Browsing by Author "Garg, Vidu"

Now showing 1 - 4 of 4
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    A Multicenter Analysis of Abnormal Chromosomal Microarray Findings in Congenital Heart Disease
    (American Heart Association, 2023) Landis, Benjamin J.; Helvaty, Lindsey R.; Geddes, Gabrielle C.; Lin, Jiuann-Huey Ivy; Yatsenko, Svetlana A.; Lo, Cecilia W.; Border, William L.; Burns Wechsler, Stephanie; Murali, Chaya N.; Azamian, Mahshid S.; Lalani, Seema R.; Hinton, Robert B.; Garg, Vidu; McBride, Kim L.; Hodge, Jennelle C.; Ware, Stephanie M.; Pediatrics, School of Medicine
    Background: Chromosomal microarray analysis (CMA) provides an opportunity to understand genetic causes of congenital heart disease (CHD). The methods for describing cardiac phenotypes in patients with CMA abnormalities have been inconsistent, which may complicate clinical interpretation of abnormal testing results and hinder a more complete understanding of genotype–phenotype relationships. Methods and Results: Patients with CHD and abnormal clinical CMA were accrued from 9 pediatric cardiac centers. Highly detailed cardiac phenotypes were systematically classified and analyzed for their association with CMA abnormality. Hierarchical classification of each patient into 1 CHD category facilitated broad analyses. Inclusive classification allowing multiple CHD types per patient provided sensitive descriptions. In 1363 registry patients, 28% had genomic disorders with well‐recognized CHD association, 67% had clinically reported copy number variants (CNVs) with rare or no prior CHD association, and 5% had regions of homozygosity without CNV. Hierarchical classification identified expected CHD categories in genomic disorders, as well as uncharacteristic CHDs. Inclusive phenotyping provided sensitive descriptions of patients with multiple CHD types, which occurred commonly. Among CNVs with rare or no prior CHD association, submicroscopic CNVs were enriched for more complex types of CHD compared with large CNVs. The submicroscopic CNVs that contained a curated CHD gene were enriched for left ventricular obstruction or septal defects, whereas CNVs containing a single gene were enriched for conotruncal defects. Neuronal‐related pathways were over‐represented in single‐gene CNVs, including top candidate causative genes NRXN3, ADCY2, and HCN1. Conclusions: Intensive cardiac phenotyping in multisite registry data identifies genotype–phenotype associations in CHD patients with abnormal CMA.
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    Endocardial HDAC3 is required for myocardial trabeculation
    (Springer Nature, 2024-05-16) Jang, Jihyun; Bentsen, Mette; Kim, Ye Jun; Kim, Erick; Garg, Vidu; Cai, Chen-Leng; Looso, Mario; Li, Deqiang; Pediatrics, School of Medicine
    Failure of proper ventricular trabeculation is often associated with congenital heart disease. Support from endocardial cells, including the secretion of extracellular matrix and growth factors is critical for trabeculation. However, it is poorly understood how the secretion of extracellular matrix and growth factors is initiated and regulated by endocardial cells. We find that genetic knockout of histone deacetylase 3 in the endocardium in mice results in early embryo lethality and ventricular hypotrabeculation. Single cell RNA sequencing identifies significant downregulation of extracellular matrix components in histone deacetylase 3 knockout endocardial cells. Secretome from cultured histone deacetylase 3 knockout mouse cardiac endothelial cells lacks transforming growth factor ß3 and shows significantly reduced capacity in stimulating cultured cardiomyocyte proliferation, which is remarkably rescued by transforming growth factor ß3 supplementation. Mechanistically, we identify that histone deacetylase 3 knockout induces transforming growth factor ß3 expression through repressing microRNA-129-5p. Our findings provide insights into the pathogenesis of congenital heart disease and conceptual strategies to promote myocardial regeneration.
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    miR‐145 transgenic mice develop cardiopulmonary complications leading to postnatal death
    (Wiley, 2021-09) Thomas, Shelby; Manivannan, Sathiyanarayanan; Sawant, Dwitiya; Kodigepalli, Karthik M.; Garg, Vidu; Conway, Simon J.; Lilly, Brenda; Pediatrics, School of Medicine
    Background: Both downregulation and elevation of microRNA miR-145 has been linked to an array of cardiopulmonary phenotypes, and a host of studies suggest that it is an important contributor in governing the differentiation of cardiac and vascular smooth muscle cell types. Methods and results: To better understand the role of elevated miR-145 in utero within the cardiopulmonary system, we utilized a transgene to overexpress miR-145 embryonically in mice and examined the consequences of this lineage-restricted enhanced expression. Overexpression of miR-145 has detrimental effects that manifest after birth as overexpressor mice are unable to survive beyond postnatal day 18. The miR-145 expressing mice exhibit respiratory distress and fail to thrive. Gross analysis revealed an enlarged right ventricle, and pulmonary dysplasia with vascular hypertrophy. Single cell sequencing of RNA derived from lungs of control and miR-145 transgenic mice demonstrated that miR-145 overexpression had global effects on the lung with an increase in immune cells and evidence of leukocyte extravasation associated with vascular inflammation. Conclusions: These data provide novel findings that demonstrate a pathological role for miR-145 in the cardiopulmonary system that extends beyond its normal function in governing smooth muscle differentiation.
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    Rationale for the Cytogenomics of Cardiovascular Malformations Consortium: A Phenotype Intensive Registry Based Approach
    (MDPI, 2015-04-29) Hinton, Robert B.; McBride, Kim L.; Bleyl, Steven B.; Bowles, Neil E.; Border, William L.; Garg, Vidu; Smolarek, Teresa A.; Lalani, Seema R.; Ware, Stephanie M.; Pediatrics, School of Medicine
    Cardiovascular malformations (CVMs) are the most common birth defect, occurring in 1%-5% of all live births. Although the genetic contribution to CVMs is well recognized, the genetic causes of human CVMs are identified infrequently. In addition, a failure of systematic deep phenotyping of CVMs, resulting from the complexity and heterogeneity of malformations, has obscured genotype-phenotype correlations and contributed to a lack of understanding of disease mechanisms. To address these knowledge gaps, we have developed the Cytogenomics of Cardiovascular Malformations (CCVM) Consortium, a multi-site alliance of geneticists and cardiologists, contributing to a database registry of submicroscopic genetic copy number variants (CNVs) based on clinical chromosome microarray testing in individuals with CVMs using detailed classification schemes. Cardiac classification is performed using a modification to the National Birth Defects Prevention Study approach, and non-cardiac diagnoses are captured through ICD-9 and ICD-10 codes. By combining a comprehensive approach to clinically relevant genetic analyses with precise phenotyping, the Consortium goal is to identify novel genomic regions that cause or increase susceptibility to CVMs and to correlate the findings with clinical phenotype. This registry will provide critical insights into genetic architecture, facilitate genotype-phenotype correlations, and provide a valuable resource for the medical community.