Gene expression in cardiac tissues from infants with idiopathic conotruncal defects

Children's Mercy Hospitals and Clinics, University of Missouri-Kansas City School of Medicine, USA.
BMC Medical Genomics (Impact Factor: 2.87). 01/2011; 4(1):1. DOI: 10.1186/1755-8794-4-1
Source: PubMed


Tetralogy of Fallot (TOF) is the most commonly observed conotruncal congenital heart defect. Treatment of these patients has evolved dramatically in the last few decades, yet a genetic explanation is lacking for the failure of cardiac development for the majority of children with TOF. Our goal was to perform genome wide analyses and characterize expression patterns in cardiovascular tissue (right ventricle, pulmonary valve and pulmonary artery) obtained at the time of reconstructive surgery from 19 children with tetralogy of Fallot.
We employed genome wide gene expression microarrays to characterize cardiovascular tissue (right ventricle, pulmonary valve and pulmonary artery) obtained at the time of reconstructive surgery from 19 children with TOF (16 idiopathic and three with 22q11.2 deletions) and compared gene expression patterns to normally developing subjects.
We detected a signal from approximately 26,000 probes reflecting expression from about half of all genes, ranging from 35% to 49% of array probes in the three tissues. More than 1,000 genes had a 2-fold change in expression in the right ventricle (RV) of children with TOF as compared to the RV from matched control infants. Most of these genes were involved in compensatory functions (e.g., hypertrophy, cardiac fibrosis and cardiac dilation). However, two canonical pathways involved in spatial and temporal cell differentiation (WNT, p = 0.017 and Notch, p = 0.003) appeared to be generally suppressed.
The suppression of developmental networks may represent a remnant of a broad malfunction of regulatory pathways leading to inaccurate boundary formation and improper structural development in the embryonic heart. We suggest that small tissue specific genomic and/or epigenetic fluctuations could be cumulative, leading to regulatory network disruption and failure of proper cardiac development.

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    • "Briefly, an equal quantity of total RNA (1 μg) together with random and oligo dT primers was reverse transcribed using Superscript III (Invitrogen by Life Technologies, Carlsbad, CA) according to the manufacturer's directions. Quantitative RT-PCR (qRT-PCR) was performed using Power SYBR Green PCR Master Mix (Applied Biosystems, Foster City, CA) according to the manufacturer's directions as previously described [21]. The reaction was carried out in an ABI7000system (Applied Biosystems, Foster City, CA) beginning with 10 min at 95 °C. "

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    • "Differences in expression were determined using t test with significance set at p ≤ 0.05 after using the Benjamini-Hochberg correction for multiple testing based on the entire set of genes in an array, as we have done previously [13,17]. Likewise, principal component analysis was performed within Partek using the set of 54 genes for partitioning. "
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    ABSTRACT: Congenital heart defects (CHD) are the most common cause of death in children under the age of 1. Tetralogy of Fallot (TOF) is a severe CHD that results from developmental defects in the conotruncal outflow tract. Recently, a tissue-specific gene expression template (GET) was derived from microarray data that accurately characterized multiple normal human tissues. We used the GET to examine spatial, temporal, and a pathological condition (TOF) within a single organ, the heart. The GET, as previously defined, generally identified temporal and spatial differences in the cardiac tissue. Differences in the stoichiometry of the GET reflected the severe developmental disturbance associated with TOF. Our analysis suggests that the homoeostatic equilibrium assessed by the GET at the inter-organ level is generally maintained at the intra-organ level as well.
    Human genomics 03/2014; 8(1):6. DOI:10.1186/1479-7364-8-6 · 2.15 Impact Factor
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    • "The developmental basis of TOF is complex, incompletely elucidated and probably multifactorial [33,34]. The implication of genomic imprinting [35-38] and a role for cardiac neural crest cells in the development of TOF have been suggested [34,39] but any implication of ART in these pathways remains to be shown. "
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    ABSTRACT: Assisted reproductive techniques (ART) are associated with a higher risk of tetralogy of Fallot (TOF) and multiple pregnancies may be associated with a higher risk of congenital anomalies. We assessed the extent to which the association between ART and risk of TOF may be mediated by the higher risk of multiple pregnancies associated with ART. We conducted a case-control study using population-based data from the Paris Registry of Congenital Malformations for the period 1987-2009 and a cohort study of congenital heart defects (EPICARD). The study population included 395 cases of TOF and 4104 malformed controls with no known associations with ART. The analysis was based on a path-analysis model using a counterfactual approach, which allows decomposition of the total effect of ART into an indirect effect (that mediated by the association between ART and multiple pregnancies) and a direct effect. ART (all methods combined) were associated with a 2.6-fold higher odds of TOF after adjustment for maternal and paternal characteristics and year of birth (adjusted OR 2.6, 95% CI, 1.5-4.5). Most (79%) of the effect associated with ART was a direct effect (i.e., not mediated by multiple pregnancies), whereas 21% of the effect of ART was due to its association with multiple pregnancies (i.e., the indirect effect). In vitro fertilization with intracytoplasmic sperm injection was associated with a 3.5-fold higher odds of TOF (adjusted OR 3.5, 95% CI, 1.1-11.2); 11% of this effect was mediated through the association of ICSI with multiple pregnancies. By far, most of the higher risk of TOF associated with ART is a direct effect and only a small proportion of the effect may be mediated by multiple pregnancies.
    Orphanet Journal of Rare Diseases 02/2014; 9(1):27. DOI:10.1186/1750-1172-9-27 · 3.36 Impact Factor
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