Advances in the Molecular Genetics of Congenital Structural Heart Disease

Mah, Caroline S.; Vaughan, Carl J.; Basson, Craig T.

doi:10.1089/gte.1999.3.157

Cited by 8 publications

(6 citation statements)

References 131 publications

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“…First, it is clear that a single genetic lesion can be associated with a spectrum of structural anomalies 14 23 24 27 30 111. Second, apparently similar cardiac anomalies have been identified with lesions of disparate chromosomal regions or genes 23 24 27 112 113.…”

Section: Discussionmentioning

confidence: 99%

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Double outlet right ventricle: aetiologies and associations

Obler

Juraszek

Smoot

et al. 2008

Journal of Medical Genetics

104

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Background: Double outlet right ventricle (DORV), a clinically significant congenital heart defect, occurs in 1-3% of individuals with congenital heart defects. In contrast to other major congenital heart defects, there are no systematic or comprehensive data regarding associations, aetiologies, and pathogenesis of DORV. We analysed reported cases in the medical literature to address these issues. Methods: We queried the PubMed database using key words ''double outlet right ventricle'' and ''DORV'' for case reports, epidemiologic analyses and animal studies with this cardiac anomaly. The anatomic subtype of DORV was classified according to criteria of Van Praagh. Results: Chromosomal abnormalities were present in 61 of the 149 cases of DORV. Trisomies 13 and 18, and del 22q11 were the most commonly associated cytogenetic lesions; different anatomic subtypes of DORV were noted in trisomies 13 and 18 versus del 22q11. DORV was reported in many uncommon or rare non-chromosomal syndromes. Mutations and non-synonymous sequence variants in the CFC1 and CSX genes were the most commonly reported monogenic loci associated with DORV in humans; numerous genes are reported in murine models of DORV. Animal studies implicate maternal diabetes and prenatal exposure to ethanol, retinoids, theophylline, and valproate in DORV teratogenesis. Conclusions: The large number of genes associated with DORV in both humans and animal models and the different anatomic subtypes seen in specific aetiologies indicate the likelihood of several distinct pathogenetic mechanisms for DORV, including impairment of neural crest derivative migration and impairment of normal cardiac situs and looping.

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Section: Discussionmentioning

confidence: 99%

“…Elucidation of the molecular genetic basis of numerous single and contiguous gene syndromes associated with cardiac lesions14 15 28 – 30 also adds to our current understanding. Despite these recent advances, double outlet right ventricle (DORV) remains one of the least understood categories of CHD.…”

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confidence: 99%

Double outlet right ventricle: aetiologies and associations

Obler

Juraszek

Smoot

et al. 2008

Journal of Medical Genetics

104

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“…Deletions in 22q11.2 have been found in several other syndromes that share part of the phenotypic spectrum found in DGS and VCFS, particularly heart defects [Wilson et al, 1991;Giannotti et al, 1994;McDonaldMcGinn et al, 1995]. Typical to these syndromes is considerable inter-and intrafamilial variability [De Silva et al, 1995;Ryan et al, 1997;Mah et al, 1999]. Most del22q11 patients have a common 3-Mb deletion, a minority has a proximal 1.5-Mb deletion, and few display unique nested deletions, which do not always overlap with one another within the 3-Mb typically deleted region [Morrow et al, 1995;Carlson et al, 1997;Kurahashi et al, 1997;O'Donnell et al, 1997;Yamagishi et al, 1999].…”

Section: Introductionmentioning

confidence: 99%

“…Heart defects that appear with the highest incidence among del22q11 patients are of conotruncal origin, particularly interrupted aortic arch type B, truncus arteriosus, tetralogy of Fallot (TOF), and pulmonary atresia [Ryan et al, 1997;Mah et al, 1999]. The reported frequency of 22q11.2 deletion among unselected TOF patients ranges between 8% and 35% [Amati et al, 1995;Digilio et al, 1996;Webber et al, 1996;Mehraein et al, 1997;Fokstuen et al, 1998;Goldmuntz et al, 1998;Iserin et al, 1998].…”

Section: Introductionmentioning

confidence: 99%

Association of tetralogy of Fallot with a distinct region of del22q11.2

et al. 2001

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Congenital heart defects (CHDs) appear in greater frequency among relatives of patients and in individuals with DiGeorge syndrome (DGS) or velo-cardio-facial syndrome (VCFS). A majority of these patients and part of the apparently nonsyndromic CHD patients with conotruncal defects manifest hemizygous deletions within chromosome 22q11.2 (del22q11). We tested myocardial tissues of 31 CHD patients, 21 with tetralogy of Fallot (TOF) and 10 with a double-chamber right ventricle (DCRV). DNA isolated from tissues removed at corrective surgery was analyzed for homo- or heterozygosity of nine polymorphic short tandem repeat (STR) markers along the 22q11.2 region. DNA from the blood of 45 healthy individuals represented the general population. Ten of the 21 TOF patients (48%) showed homozygosity for three or more consecutive markers, indicating deletions of various sizes. No such indication was found for DCRV patients. Heterozygosity for markers D22S1648, D22S941, and D22S944 was lower in the TOF group than in normal controls, defining a minimal critical region (MCR) for the deletion. Our findings support an association between TOF and hemizygosity in 22q11.2, suggesting a distinct region, between markers D22S1638 and COMT, that may harbor TOF susceptibility genes.

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“…As indicated earlier, some of the genes involved in normal cardiogenesis include transcription factors (e.g., NKX2.5, GATA6, GATA4, HAND1, HAND2, and NFATC), which can regulate the expression of genes in a tissue specific and quantitative manner, as well as soluble factors including bone morphogenic proteins (acts as a positive facilitator of nodal induction and left-right asymmetry), transforming growth factor beta isoforms and fibroblast growth factor isoforms (may play a role in cardiac hypoplasia) [6][7][8], These genes identified in lower animals also participate in human cardiogenesis. For example, Glnl70ter, Thrl78Met, and Glnl98ter mutations in the transcription factor, NKX2.5, in humans cause atrial septal defects and conduction disease [9], while HAND genes are essential for normal cardiac and extra embryonic development and are expressed in adult heart but are downregulated in cardiomyopathies [10].…”

Section: Genes and Cardiovascular Developmentmentioning

confidence: 99%

Gene expression in pediatric heart disease with emphasis on conotruncal defects

Bittel

Kibiryeva

O’Brien

et al. 2005

Progress in Pediatric Cardiology

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Developmental abnormalities of the heart are the underlying cause of many congenital heart malformations. The embryological development of the integrated cardiovascular tissue is the result of multiple tissue and cell-to-cell interactions involving temporal and spatial events under genetic control. Recent technological advances, like microarray analysis of gene expression, are providing new tools to aid in deciphering the complex networks of gene expression that regulate cardiac development. Here, we review our current understanding of the genetics of congenital heart disorders with emphasis on gene expression studies and report preliminary data from infants with conotruncal defects. We report our microarray analysis showing over-and underexpression of individual genes and gene network interactions from dysplastic pulmonic tissue from two infants with tetralogy of Fallot compared with normal pulmonic tissue from an unaffected control infant.

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Advances in the Molecular Genetics of Congenital Structural Heart Disease

Cited by 8 publications

References 131 publications

Double outlet right ventricle: aetiologies and associations

Double outlet right ventricle: aetiologies and associations

Association of tetralogy of Fallot with a distinct region of del22q11.2

Gene expression in pediatric heart disease with emphasis on conotruncal defects

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