Person: Seidman, Christine
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Seidman
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Christine
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Seidman, Christine
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Publication Complement genes contribute sex-biased vulnerability in diverse disorders(Springer Science and Business Media LLC, 2020-05-11) Kamitaki, Nolan; Sekar, Aswin; Handsaker, Robert E.; de Rivera, Heather; Tooley, Katherine; Morris, David L.; Taylor, Kimberly E.; Whelan, Christopher W.; Tombleson, Philip; Loohuis, Loes M. Olde; Boehnke, Michael; Kimberly, Robert P.; Kaufman, Kenneth M.; Harley, John B.; Langefeld, Carl D.; Seidman, Christine; Pato, Michele T.; Pato, Carlos N.; Ophoff, Roel A.; Graham, Robert R.; Criswell, Lindsey A.; Vyse, Timothy J.; McCarroll, StevenMany common illnesses differentially affect men and women for unknown reasons. The autoimmune diseases lupus and Sjögren’s syndrome affect nine times more women than men, whereas schizophrenia affects men more frequently and severely. All three illnesses have their strongest common genetic associations in the Major Histocompatibility Complex (MHC) locus, an association that in lupus and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus. Here we show that the complement component 4 (C4) genes, which are also in the MHC locus and were recently found to increase risk for schizophrenia, generate 7-fold variation in risk for lupus (95% CI: 5.88-8.61; p < 10-117 in total) and 16-fold variation in risk for Sjögren’s syndrome (95% CI: 8.59-30.89; p < 10-23 in total) among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduced risk for lupus and Sjögren’s syndrome. In all three illnesses, C4 alleles acted more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for lupus, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (vs. 6-fold, 15-fold, and 1.26-fold among women respectively). At a protein level, both C4 and its effector C3 were present at greater levels in men than women in cerebrospinal fluid (p < 10-5 for both C4 and C3) and plasma among adults ages 20-50, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help explain the larger effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s, and men’s greater vulnerability in schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.Publication NKX2-5 Mutations in an Inbred Consanguineous Population: Genetic and Phenotypic Diversity(Nature Publishing Group, 2015) Abou Hassan, Ossama K.; Fahed, Akl; Batrawi, Manal; Arabi, Mariam; Refaat, Marwan M.; DePalma, Steven; Seidman, J. G.; Seidman, Christine; Bitar, Fadi F.; Nemer, Georges M.NKX2-5 mutations are associated with different forms of congenital heart disease. Despite the knowledge gained from molecular and animal studies, genotype-phenotype correlations in humans are limited by the lack of large cohorts and the incomplete assessment of family members. We hypothesized that studying the role of NKX2-5 in inbred populations with homogeneous genetic backgrounds and high consanguinity rates such as Lebanon could help closing this gap. We sequenced NKX2-5 in 188 index CHD cases (25 with ASD). Five variants (three segregated in families) were detected in eleven families including the previously documented p.R25C variant, which was found in seven patients from different families, and in one healthy individual. In 3/5 familial dominant ASD cases, we identified an NKX2-5 mutation. In addition to the heterogeneity of NKX2-5 mutations, a diversity of phenotypes occurred within the families with predominant ASD and AV block. We did in fact identify a large prevalence of Sudden Cardiac Death (SCD) in families with truncating mutations, and two patients with coronary sinus disease. NKX2-5 is thus responsible for dominant familial ASD even in consanguineous populations, and a wide genetic and phenotypic diversity is characteristic of NKX2-5 mutations in the Lebanese population.Publication A Novel Role for CSRP1 in a Lebanese Family with Congenital Cardiac Defects(Frontiers Media S.A., 2017) Kamar, Amina; Fahed, Akl; Shibbani, Kamel; El-Hachem, Nehme; Bou-Slaiman, Salim; Arabi, Mariam; Kurban, Mazen; Seidman, Jonathan; Seidman, Christine; Haidar, Rachid; Baydoun, Elias; Nemer, Georges; Bitar, FadiDespite an obvious role for consanguinity in congenital heart disease (CHD), most studies fail to document a monogenic model of inheritance except for few cases. We hereby describe a first-degree cousins consanguineous Lebanese family with 7 conceived children: 2 died in utero of unknown causes, 3 have CHD, and 4 have polydactyly. The aim of the study is to unveil the genetic variant(s) causing these phenotypes using next generation sequencing (NGS) technology. Targeted exome sequencing identified a heterozygous duplication in CSRP1 which leads to a potential frameshift mutation at position 154 of the protein. This mutation is inherited from the father, and segregates only with the CHD phenotype. The in vitro characterization demonstrates that the mutation dramatically abrogates its transcriptional activity over cardiac promoters like NPPA. In addition, it differentially inhibits the physical association of CSRP1 with SRF, GATA4, and with the newly described partner herein TBX5. Whole exome sequencing failed to show any potential variant linked to polydactyly, but revealed a novel missense mutation in TRPS1. This mutation is inherited from the healthy mother, and segregating only with the cardiac phenotype. Both TRPS1 and CSRP1 physically interact, and the mutations in each abrogate their partnership. Our findings add fundamental knowledge into the molecular basis of CHD, and propose the di-genic model of inheritance as responsible for such malformations.Publication Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands(2017) Jin, Sheng Chih; Homsy, Jason; Zaidi, Samir; Lu, Qiongshi; Morton, Sarah; DePalma, Steven; Zeng, Xue; Qi, Hongjian; Chang, Weni; Sierant, Michael C.; Hung, Wei-Chien; Haider, Shozeb; Zhang, Junhui; Knight, James; Bjornson, Robert D.; Castaldi, Christopher; Tikhonoa, Irina R.; Bilguvar, Kaya; Mane, Shrikant M.; Sanders, Stephan J.; Mital, Seema; Russell, Mark; Gaynor, William; Deanfield, John; Giardini, Alessandro; Porter, George A.; Srivastava, Deepak; Lo, Cecelia W.; Shen, Yufeng; Watkins, W. Scott; Yandell, Mark; Yost, H. Joseph; Tristani-Firouzi, Martin; Newburger, Jane W.; Roberts, Amy E.; Kim, Richard; Zhao, Hongyu; Kaltman, Jonathan R.; Goldmuntz, Elizabeth; Chung, Wendy K.; Seidman, Jonathan; Gelb, Bruce D.; Seidman, Christine; Lifton, Richard P.; Brueckner, MartinaCongenital heart disease (CHD) is the leading cause of mortality from birth defects. 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. Seven genes surpassed thresholds for genome-wide significance and 12 genes not previously implicated in CHD had > 70% probability of being disease-related; DNMs in ~440 genes are inferred to contribute to CHD. There was striking overlap between genes with damaging DNMs in probands with CHD and autism.Publication Dynamic Cellular Integration Drives Functional Assembly of the Heart’s Pacemaker Complex(2018) Bressan, Michael; Henley, Trevor; Louie, Jonathan D.; Liu, Gary; Christodoulou, Danos; Bai, Xue; Taylor, Joan; Seidman, Christine; Seidman, J.G.; Mikawa, TakashiSUMMARY Impulses generated by a multicellular, bioelectric signaling center termed the sinoatrial node (SAN) stimulate the rhythmic contraction of the heart. The SAN consists of a network of electrochemically oscillating pacemaker cells encased in a heterogeneous connective tissue microenvironment. Although the cellular composition of the SAN has been a point of interest for more than a century, the biological processes that drive the tissue-level assembly of the cells within the SAN are unknown. Here, we demonstrate that the SAN’s structural features result from a developmental process during which mesenchymal cells derived from a multipotent progenitor structure, the proepicardium, integrate with and surround pacemaker myocardium. This process actively remodels the forming SAN and is necessary for sustained electrogenic signal generation and propagation. Collectively, these findings provide experimental evidence for how the microenvironmental architecture of the SAN is patterned and demonstrate that proper cellular arrangement is critical for cardiac pacemaker biorhythmicity.Publication Cardiac-enriched BAF chromatin-remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function(The Company of Biologists Ltd, 2018) Sun, Xin; Hota, Swetansu K.; Zhou, Yu-Qing; Novak, Stefanie; Miguel-Perez, Dario; Christodoulou, Danos; Seidman, Christine; Seidman, J. G.; Gregorio, Carol C.; Henkelman, R. Mark; Rossant, Janet; Bruneau, Benoit G.ABSTRACT 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. Baf60c regulates a gene expression program that includes genes encoding contractile proteins, modulators of sarcomere function, and cardiac metabolic genes. Many of the genes deregulated in Baf60c null embryos are targets of the MEF2/SRF co-factor Myocardin (MYOCD). In a yeast two-hybrid screen, we identified MYOCD as a BAF60c interacting factor; we showed that BAF60c and MYOCD directly and functionally interact. We conclude that Baf60c is essential for coordinating a program of gene expression that regulates the fundamental functional properties of cardiomyocytes.Publication ViroFind: A novel target-enrichment deep-sequencing platform reveals a complex JC virus population in the brain of PML patients(Public Library of Science, 2018) Chalkias, Spyros; Gorham, Joshua; Mazaika, Erica; Parfenov, Michael; Dang, Xin; DePalma, Steve; McKean, David; Seidman, Christine; Seidman, Jonathan; Koralnik, Igor J.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. ViroFind comprises 165,433 viral probes that cover the genomes of 535 selected DNA and RNA viruses that infect humans or could cause zoonosis. The ViroFind probes are used in a hybridization reaction to enrich viral sequences and therefore enhance the detection of viral genomes via deep sequencing. We used ViroFind to detect and analyze all viral populations in the brain of 5 patients with progressive multifocal leukoencephalopathy (PML) and of 18 control subjects with no known neurological disease. Compared to direct deep sequencing, by using ViroFind we enriched viral sequences present in the clinical samples up to 127-fold. We discovered highly complex polyoma virus JC populations in the PML brain samples with a remarkable degree of genetic divergence among the JC virus variants of each PML brain sample. Specifically for the viral capsid protein VP1 gene, we identified 24 single nucleotide substitutions, 12 of which were associated with amino acid changes. The most frequent (4 of 5 samples, 80%) amino acid change was D66H, which is associated with enhanced tissue tropism, and hence likely a viral fitness advantage, compared to other variants. Lastly, we also detected sparse JC virus sequences in 10 of 18 (55.5%) of control samples and sparse human herpes virus 6B (HHV6B) sequences in the brain of 11 of 18 (61.1%) control subjects. In sum, ViroFind enabled the in-depth analysis of all viral genomes in PML and control brain samples and allowed us to demonstrate a high degree of JC virus genetic divergence in vivo that has been previously underappreciated. ViroFind can be used to investigate the structure of the virome with unprecedented depth in health and disease state.Publication Advanced assessment of cardiac morphology and prediction of gene carriage by CMR in hypertrophic cardiomyopathy - the HCMNet/UCL collaboration(BioMed Central, 2014) Captur, Gaby; Mohun, Timothy J; Finocchiaro, Gherardo; Wilson, Robert; Levine, Jonathan; Conner, Lauren; Lopes, Luis; Patel, Vimal; Sado, Daniel; Li, Chunming; Bassett, Paul; Herrey, Anna S; Tome Esteban, Maite T; McKenna, William J; Seidman, Christine; Muthurangu, Vivek; Bluemke, David; Ho, Carolyn Y; Elliott, Perry M; Moon, JamesPublication The MedSeq Project: a randomized trial of integrating whole genome sequencing into clinical medicine(BioMed Central, 2014) Vassy, Jason; Lautenbach, Denise M; McLaughlin, Heather M; Kong, Sek Won; Christensen, Kurt; Krier, Joel; Kohane, Isaac; Feuerman, Lindsay Z; Blumenthal-Barby, Jennifer; Roberts, J Scott; Lehmann, Lisa Soleymani; Ho, Carolyn; Ubel, Peter A; MacRae, Calum; Seidman, Christine; Murray, Michael F; McGuire, Amy L; Rehm, Heidi; Green, RobertBackground: Whole genome sequencing (WGS) is already being used in certain clinical and research settings, but its impact on patient well-being, health-care utilization, and clinical decision-making remains largely unstudied. It is also unknown how best to communicate sequencing results to physicians and patients to improve health. We describe the design of the MedSeq Project: the first randomized trials of WGS in clinical care. Methods/Design This pair of randomized controlled trials compares WGS to standard of care in two clinical contexts: (a) disease-specific genomic medicine in a cardiomyopathy clinic and (b) general genomic medicine in primary care. We are recruiting 8 to 12 cardiologists, 8 to 12 primary care physicians, and approximately 200 of their patients. Patient participants in both the cardiology and primary care trials are randomly assigned to receive a family history assessment with or without WGS. Our laboratory delivers a genome report to physician participants that balances the needs to enhance understandability of genomic information and to convey its complexity. We provide an educational curriculum for physician participants and offer them a hotline to genetics professionals for guidance in interpreting and managing their patients’ genome reports. Using varied data sources, including surveys, semi-structured interviews, and review of clinical data, we measure the attitudes, behaviors and outcomes of physician and patient participants at multiple time points before and after the disclosure of these results. Discussion The impact of emerging sequencing technologies on patient care is unclear. We have designed a process of interpreting WGS results and delivering them to physicians in a way that anticipates how we envision genomic medicine will evolve in the near future. That is, our WGS report provides clinically relevant information while communicating the complexity and uncertainty of WGS results to physicians and, through physicians, to their patients. This project will not only illuminate the impact of integrating genomic medicine into the clinical care of patients but also inform the design of future studies. Trial registration ClinicalTrials.gov identifier NCT01736566Publication De novo mutations in histone modifying genes in congenital heart disease(2013) Zaidi, Samir; Choi, Murim; Wakimoto, Hiroko; Ma, Lijiang; Jiang, Jianming; Overton, John D.; Romano-Adesman, Angela; Bjornson, Robert D.; Breitbart, Roger E.; Brown, Kerry K.; Carriero, Nicholas J.; Cheung, Yee Him; Deanfield, John; DePalma, Steven; Fakhro, Khalid A.; Glessner, Joseph; Hakonarson, Hakon; Italia, Michael; Kaltman, Jonathan R.; Kaski, Juan; Kim, Richard; Kline, Jennie K.; Lee, Teresa; Leipzig, Jeremy; Lopez, Alexander; Mane, Shrikant M.; Mitchell, Laura E.; Newburger, Jane W.; Parfenov, Michael; Pe'er, Itsik; Porter, George; Roberts, Amy; Sachidanandam, Ravi; Sanders, Stephan J.; Seiden, Howard S.; State, Mathew W.; Subramanian, Sailakshmi; Tikhonova, Irina R.; Wang, Wei; Warburton, Dorothy; White, Peter S.; Williams, Ismee A.; Zhao, Hongyu; Seidman, Jonathan; Brueckner, Martina; Chung, Wendy K.; Gelb, Bruce D.; Goldmuntz, Elizabeth; Seidman, Christine; Lifton, Richard P.Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births1. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. By analysis of exome sequencing of parent-offspring trios, we compared the incidence of de novo mutations in 362 severe CHD cases and 264 controls. CHD cases showed a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging mutations. Similar odds ratios were seen across major classes of severe CHD. We found a marked excess of de novo mutations in genes involved in production, removal or reading of H3K4 methylation (H3K4me), or ubiquitination of H2BK120, which is required for H3K4 methylation2–4. There were also two de novo mutations in SMAD2; SMAD2 signaling in the embryonic left-right organizer induces demethylation of H3K27me5. H3K4me and H3K27me mark `poised' promoters and enhancers that regulate expression of key developmental genes6. These findings implicate de novo point mutations in several hundred genes that collectively contribute to ~10% of severe CHD.
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