Publications by authors named "Christine E Seidman"

273 Publications

Probing the subcellular nanostructure of engineered human cardiomyocytes in 3D tissue.

Microsyst Nanoeng 2021 27;7:10. Epub 2021 Jan 27.

Department of Mechanical Engineering, Boston University, Boston, MA 02215 USA.

The structural and functional maturation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is essential for pharmaceutical testing, disease modeling, and ultimately therapeutic use. Multicellular 3D-tissue platforms have improved the functional maturation of hiPSC-CMs, but probing cardiac contractile properties in a 3D environment remains challenging, especially at depth and in live tissues. Using small-angle X-ray scattering (SAXS) imaging, we show that hiPSC-CMs matured and examined in a 3D environment exhibit a periodic spatial arrangement of the myofilament lattice, which has not been previously detected in hiPSC-CMs. The contractile force is found to correlate with both the scattering intensity (  = 0.44) and lattice spacing (  = 0.46). The scattering intensity also correlates with lattice spacing (  = 0.81), suggestive of lower noise in our structural measurement than in the functional measurement. Notably, we observed decreased myofilament ordering in tissues with a myofilament mutation known to lead to hypertrophic cardiomyopathy (HCM). Our results highlight the progress of human cardiac tissue engineering and enable unprecedented study of structural maturation in hiPSC-CMs.
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http://dx.doi.org/10.1038/s41378-020-00234-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433147PMC
January 2021

Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.

Nat Med 2021 10 23;27(10):1818-1824. Epub 2021 Sep 23.

Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80-160 mg daily in children) or placebo for 2 years ( NCT01912534 ). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.
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http://dx.doi.org/10.1038/s41591-021-01505-4DOI Listing
October 2021

Contribution of Noncanonical Splice Variants to Truncating Variant Cardiomyopathy.

Circ Genom Precis Med 2021 10 31;14(5):e003389. Epub 2021 Aug 31.

Department of Genetics (P.N.P., K.I., J.A.L.W., A.H., M.Y.J., J.M.G., S.R.D., L.L., B.M., C.E.S., J.G.S.), Harvard Medical School, Boston, MA.

Background: Heterozygous truncating variants cause 10% to 20% of idiopathic dilated cardiomyopathy (DCM). Although variants which disrupt canonical splice signals (ie, invariant dinucleotide of the splice donor site, invariant dinucleotide of the splice acceptor site) at exon-intron junctions are readily recognized as truncating variants, the effects of other nearby sequence variations on splicing and their contribution to disease is uncertain.

Methods: Rare variants of unknown significance located in the splice regions of highly expressed exons from 203 DCM cases, 3329 normal subjects, and clinical variant databases were identified. The effects of these variants on splicing were assessed using an in vitro splice assay.

Results: Splice-altering variants of unknown significance were enriched in DCM cases over controls and present in 2% of DCM patients (=0.002). Application of this method to clinical variant databases demonstrated 20% of similar variants of unknown significance in splice regions affect splicing. Noncanonical splice-altering variants were most frequently located at position +5 of the donor site (=4.4×10) and position -3 of the acceptor site (=0.002). SpliceAI, an emerging in silico prediction tool, had a high positive predictive value (86%-95%) but poor sensitivity (15%-50%) for the detection of splice-altering variants. Alternate exons spliced out of most transcripts frequently lacked the consensus base at +5 donor and -3 acceptor positions.

Conclusions: Noncanonical splice-altering variants in explain 1-2% of DCM and offer a 10-20% increase in the diagnostic power of sequencing in this disease. These data suggest rules that may improve efforts to detect splice-altering variants in other genes and may explain the low percent splicing observed for many alternate exons.
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http://dx.doi.org/10.1161/CIRCGEN.121.003389DOI Listing
October 2021

Cardiomyopathy: Consequences of Impaired Autophagy in the Heart.

J Am Heart Assoc 2021 09 28;10(17):e018829. Epub 2021 Aug 28.

Department of Genetics Harvard Medical School Boston MA.

Background Human mutations in the X-linked lysosome-associated membrane protein-2 () gene can cause a multisystem Danon disease or a primary cardiomyopathy characterized by massive hypertrophy, conduction system abnormalities, and malignant ventricular arrhythmias. We introduced an mutation (denoted L2) causing human cardiomyopathy, into mouse gene, to elucidate its consequences on cardiomyocyte biology. This mutation results in deletion of 41 amino acids, compatible with presence of some defective LAMP2 protein. Methods and Results Left ventricular tissues from L2 and wild-type mice had equivalent amounts of RNA, but a significantly lower level of LAMP2 protein. By 20 weeks of age male mutant mice developed left ventricular hypertrophy which was followed by left ventricular dilatation and reduced systolic function. Cardiac electrophysiology and isolated cardiomyocyte studies demonstrated ventricular arrhythmia, conduction disturbances, abnormal calcium transients and increased sensitivity to catecholamines. Myocardial fibrosis was strikingly increased in 40-week-old L2 mice, recapitulating findings of human LAMP2 cardiomyopathy. Immunofluorescence and transmission electron microscopy identified mislocalization of lysosomes and accumulation of autophagosomes between sarcomeres, causing profound morphological changes disrupting the cellular ultrastructure. Transcription profile and protein expression analyses of L2 hearts showed significantly increased expression of genes encoding activators and protein components of autophagy, hypertrophy, and apoptosis. Conclusions We suggest that impaired autophagy results in cardiac hypertrophy and profound transcriptional reactions that impacted metabolism, calcium homeostasis, and cell survival. These responses define the molecular pathways that underlie the pathology and aberrant electrophysiology in cardiomyopathy of Danon disease.
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http://dx.doi.org/10.1161/JAHA.120.018829DOI Listing
September 2021

Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation.

Circ Res 2021 Sep 18;129(7):751-766. Epub 2021 Aug 18.

Department of Genetics (R.A., C.N.T., Q.Z., J.G., S.R.D., C.E.S., J.G.S.), Harvard Medical School, Boston, MA.

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317076DOI Listing
September 2021

Genomic frontiers in congenital heart disease.

Nat Rev Cardiol 2021 Jul 16. Epub 2021 Jul 16.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

The application of next-generation sequencing to study congenital heart disease (CHD) is increasingly providing new insights into the causes and mechanisms of this prevalent birth anomaly. Whole-exome sequencing analysis identifies damaging gene variants altering single or contiguous nucleotides that are assigned pathogenicity based on statistical analyses of families and cohorts with CHD, high expression in the developing heart and depletion of damaging protein-coding variants in the general population. Gene classes fulfilling these criteria are enriched in patients with CHD and extracardiac abnormalities, evidencing shared pathways in organogenesis. Developmental single-cell transcriptomic data demonstrate the expression of CHD-associated genes in particular cell lineages, and emerging insights indicate that genetic variants perturb multicellular interactions that are crucial for cardiogenesis. Whole-genome sequencing analyses extend these observations, identifying non-coding variants that influence the expression of genes associated with CHD and contribute to the estimated ~55% of unexplained cases of CHD. These approaches combined with the assessment of common and mosaic genetic variants have provided a more complete knowledge of the causes and mechanisms of CHD. Such advances provide knowledge to inform the clinical care of patients with CHD or other birth defects and deepen our understanding of the complexity of human development. In this Review, we highlight known and candidate CHD-associated human genes and discuss how the integration of advances in developmental biology research can provide new insights into the genetic contributions to CHD.
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http://dx.doi.org/10.1038/s41569-021-00587-4DOI Listing
July 2021

Cardiomyocyte Proliferative Capacity Is Restricted in Mice With Mutation.

Front Cardiovasc Med 2021 23;8:639148. Epub 2021 Jun 23.

Department of Cardiovascular Medicine, Nara Medical University, Kashihara, Japan.

is one of the leading causative genes of genetically inherited dilated cardiomyopathy (DCM). Unlike most DCM-causative genes, which encode sarcomeric or sarcomere-related proteins, encodes nuclear envelope proteins, lamin A and C, and does not directly associate with contractile function. However, a mutation in this gene could lead to the development of DCM. The molecular mechanism of how mutation contributes to DCM development remains largely unclear and yet to be elucidated. The objective of this study was to clarify the mechanism of developing DCM caused by mutation. We assessed cardiomyocyte phenotypes and characteristics focusing on cell cycle activity in mice with mutation. Both cell number and cell size were reduced, cardiomyocytes were immature, and cell cycle activity was retarded in mutant mice at both 5 weeks and 2 years of age. RNA-sequencing and pathway analysis revealed "proliferation of cells" had the most substantial impact on mutant mice. , which encodes the cell cycle regulating protein p21, was strongly upregulated in mutants, and upregulation of p21 was confirmed by Western blot and immunostaining. DNA damage, which is known to upregulate , was more abundantly detected in mutant mice. To assess the proliferative capacity of cardiomyocytes, the apex of the neonate mouse heart was resected, and recovery from the insult was observed. A restricted cardiomyocyte proliferating capacity after resecting the apex of the heart was observed in mutant mice. Our results strongly suggest that loss of lamin function contributes to impaired cell proliferation through cell cycle defects. The inadequate inborn or responsive cell proliferation capacity plays an essential role in developing DCM with mutation.
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http://dx.doi.org/10.3389/fcvm.2021.639148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260675PMC
June 2021

Isolation of Nuclei from Mammalian Cells and Tissues for Single-Nucleus Molecular Profiling.

Curr Protoc 2021 May;1(5):e132

Department of Genetics, Harvard Medical School, Boston, Massachusetts.

Both single-cell RNA sequencing (scRNAseq) and single-nucleus RNA sequencing (snRNAseq) can be used to characterize the transcriptional profile of individual cells, and based on these transcriptional profiles, help define cell type distribution in mixed cell populations. However, scRNAseq analyses are confounded if some of the cells are large (>50 µm) or if some of cells adhere more tightly to some adjacent cells than to others. Further, single cell isolation for scRNAseq requires fresh tissue, which may not be available for human or animal model tissues. Additionally, the current enzymatic and mechanical methods for single-cell dissociation can lead to stress-induced transcriptional artifacts. Nuclei for snRNAseq, on the other hand, can be isolated from any cell, regardless of size, and from either fresh or frozen tissues, and compared to whole cells, they are more resistant to mechanical pressures and appear not to exhibit as many cell isolation-based transcriptional artifacts. Here, we describe a time- and cost-effective procedure to isolate nuclei from mammalian cells and tissues. The protocol incorporates steps to mechanically disrupt samples to release nuclei. Compared to conventional nuclei isolation protocols, the approach described here increases overall efficiency, eliminates risk of contaminant exposure, and reduces volumes of expensive reagents. A series of RNA quality control checks are also incorporated to ensure success and reduce costs of subsequent snRNAseq experiments. Nuclei isolated by this procedure can be separated on the 10× Genomics Chromium system for either snRNAseq and/or Single-Nucleus ATAC-Seq (snATAC-Seq), and is also compatible with other single cell platforms. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Sample preparation and quality control check via RNA Isolation and Analysis Basic Protocol 2: Nuclei Isolation.
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http://dx.doi.org/10.1002/cpz1.132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191490PMC
May 2021

CalTrack: High-Throughput Automated Calcium Transient Analysis in Cardiomyocytes.

Circ Res 2021 07 21;129(2):326-341. Epub 2021 May 21.

Division of Cardiovascular Medicine, Radcliffe Department of Medicine (Y.P., F.M., A.J.S., M.S., V.S., C.S.R., H.C.W., P.R., C.N.T.), University of Oxford, United Kingdom.

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.121.318868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260473PMC
July 2021

Genetic and Phenotypic Landscape of Peripartum Cardiomyopathy.

Circulation 2021 May 20;143(19):1852-1862. Epub 2021 Apr 20.

University of Pittsburgh Medical Center, PA (D.M.M.).

Background: Peripartum cardiomyopathy (PPCM) occurs in ≈1:2000 deliveries in the United States and worldwide. The genetic underpinnings of PPCM remain poorly defined. Approximately 10% of women with PPCM harbor truncating variants in (TTNtvs). Whether mutations in other genes can predispose to PPCM is not known. It is also not known if the presence of TTNtvs predicts clinical presentation or outcomes. Nor is it known if the prevalence of TTNtvs differs in women with PPCM and preeclampsia, the strongest risk factor for PPCM.

Methods: Women with PPCM were retrospectively identified from several US and international academic centers, and clinical information and DNA samples were acquired. Next-generation sequencing was performed on 67 genes, including , and evaluated for burden of truncating and missense variants. The impact of TTNtvs on the severity of clinical presentation, and on clinical outcomes, was evaluated.

Results: Four hundred sixty-nine women met inclusion criteria. Of the women with PPCM, 10.4% bore TTNtvs (odds ratio=9.4 compared with 1.2% in the reference population; Bonferroni-corrected [*]=1.2×10). We additionally identified overrepresentation of truncating variants in FLNC (odds ratio=24.8, *=7.0×10), DSP (odds ratio=14.9, *=1.0×10), and BAG3 (odds ratio=53.1, *=0.02), genes not previously associated with PPCM. This profile is highly similar to that found in nonischemic dilated cardiomyopathy. Women with TTNtvs had lower left ventricular ejection fraction on presentation than did women without TTNtvs (23.5% versus 29%, =2.5×10), but did not differ significantly in timing of presentation after delivery, in prevalence of preeclampsia, or in rates of clinical recovery.

Conclusions: This study provides the first extensive genetic and phenotypic landscape of PPCM and demonstrates that predisposition to heart failure is an important risk factor for PPCM. The work reveals a degree of genetic similarity between PPCM and dilated cardiomyopathy, suggesting that gene-specific therapeutic approaches being developed for dilated cardiomyopathy may also apply to PPCM, and that approaches to genetic testing in PPCM should mirror those taken in dilated cardiomyopathy. Last, the clarification of genotype/phenotype associations has important implications for genetic counseling.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113098PMC
May 2021

Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.

Eur Heart J 2021 05;42(20):2000-2011

Université de Paris, INSERM, UMR-S970, Integrative Epidemiology of cardiovascular disease, Paris, France.

Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure.

Methods And Results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene.

Conclusion: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
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http://dx.doi.org/10.1093/eurheartj/ehab030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139853PMC
May 2021

Discordant clinical features of identical hypertrophic cardiomyopathy twins.

Proc Natl Acad Sci U S A 2021 03;118(10)

Department of Genetics, Harvard Medical School, Boston, MA 02115;

Hypertrophic cardiomyopathy (HCM) is a disease of heart muscle, which affects ∼1 in 500 individuals and is characterized by increased left ventricular wall thickness. While HCM is caused by pathogenic variants in any one of eight sarcomere protein genes, clinical expression varies considerably, even among patients with the same pathogenic variant. To determine whether background genetic variation or environmental factors drive these differences, we studied disease progression in 11 pairs of monozygotic HCM twins. The twin pairs were followed for 5 to 14 y, and left ventricular wall thickness, left atrial diameter, and left ventricular ejection fraction were collected from echocardiograms at various time points. All nine twin pairs with sarcomere protein gene variants and two with unknown disease etiologies had discordant morphologic features of the heart, demonstrating the influence of nonhereditable factors on clinical expression of HCM. Whole genome sequencing analysis of the six monozygotic twins with discordant HCM phenotypes did not reveal notable somatic genetic variants that might explain their clinical differences. Discordant cardiac morphology of identical twins highlights a significant role for epigenetics and environment in HCM disease progression.
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http://dx.doi.org/10.1073/pnas.2021717118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958207PMC
March 2021

Conquering Atherosclerotic Cardiovascular Disease - 50 Years of Progress.

N Engl J Med 2021 Mar 27;384(9):785-788. Epub 2021 Feb 27.

From the National Heart, Lung, and Blood Institute, Bethesda, MD (G.H.G.); Brigham and Women's Hospital and Harvard Medical School, Boston, and Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.); and the Scripps Research Translational Institute, La Jolla, CA (E.J.T.).

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http://dx.doi.org/10.1056/NEJMp2033115DOI Listing
March 2021

Modeling Human TBX5 Haploinsufficiency Predicts Regulatory Networks for Congenital Heart Disease.

Dev Cell 2021 02 14;56(3):292-309.e9. Epub 2020 Dec 14.

Gladstone Institutes, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA; Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, CA 94158, USA. Electronic address:

Haploinsufficiency of transcriptional regulators causes human congenital heart disease (CHD); however, the underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define transcriptional consequences of reduced dosage of the CHD transcription factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways-including lineage decisions and genes associated with heart development, cardiomyocyte function, and CHD genetics-in discrete subpopulations of cardiomyocytes. Spatial transcriptomic mapping revealed chamber-restricted expression for many TBX5-sensitive transcripts. GRN analysis indicated that cardiac network stability, including vulnerable CHD-linked nodes, is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between Tbx5 and Mef2c, manifesting as ventricular septation defects, was validated in mice. These results demonstrate exquisite and diverse sensitivity to TBX5 dosage in heterogeneous subsets of iPSC-derived cardiomyocytes and predicts candidate GRNs for human CHDs, with implications for quantitative transcriptional regulation in disease.
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http://dx.doi.org/10.1016/j.devcel.2020.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878434PMC
February 2021

Associations Between Female Sex, Sarcomere Variants, and Clinical Outcomes in Hypertrophic Cardiomyopathy.

Circ Genom Precis Med 2021 02 7;14(1):e003062. Epub 2020 Dec 7.

Brigham and Women's Hospital (N.K.L., A.L.C., C.E.S., C.Y.H.), Harvard Medical School, MA.

Background: The impact of sex on phenotypic expression in hypertrophic cardiomyopathy (HCM) has not been well characterized in genotyped cohorts.

Methods: Retrospective cohort study from an international registry of patients receiving care at experienced HCM centers. Sex-based differences in baseline characteristics and clinical outcomes were assessed.

Results: Of 5873 patients (3788 genotyped), 2226 (37.9%) were women. At baseline, women were older (49.0±19.9 versus 42.9±18.4 years, <0.001) and more likely to have pathogenic/likely pathogenic sarcomeric variants (HCM patients with a sarcomere mutation; 51% versus 43%, <0.001) despite equivalent utilization of genetic testing. Age at diagnosis varied by sex and genotype despite similar distribution of causal genes. Women were 3.6 to 7.1 years older at diagnosis (<0.02) except for patients with variants where age at diagnosis was comparable for women and men (n=492; 34.8±19.2 versus 33.3±16.8 years, =0.39). Over 7.7 median years of follow-up, New York Heart Association III-IV heart failure was more common in women (hazard ratio, 1.87 [CI, 1.48-2.36], <0.001), after controlling for their higher burden of symptoms and outflow tract obstruction at baseline, reduced ejection fraction, HCM patients with a sarcomere mutation, age, and hypertension. All-cause mortality was increased in women (hazard ratio, 1.50 [CI, 1.13-1.99], <0.01) but neither implantable cardioverter-defibrillator utilization nor ventricular arrhythmia varied by sex.

Conclusions: In HCM, women are older at diagnosis, partly modified by genetic substrate. Regardless of genotype, women were at higher risk of mortality and developing severe heart failure symptoms. This points to a sex-effect on long-term myocardial performance in HCM, which should be investigated further.
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http://dx.doi.org/10.1161/CIRCGEN.120.003062DOI Listing
February 2021

Rare genetic variation at transcription factor binding sites modulates local DNA methylation profiles.

PLoS Genet 2020 11 20;16(11):e1009189. Epub 2020 Nov 20.

The Mindich Child Health and Development Institute and Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.

Although DNA methylation is the best characterized epigenetic mark, the mechanism by which it is targeted to specific regions in the genome remains unclear. Recent studies have revealed that local DNA methylation profiles might be dictated by cis-regulatory DNA sequences that mainly operate via DNA-binding factors. Consistent with this finding, we have recently shown that disruption of CTCF-binding sites by rare single nucleotide variants (SNVs) can underlie cis-linked DNA methylation changes in patients with congenital anomalies. These data raise the hypothesis that rare genetic variation at transcription factor binding sites (TFBSs) might contribute to local DNA methylation patterning. In this work, by combining blood genome-wide DNA methylation profiles, whole genome sequencing-derived SNVs from 247 unrelated individuals along with 133 predicted TFBS motifs derived from ENCODE ChIP-Seq data, we observed an association between the disruption of binding sites for multiple TFs by rare SNVs and extreme DNA methylation values at both local and, to a lesser extent, distant CpGs. While the majority of these changes affected only single CpGs, 24% were associated with multiple outlier CpGs within ±1kb of the disrupted TFBS. Interestingly, disruption of functionally constrained sites within TF motifs lead to larger DNA methylation changes at nearby CpG sites. Altogether, these findings suggest that rare SNVs at TFBS negatively influence TF-DNA binding, which can lead to an altered local DNA methylation profile. Furthermore, subsequent integration of DNA methylation and RNA-Seq profiles from cardiac tissues enabled us to observe an association between rare SNV-directed DNA methylation and outlier expression of nearby genes. In conclusion, our findings not only provide insights into the effect of rare genetic variation at TFBS on shaping local DNA methylation and its consequences on genome regulation, but also provide a rationale to incorporate DNA methylation data to interpret the functional role of rare variants.
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http://dx.doi.org/10.1371/journal.pgen.1009189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679001PMC
November 2020

Association of Damaging Variants in Genes With Increased Cancer Risk Among Patients With Congenital Heart Disease.

JAMA Cardiol 2021 Apr;6(4):457-462

Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Patients with congenital heart disease (CHD), the most common birth defect, have increased risks for cancer. Identification of the variables that contribute to cancer risk is essential for recognizing patients with CHD who warrant longitudinal surveillance and early interventions.

Objective: To compare the frequency of damaging variants in cancer risk genes among patients with CHD and control participants and identify associated clinical variables in patients with CHD who have cancer risk variants.

Design, Setting, And Participants: This multicenter case-control study included participants with CHD who had previously been recruited to the Pediatric Cardiac Genomics Consortium based on presence of structural cardiac anomaly without genetic diagnosis at the time of enrollment. Permission to use published sequencing data from unaffected adult participants was obtained from 2 parent studies. Data were collected for this study from December 2010 to April 2019.

Exposures: Presence of rare (allele frequency, <1 × 10-5) loss-of-function (LoF) variants in cancer risk genes.

Main Outcomes And Measures: Frequency of LoF variants in cancer risk genes (defined in the Catalogue of Somatic Mutations in Cancer-Cancer Gene Consensus database), were statistically assessed by binomial tests in patients with CHD and control participants.

Results: A total of 4443 individuals with CHD (mean [range] age, 13.0 [0-84] years; 2225 of 3771 with reported sex [59.0%] male) and 9808 control participants (mean [range] age, 52.1 [1-92] years; 4967 of 9808 [50.6%] male) were included. The frequency of LoF variants in regulatory cancer risk genes was significantly higher in patients with CHD than control participants (143 of 4443 [3.2%] vs 166 of 9808 [1.7%]; odds ratio [OR], 1.93 [95% CI, 1.54-2.42]; P = 1.38 × 10-12), and among CHD genes previously associated with cancer risk (58 of 4443 [1.3%] vs 18 of 9808 [0.18%]; OR, 7.2 [95% CI, 4.2-12.2]; P < 2.2 × 10-16). The LoF variants were also nominally increased in 14 constrained cancer risk genes with high expression in the developing heart. Seven of these genes (ARHGEF12, CTNNB1, LPP, MLLT4, PTEN, TCF12, and TFRC) harbored LoF variants in multiple patients with unexplained CHD. The highest rates for LoF variants in cancer risk genes occurred in patients with CHD and extracardiac anomalies (248 of 1482 individuals [16.7%]; control: 1099 of 9808 individuals [11.2%]; OR, 1.59 [95% CI, 1.37-1.85]; P = 1.3 × 10-10) and/or neurodevelopmental delay (209 of 1393 individuals [15.0%]; control: 1099 of 9808 individuals [11.2%]; OR, 1.40 [95% CI, 1.19-1.64]; P = 9.6 × 10-6).

Conclusions And Relevance: Genotypes of CHD may account for increased cancer risks. In this cohort, damaging variants were prominent in the 216 genes that predominantly encode regulatory proteins. Consistent with their fundamental developmental functions, patients with CHD and damaging variants in these genes often had extracardiac manifestations. These data may also implicate cancer risk genes that are repeatedly varied in patients with unexplained CHD as CHD genes.
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http://dx.doi.org/10.1001/jamacardio.2020.4947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578917PMC
April 2021

mutations in hiPSCs inform mechanisms for maldevelopment of the heart, pancreas, and diaphragm.

Elife 2020 10 15;9. Epub 2020 Oct 15.

Department of Genetics, Harvard Medical School, Boston, United States.

Damaging variants cause cardiac outflow tract defects, sometimes with pancreatic and diaphragmic malformations. To define molecular mechanisms for these diverse developmental defects, we studied transcriptional and epigenetic responses to loss of function (LoF) and missense variants during cardiomyocyte differentiation of isogenic human induced pluripotent stem cells. We show that GATA6 is a pioneer factor in cardiac development, regulating that activates and that with orchestrates outflow tract formation. LoF variants perturbed cardiac genes and also endoderm lineage genes that direct expression and pancreatic development. Remarkably, an exon 4 missense variant, highly associated with extra-cardiac malformations, caused ectopic pioneer activities, profoundly diminishing , and expression and increasing normal retinoic acid signaling that promotes diaphragm development. These aberrant epigenetic and transcriptional signatures illuminate the molecular mechanisms for cardiovascular malformations, pancreas and diaphragm dysgenesis that arise in patients with distinct variants.
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http://dx.doi.org/10.7554/eLife.53278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593088PMC
October 2020

Cells of the adult human heart.

Nature 2020 12 24;588(7838):466-472. Epub 2020 Sep 24.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.
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http://dx.doi.org/10.1038/s41586-020-2797-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681775PMC
December 2020

Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.

Circ Genom Precis Med 2020 10 4;13(5):444-452. Epub 2020 Sep 4.

Department of Genetics (S.R.D., B.M., J.G.S., C.E.S.), Harvard Medical School, Boston.

Background: Cardiac troponin I () gene mutations account for 3% of hypertrophic cardiomyopathy and carriers have a heterogeneous phenotype, with increased risk of sudden cardiac death (SCD). Only one mutation (p.Arg21Cys) has been reported in the N terminus of the protein. In model organisms, it impairs PKA (protein kinase A) phosphorylation, increases calcium sensitivity, and causes diastolic dysfunction. The phenotype of this unique mutation in patients with hypertrophic cardiomyopathy remains unknown.

Methods: We sequenced 29 families with hypertrophic cardiomyopathy enriched for pediatric-onset disease and identified 5 families with the p.Arg21Cys mutation. Using cascade screening, we studied the clinical phenotype of 57 individuals from the 5 families with p.Arg21Cys-related cardiomyopathy. We performed survival analysis investigating the age at first SCD in carriers of the mutation.

Results: All 5 families with p.Arg21Cys were from South Lebanon. p.Arg21Cys-related cardiomyopathy manifested a malignant phenotype-SCD occurred in 30 (53%) of 57 affected individuals at a median age of 22.5 years. In select carriers without left ventricular hypertrophy on echocardiogram, SCD occurred, myocyte disarray was found on autopsy heart, and tissue Doppler and cardiac magnetic resonance imaging identified subclinical disease features such as diastolic dysfunction and late gadolinium enhancement.

Conclusions: The p.Arg21Cys mutation has a founder effect in South Lebanon and causes malignant hypertrophic cardiomyopathy with early SCD even in the absence of hypertrophy. Genetic diagnosis with this mutation may be sufficient for risk stratification for SCD.
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http://dx.doi.org/10.1161/CIRCGEN.120.002991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676616PMC
October 2020

Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in and That Are Common in Chinese Patients.

Circ Genom Precis Med 2020 10 20;13(5):424-434. Epub 2020 Aug 20.

Cardiovascular Research Center, Royal Brompton Hospital, London, United Kingdom (N.W., A.d.M., R.G., R.J.B., P.J.R.B., J.S.W., S.A.C.).

Background: To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry.

Methods: We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3634), compared findings with additional populations and White HCM cohorts (n=6179), and performed in vitro functional studies.

Results: Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (pathogenic/likely pathogenic: 18%, <0.0001) but an excess of variants of uncertain significance (24%, <0.0001), as compared to Whites (pathogenic/likely pathogenic: 31%, excess of variants of uncertain significance: 7%). Two missense variants in thin filament encoding genes were commonly seen in Singaporean HCM (TNNI3:p.R79C, disease allele frequency [AF]=0.018; TNNT2:p.R286H, disease AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls (TNNI3:p.R79C, Singaporean controls AF=0.0055, =0.0057, genome aggregation database-East Asian AF=0.0062, =0.0086; TNNT2:p.R286H, Singaporean controls AF=0.0017, <0.0001, genome aggregation database-East Asian AF=0.0009, <0.0001). Both these variants have conflicting annotations in ClinVar and are of low penetrance (TNNI3:p.R79C, 0.7%; TNNT2:p.R286H, 2.7%) but are predicted to be deleterious by computational tools. In population controls, TNNI3:p.R79C carriers had significantly thicker left ventricular walls compared with noncarriers while its etiological fraction is limited (0.70 [95% CI, 0.35-0.86]) and thus TNNI3:p.R79C is considered variant of uncertain significance. Mutant TNNT2:p.R286H iPSC-CMs (induced pluripotent stem cells derived cardiomyocytes) show hypercontractility, increased metabolic requirements, and cellular hypertrophy and the etiological fraction (0.93 [95% CI, 0.83-0.97]) support the likely pathogenicity of TNNT2:p.R286H.

Conclusions: As compared with Whites, Chinese HCM patients commonly have low penetrance risk alleles in or but exhibit few clinically actionable HCM variants overall. This highlights the need for greater study of HCM genetics in non-White populations.
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http://dx.doi.org/10.1161/CIRCGEN.119.002823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676617PMC
October 2020

De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease.

Circ Genom Precis Med 2020 08 30;13(4):e002836. Epub 2020 Jun 30.

Department of Genetics (R.L., M.B.), Yale University School of Medicine, New Haven, CT.

Background: De novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.

Methods: We studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network).

Results: Two hundred ninety-four patients (11.7%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (=5.63×10). In 1268 patients (50.4%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; =5.33×10) and longer times to final extubation (hazard ratio, 0.74; =0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; =0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; =1.61×10) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation.

Conclusions: In patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.
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http://dx.doi.org/10.1161/CIRCGEN.119.002836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439931PMC
August 2020

BET bromodomain proteins regulate transcriptional reprogramming in genetic dilated cardiomyopathy.

JCI Insight 2020 08 6;5(15). Epub 2020 Aug 6.

Emory University School of Medicine, Atlanta, Georgia, USA.

The bromodomain and extraterminal (BET) family comprises epigenetic reader proteins that are important regulators of inflammatory and hypertrophic gene expression in the heart. We previously identified the activation of proinflammatory gene networks as a key early driver of dilated cardiomyopathy (DCM) in transgenic mice expressing a mutant form of phospholamban (PLNR9C) - a genetic cause of DCM in humans. We hypothesized that BETs coactivate this inflammatory process, representing a critical node in the progression of DCM. To test this hypothesis, we treated PLNR9C or age-matched WT mice longitudinally with the small molecule BET bromodomain inhibitor JQ1 or vehicle. BET inhibition abrogated adverse cardiac remodeling, reduced cardiac fibrosis, and prolonged survival in PLNR9C mice by inhibiting expression of proinflammatory gene networks at all stages of disease. Specifically, JQ1 had profound effects on proinflammatory gene network expression in cardiac fibroblasts, while having little effect on gene expression in cardiomyocytes. Cardiac fibroblast proliferation was also substantially reduced by JQ1. Mechanistically, we demonstrated that BRD4 serves as a direct and essential regulator of NF-κB-mediated proinflammatory gene expression in cardiac fibroblasts. Suppressing proinflammatory gene expression via BET bromodomain inhibition could be a novel therapeutic strategy for chronic DCM in humans.
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http://dx.doi.org/10.1172/jci.insight.138687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455078PMC
August 2020

Genomic analyses implicate noncoding de novo variants in congenital heart disease.

Nat Genet 2020 08 29;52(8):769-777. Epub 2020 Jun 29.

Flatiron Institute, Simons Foundation, New York, NY, USA.

A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in individuals with CHD (n = 2,238 DNVs) compared to controls (n = 4,177; P = 8.7 × 10). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10). We observed significant overlap between these transcription-based approaches (odds ratio (OR) = 2.5, 95% confidence interval (CI) 1.1-5.0, P = 5.4 × 10). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. Finally, we observed a DNV burden in RNA-binding-protein regulatory sites (OR = 1.13, 95% CI 1.1-1.2, P = 8.8 × 10). Our findings demonstrate an enrichment of potentially disruptive regulatory noncoding DNVs in a fraction of CHD at least as high as that observed for damaging coding DNVs.
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http://dx.doi.org/10.1038/s41588-020-0652-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415662PMC
August 2020

Complement genes contribute sex-biased vulnerability in diverse disorders.

Nature 2020 06 11;582(7813):577-581. Epub 2020 May 11.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men, whereas schizophrenia affects men with greater frequency and severity relative to women. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE 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 variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome 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 reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.
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http://dx.doi.org/10.1038/s41586-020-2277-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319891PMC
June 2020

Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants.

Am Heart J 2020 07 21;225:108-119. Epub 2020 Apr 21.

Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Victoria, Australia; Department of Pediatrics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Victoria, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Victoria, Australia.

Introduction: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined.

Methods And Results: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10; U.S. cohort, P = 2.2×10).

Conclusion: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.
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http://dx.doi.org/10.1016/j.ahj.2020.03.023DOI Listing
July 2020

Marked Up-Regulation of ACE2 in Hearts of Patients With Obstructive Hypertrophic Cardiomyopathy: Implications for SARS-CoV-2-Mediated COVID-19.

Mayo Clin Proc 2020 07 28;95(7):1354-1368. Epub 2020 Apr 28.

Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN; Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN; Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, MN. Electronic address:

Objective: To explore the transcriptomic differences between patients with hypertrophic cardiomyopathy (HCM) and controls.

Patients And Methods: RNA was extracted from cardiac tissue flash frozen at therapeutic surgical septal myectomy for 106 patients with HCM and 39 healthy donor hearts. Expression profiling of 37,846 genes was performed using the Illumina Human HT-12v3 Expression BeadChip. All patients with HCM were genotyped for pathogenic variants causing HCM. Technical validation was performed using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. This study was started on January 1, 1999, and final analysis was completed on April 20, 2020.

Results: Overall, 22% of the transcriptome (8443 of 37,846 genes) was expressed differentially between HCM and control tissues. Analysis by genotype revealed that gene expression changes were similar among genotypic subgroups of HCM, with only 4% (1502 of 37,846) to 6% (2336 of 37,846) of the transcriptome exhibiting differential expression between genotypic subgroups. The qRT-PCR confirmed differential expression in 92% (11 of 12 genes) of tested transcripts. Notably, in the context of coronavirus disease 2019 (COVID-19), the transcript for angiotensin I converting enzyme 2 (ACE2), a negative regulator of the angiotensin system, was the single most up-regulated gene in HCM (fold-change, 3.53; q-value =1.30×10), which was confirmed by qRT-PCR in triplicate (fold change, 3.78; P=5.22×10), and Western blot confirmed greater than 5-fold overexpression of ACE2 protein (fold change, 5.34; P=1.66×10).

Conclusion: More than 20% of the transcriptome is expressed differentially between HCM and control tissues. Importantly, ACE2 was the most up-regulated gene in HCM, indicating perhaps the heart's compensatory effort to mount an antihypertrophic, antifibrotic response. However, given that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 for viral entry, this 5-fold increase in ACE2 protein may confer increased risk for COVID-19 manifestations and outcomes in patients with increased ACE2 transcript expression and protein levels in the heart.
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http://dx.doi.org/10.1016/j.mayocp.2020.04.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186205PMC
July 2020

Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects.

JACC Basic Transl Sci 2020 Apr 8;5(4):376-386. Epub 2020 Apr 8.

Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins , , and and the regulators of small GTPase signaling and are critical to cardiac development.
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http://dx.doi.org/10.1016/j.jacbts.2020.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188873PMC
April 2020
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