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De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot.

Greenway SC, Pereira AC, Lin JC, DePalma SR, Israel SJ, Mesquita SM, Ergul E, Conta JH, Korn JM, McCarroll SA, Gorham JM, Gabriel S, Altshuler DM, Quintanilla-Dieck Mde L, Artunduaga MA, Eavey RD, Plenge RM, Shadick NA, Weinblatt ME, De Jager PL, Hafler DA, Breitbart RE, Seidman JG, Seidman CE - Nat. Genet. (2009)

Bottom Line: We also identified recurrent CNVs at 3p25.1, 7p21.3 and 22q11.2.CNVs in a single subject with TOF occurred at six loci, two that encode known (NOTCH1, JAG1) disease-associated genes.Our findings predict that at least 10% (4.5-15.5%, 95% confidence interval) of sporadic nonsyndromic TOF cases result from de novo CNVs and suggest that mutations within these loci might be etiologic in other cases of TOF.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT
Tetralogy of Fallot (TOF), the most common severe congenital heart malformation, occurs sporadically, without other anomaly, and from unknown cause in 70% of cases. Through a genome-wide survey of 114 subjects with TOF and their unaffected parents, we identified 11 de novo copy number variants (CNVs) that were absent or extremely rare (<0.1%) in 2,265 controls. We then examined a second, independent TOF cohort (n = 398) for additional CNVs at these loci. We identified CNVs at chromosome 1q21.1 in 1% (5/512, P = 0.0002, OR = 22.3) of nonsyndromic sporadic TOF cases. We also identified recurrent CNVs at 3p25.1, 7p21.3 and 22q11.2. CNVs in a single subject with TOF occurred at six loci, two that encode known (NOTCH1, JAG1) disease-associated genes. Our findings predict that at least 10% (4.5-15.5%, 95% confidence interval) of sporadic nonsyndromic TOF cases result from de novo CNVs and suggest that mutations within these loci might be etiologic in other cases of TOF.

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Anatomy and pathophysiology of tetralogy of Fallot (TOF). Normal heart structure (a) promotes unidirectional flow of deoxygenated blood (blue) into the lungs and oxygenated blood (red) into the aorta. In TOF (b) pulmonary stenosis and narrowing of the right ventricular outflow tract (RVOT) impedes the flow of deoxygenated blood into the lungs, and both the ventricular septal defect (VSD) and overriding aorta (*) promote the flow of deoxygenated blood into the systemic circulation, to produce cyanosis (sometimes referred to as “blue baby” syndrome). Right ventricular hypertrophy (RVH) is also present. (c) A Doppler echocardiogram shows mixing of deoxygenated blood from the right ventricle (RV) and oxygenated blood from the left ventricle (LV) as blood is pumped out the overriding aorta (Ao) in a patient with TOF. RA, right atrium; LA, left atrium. Images from Multimedia Library of Congenital Heart Disease, Children’s Hospital, Boston, MA, editor Robert Geggel, MD, www.childrenshospital.org/mml/cvp, with permission.
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Figure 1: Anatomy and pathophysiology of tetralogy of Fallot (TOF). Normal heart structure (a) promotes unidirectional flow of deoxygenated blood (blue) into the lungs and oxygenated blood (red) into the aorta. In TOF (b) pulmonary stenosis and narrowing of the right ventricular outflow tract (RVOT) impedes the flow of deoxygenated blood into the lungs, and both the ventricular septal defect (VSD) and overriding aorta (*) promote the flow of deoxygenated blood into the systemic circulation, to produce cyanosis (sometimes referred to as “blue baby” syndrome). Right ventricular hypertrophy (RVH) is also present. (c) A Doppler echocardiogram shows mixing of deoxygenated blood from the right ventricle (RV) and oxygenated blood from the left ventricle (LV) as blood is pumped out the overriding aorta (Ao) in a patient with TOF. RA, right atrium; LA, left atrium. Images from Multimedia Library of Congenital Heart Disease, Children’s Hospital, Boston, MA, editor Robert Geggel, MD, www.childrenshospital.org/mml/cvp, with permission.

Mentions: The combination of a malpositioned aorta that overrides both ventricles, ventricular septal defect, pulmonary stenosis (which obstructs blood flow into the lungs) and right ventricular hypertrophy (Figure 1) defines TOF. The most prevalent form of cyanotic heart disease, TOF occurs in one of 3,000 live births and accounts for 10% of all major congenital heart disease1. With recent advances in corrective surgery early lethality from TOF is rare but long-term sequelae, including arrhythmia, ventricular dysfunction and often life-long disability, persist.


De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot.

Greenway SC, Pereira AC, Lin JC, DePalma SR, Israel SJ, Mesquita SM, Ergul E, Conta JH, Korn JM, McCarroll SA, Gorham JM, Gabriel S, Altshuler DM, Quintanilla-Dieck Mde L, Artunduaga MA, Eavey RD, Plenge RM, Shadick NA, Weinblatt ME, De Jager PL, Hafler DA, Breitbart RE, Seidman JG, Seidman CE - Nat. Genet. (2009)

Anatomy and pathophysiology of tetralogy of Fallot (TOF). Normal heart structure (a) promotes unidirectional flow of deoxygenated blood (blue) into the lungs and oxygenated blood (red) into the aorta. In TOF (b) pulmonary stenosis and narrowing of the right ventricular outflow tract (RVOT) impedes the flow of deoxygenated blood into the lungs, and both the ventricular septal defect (VSD) and overriding aorta (*) promote the flow of deoxygenated blood into the systemic circulation, to produce cyanosis (sometimes referred to as “blue baby” syndrome). Right ventricular hypertrophy (RVH) is also present. (c) A Doppler echocardiogram shows mixing of deoxygenated blood from the right ventricle (RV) and oxygenated blood from the left ventricle (LV) as blood is pumped out the overriding aorta (Ao) in a patient with TOF. RA, right atrium; LA, left atrium. Images from Multimedia Library of Congenital Heart Disease, Children’s Hospital, Boston, MA, editor Robert Geggel, MD, www.childrenshospital.org/mml/cvp, with permission.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2747103&req=5

Figure 1: Anatomy and pathophysiology of tetralogy of Fallot (TOF). Normal heart structure (a) promotes unidirectional flow of deoxygenated blood (blue) into the lungs and oxygenated blood (red) into the aorta. In TOF (b) pulmonary stenosis and narrowing of the right ventricular outflow tract (RVOT) impedes the flow of deoxygenated blood into the lungs, and both the ventricular septal defect (VSD) and overriding aorta (*) promote the flow of deoxygenated blood into the systemic circulation, to produce cyanosis (sometimes referred to as “blue baby” syndrome). Right ventricular hypertrophy (RVH) is also present. (c) A Doppler echocardiogram shows mixing of deoxygenated blood from the right ventricle (RV) and oxygenated blood from the left ventricle (LV) as blood is pumped out the overriding aorta (Ao) in a patient with TOF. RA, right atrium; LA, left atrium. Images from Multimedia Library of Congenital Heart Disease, Children’s Hospital, Boston, MA, editor Robert Geggel, MD, www.childrenshospital.org/mml/cvp, with permission.
Mentions: The combination of a malpositioned aorta that overrides both ventricles, ventricular septal defect, pulmonary stenosis (which obstructs blood flow into the lungs) and right ventricular hypertrophy (Figure 1) defines TOF. The most prevalent form of cyanotic heart disease, TOF occurs in one of 3,000 live births and accounts for 10% of all major congenital heart disease1. With recent advances in corrective surgery early lethality from TOF is rare but long-term sequelae, including arrhythmia, ventricular dysfunction and often life-long disability, persist.

Bottom Line: We also identified recurrent CNVs at 3p25.1, 7p21.3 and 22q11.2.CNVs in a single subject with TOF occurred at six loci, two that encode known (NOTCH1, JAG1) disease-associated genes.Our findings predict that at least 10% (4.5-15.5%, 95% confidence interval) of sporadic nonsyndromic TOF cases result from de novo CNVs and suggest that mutations within these loci might be etiologic in other cases of TOF.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT
Tetralogy of Fallot (TOF), the most common severe congenital heart malformation, occurs sporadically, without other anomaly, and from unknown cause in 70% of cases. Through a genome-wide survey of 114 subjects with TOF and their unaffected parents, we identified 11 de novo copy number variants (CNVs) that were absent or extremely rare (<0.1%) in 2,265 controls. We then examined a second, independent TOF cohort (n = 398) for additional CNVs at these loci. We identified CNVs at chromosome 1q21.1 in 1% (5/512, P = 0.0002, OR = 22.3) of nonsyndromic sporadic TOF cases. We also identified recurrent CNVs at 3p25.1, 7p21.3 and 22q11.2. CNVs in a single subject with TOF occurred at six loci, two that encode known (NOTCH1, JAG1) disease-associated genes. Our findings predict that at least 10% (4.5-15.5%, 95% confidence interval) of sporadic nonsyndromic TOF cases result from de novo CNVs and suggest that mutations within these loci might be etiologic in other cases of TOF.

Show MeSH
Related in: MedlinePlus