole genome sequencing (WGS) are entering clinical use, posing questions about their incremental value compared with disease-specific multigene panels that have been the cornerstone of genetic testing. METHODS AND RESULTS: Forty-one patients with hypertrophic cardiomyopathy who had undergone targeted hypertrophic cardiomyopathy genetic testing (either multigene panel or familial variant test) were recruited into the MedSeq Project, a clinical trial of WGS...
October 2017: Circulation. Cardiovascular Genetics
Sheng Chih Jin, Jason Homsy, Samir Zaidi, Qiongshi Lu, Sarah Morton, Steven R DePalma, Xue Zeng, Hongjian Qi, Weni Chang, Michael C Sierant, Wei-Chien Hung, Shozeb Haider, Junhui Zhang, James Knight, Robert D Bjornson, Christopher Castaldi, Irina R Tikhonoa, Kaya Bilguvar, Shrikant M Mane, Stephan J Sanders, Seema Mital, Mark W Russell, J William Gaynor, John Deanfield, Alessandro Giardini, George A Porter, Deepak Srivastava, Cecelia W Lo, Yufeng Shen, W Scott Watkins, Mark Yandell, H Joseph Yost, Martin Tristani-Firouzi, Jane W Newburger, Amy E Roberts, Richard Kim, Hongyu Zhao, Jonathan R Kaltman, Elizabeth Goldmuntz, Wendy K Chung, Jonathan G Seidman, Bruce D Gelb, Christine E Seidman, Richard P Lifton, Martina Brueckner
Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies...
November 2017: Nature Genetics
Berglind Adalsteinsdottir, Runolfur Palsson, Robert J Desnick, Marianna Gardarsdottir, Polakit Teekakirikul, Martin Maron, Evan Appelbaum, Ulf Neisius, Barry J Maron, Michael A Burke, Brenden Chen, Silvere Pagant, Christoffer V Madsen, Ragnar Danielsen, Reynir Arngrimsson, Ulla Feldt-Rasmussen, Jonathan G Seidman, Christine E Seidman, Gunnar Th Gunnarsson
BACKGROUND: The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA(α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). METHODS AND RESULTS: Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes)...
August 2017: Circulation. Cardiovascular Genetics
Louis A Saddic, Sarah M Nicoloro, Olga T Gupta, Michael P Czech, Joshua Gorham, Stanton K Shernan, Christine E Seidman, Jon G Seidman, Sary F Aranki, Simon C Body, Timothy P Fitzgibbons, Jochen D Muehlschlegel
BACKGROUND: Omentin-1, also known as Intelectin-1 (ITLN1), is an adipokine with plasma levels associated with diabetes, obesity, and coronary artery disease. Recent studies suggest that ITLN1 can mitigate myocardial ischemic injury but the expression of ITLN1 in the heart itself has not been well characterized. The purpose of this study is to discern the relationship between the expression pattern of ITLN1 RNA in the human heart and the level of circulating ITLN1 protein in plasma from the same patients following myocardial ischemia...
July 7, 2017: Cardiovascular Diabetology
Kaoru Ito, Parth N Patel, Joshua M Gorham, Barbara McDonough, Steven R DePalma, Emily E Adler, Lien Lam, Calum A MacRae, Syed M Mohiuddin, Diane Fatkin, Christine E Seidman, J G Seidman
Genetic variants that cause haploinsufficiency account for many autosomal dominant (AD) disorders. Gene-based diagnosis classifies variants that alter canonical splice signals as pathogenic, but due to imperfect understanding of RNA splice signals other variants that may create or eliminate splice sites are often clinically classified as variants of unknown significance (VUS). To improve recognition of pathogenic splice-altering variants in AD disorders, we used computational tools to prioritize VUS and developed a cell-based minigene splicing assay to confirm aberrant splicing...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
Joseph A Hill, Reza Ardehali, Kimberli Taylor Clarke, Gregory J Del Zoppo, Lee L Eckhardt, Kathy K Griendling, Peter Libby, Dan M Roden, Hesham A Sadek, Christine E Seidman, Douglas E Vaughan
Recent decades have witnessed robust successes in conquering the acutely lethal manifestations of heart and vascular diseases. Many patients who previously would have died now survive. Lifesaving successes like these provide a tremendous and easily recognized benefit to individuals and society. Although cardiovascular mortality has declined, the devastating impact of chronic heart disease and comorbidities on quality of life and healthcare resources continues unabated. Future strides, extending those made in recent decades, will require continued research into mechanisms underlying disease prevention, pathogenesis, progression, and therapeutic intervention...
July 21, 2017: Circulation Research
J Travis Hinson, Anant Chopra, Andre Lowe, Calvin C Sheng, Rajat M Gupta, Rajarajan Kuppusamy, John O'Sullivan, Glenn Rowe, Hiroko Wakimoto, Joshua Gorham, Michael A Burke, Kehan Zhang, Kiran Musunuru, Robert E Gerszten, Sean M Wu, Christopher S Chen, Jonathan G Seidman, Christine E Seidman
No abstract text is available yet for this article.
June 13, 2017: Cell Reports
Lorenzo Alamo, James S Ware, Antonio Pinto, Richard E Gillilan, Jonathan G Seidman, Christine E Seidman, Raúl Padrón
Cardiac β-myosin variants cause hypertrophic (HCM) or dilated (DCM) cardiomyopathy by disrupting sarcomere contraction and relaxation. The locations of variants on isolated myosin head structures predict contractility effects but not the prominent relaxation and energetic deficits that characterize HCM. During relaxation, pairs of myosins form interacting-heads motif (IHM) structures that with other sarcomere proteins establish an energy-saving, super-relaxed (SRX) state. Using a human β-cardiac myosin IHM quasi-atomic model, we defined interactions sites between adjacent myosin heads and associated protein partners, and then analyzed rare variants from 6112 HCM and 1315 DCM patients and 33,370 ExAC controls...
June 13, 2017: ELife
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