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. 2009 Aug;41(8):931-5.
doi: 10.1038/ng.415. Epub 2009 Jul 13.

De Novo Copy Number Variants Identify New Genes and Loci in Isolated Sporadic Tetralogy of Fallot

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De Novo Copy Number Variants Identify New Genes and Loci in Isolated Sporadic Tetralogy of Fallot

Steven C Greenway et al. Nat Genet. .
Free PMC article

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.

Figures

Figure 1
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.
Figure 2
Figure 2
CNVs associated with TOF. (a) Duplications in four TOF patients (749, 201.670, 200.430, 200.250) and a deletion (patient 3701) overlap a 875,266 bp region at 1q21 (chr1:144,965,244-145,840,510) which encompasses six known genes that are expressed in the human right ventricular outflow tract. Previously described duplications at this locus are associated with mental retardation (MR), TOF, macrocephaly (MaC) and other congenital phenotypes. Studies have identified multiple patients (number of patients in parentheses, only the minimal overlapping region between patients is shown) that carry deletions at this locus with congenital heart disease other than TOF (CHD), MR, schizophrenia (SCZ), microcephaly (MiC) or that carry deletions with CHD and MR. (b) Plot showing normalized probe intensity measurements across 1q21 in the four TOF patients carrying a deletion (turquoise), the one TOF patient with a duplication (green) and 273 CN-neutral controls (gray lines and summarized as mean (black) ± 2*median absolute deviation (dark blue lines). The vertical dotted lines indicate the boundaries of the 875,266 bp overlapping region. The absence of circles on the colored lines indicates an absence of probes due to segmental duplications and there is a known CNP downstream of our region of interest. (c) A 12,380,330 bp duplication on chromosome 3 was found in a single TOF patient (756) and an inherited duplication was found within this interval in patient 419 which narrows the interval to a region (chr3:12,605,755-12,781,130) affecting RAF1. White bars indicate deletion, black bars indicate duplication, and red bars indicate the region of overlap between TOF CNVs. Chromosome position is indicated in Mb by the blue bar. All coordinates are based on build 36.1 of the human reference genome.
Figure 2
Figure 2
CNVs associated with TOF. (a) Duplications in four TOF patients (749, 201.670, 200.430, 200.250) and a deletion (patient 3701) overlap a 875,266 bp region at 1q21 (chr1:144,965,244-145,840,510) which encompasses six known genes that are expressed in the human right ventricular outflow tract. Previously described duplications at this locus are associated with mental retardation (MR), TOF, macrocephaly (MaC) and other congenital phenotypes. Studies have identified multiple patients (number of patients in parentheses, only the minimal overlapping region between patients is shown) that carry deletions at this locus with congenital heart disease other than TOF (CHD), MR, schizophrenia (SCZ), microcephaly (MiC) or that carry deletions with CHD and MR. (b) Plot showing normalized probe intensity measurements across 1q21 in the four TOF patients carrying a deletion (turquoise), the one TOF patient with a duplication (green) and 273 CN-neutral controls (gray lines and summarized as mean (black) ± 2*median absolute deviation (dark blue lines). The vertical dotted lines indicate the boundaries of the 875,266 bp overlapping region. The absence of circles on the colored lines indicates an absence of probes due to segmental duplications and there is a known CNP downstream of our region of interest. (c) A 12,380,330 bp duplication on chromosome 3 was found in a single TOF patient (756) and an inherited duplication was found within this interval in patient 419 which narrows the interval to a region (chr3:12,605,755-12,781,130) affecting RAF1. White bars indicate deletion, black bars indicate duplication, and red bars indicate the region of overlap between TOF CNVs. Chromosome position is indicated in Mb by the blue bar. All coordinates are based on build 36.1 of the human reference genome.
Figure 2
Figure 2
CNVs associated with TOF. (a) Duplications in four TOF patients (749, 201.670, 200.430, 200.250) and a deletion (patient 3701) overlap a 875,266 bp region at 1q21 (chr1:144,965,244-145,840,510) which encompasses six known genes that are expressed in the human right ventricular outflow tract. Previously described duplications at this locus are associated with mental retardation (MR), TOF, macrocephaly (MaC) and other congenital phenotypes. Studies have identified multiple patients (number of patients in parentheses, only the minimal overlapping region between patients is shown) that carry deletions at this locus with congenital heart disease other than TOF (CHD), MR, schizophrenia (SCZ), microcephaly (MiC) or that carry deletions with CHD and MR. (b) Plot showing normalized probe intensity measurements across 1q21 in the four TOF patients carrying a deletion (turquoise), the one TOF patient with a duplication (green) and 273 CN-neutral controls (gray lines and summarized as mean (black) ± 2*median absolute deviation (dark blue lines). The vertical dotted lines indicate the boundaries of the 875,266 bp overlapping region. The absence of circles on the colored lines indicates an absence of probes due to segmental duplications and there is a known CNP downstream of our region of interest. (c) A 12,380,330 bp duplication on chromosome 3 was found in a single TOF patient (756) and an inherited duplication was found within this interval in patient 419 which narrows the interval to a region (chr3:12,605,755-12,781,130) affecting RAF1. White bars indicate deletion, black bars indicate duplication, and red bars indicate the region of overlap between TOF CNVs. Chromosome position is indicated in Mb by the blue bar. All coordinates are based on build 36.1 of the human reference genome.

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