Pediatr Cardiol (2011) 32:1147–1157 DOI 10.1007/s00246-011-0034-5
ORIGINAL ARTICLE
The Contribution of Chromosomal Abnormalities to Congenital Heart Defects: A Population-Based Study Robert J. Hartman • Sonja A. Rasmussen • Lorenzo D. Botto • Tiffany Riehle-Colarusso Christa L. Martin • Janet D. Cragan • Mikyong Shin • Adolfo Correa
•
Received: 13 December 2010 / Accepted: 15 June 2011 / Published online: 5 July 2011 Ó Springer Science+Business Media, LLC (outside the USA) 2011
Abstract We aimed to assess the frequency of chromosomal abnormalities among infants with congenital heart defects (CHDs) in an analysis of population-based surveillance data. We reviewed data from the Metropolitan Atlanta Congenital Defects Program, a population-based birth-defects surveillance system, to assess the frequency of chromosomal abnormalities among live-born infants and fetal deaths with CHDs delivered from January 1, 1994, to December 31, 2005. Among 4430 infants with CHDs, 547 (12.3%) had a chromosomal abnormality. CHDs most likely to be associated with a chromosomal abnormality were interrupted aortic arch (type B and not otherwise specified; 69.2%), atrioventricular septal defect (67.2%), and double-outlet right ventricle (33.3%). The most common chromosomal abnormalities observed were trisomy 21 (52.8%), trisomy 18 (12.8%), 22q11.2 deletion (12.2%),
R. J. Hartman S. A. Rasmussen (&) T. Riehle-Colarusso J. D. Cragan M. Shin A. Correa National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, 1600 Clifton Road, MS E-86, Atlanta, GA, USA e-mail:
[email protected] R. J. Hartman Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA L. D. Botto Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA C. L. Martin Department of Human Genetics, Emory University, Atlanta, GA, USA M. Shin RTI International, Triangle Research Park, NC, USA
and trisomy 13 (5.7%). In conclusion, in our study, approximately 1 in 8 infants with a CHD had a chromosomal abnormality. Clinicians should have a low threshold at which to obtain testing for chromosomal abnormalities in infants with CHDs, especially those with certain types of CHDs. Use of new technologies that have become recently available (e.g., chromosomal microarray) may increase the identified contribution of chromosomal abnormalities even further. Keywords Chromosomal abnormality Congenital heart defect Congenital heart disease Prevalence Epidemiology
Introduction Congenital heart defects (CHDs) are the most common type of birth defect, with an estimated birth prevalence of 1/125 live births [26]. Birth defects are one of the most common causes of infant mortality, resulting in approximately 20% of deaths during the first year of life [20]; among birth defects, CHDs are the most frequent contributor to neonatal mortality [37]. In addition, costs associated with the care of a child with a CHD are significant [5, 36]. The association between CHDs and many types of chromosomal abnormalities is well recognized [23, 28]. However, estimates of the proportion of CHDs associated with a chromosomal abnormality vary widely from 9% to 18% [3, 9–11, 13, 14, 16, 24, 29, 31] depending on the study location, inclusion criteria for infants with CHDs, and whether the analysis was clinic- or population-based (Table 1). Most estimates of the contribution of chromosomal abnormalities to CHD etiology have only included aneuploidies; information on the contribution of other
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chromosomal abnormalities, such as 22q11.2 deletion, has not typically been included. Advances in cardiac imaging and in cytogenetic technologies provide an opportunity to determine whether the contribution has changed from previous estimates. We present findings from a populationbased study of the contribution of chromosomal abnormalities to CHDs in a recent birth cohort of infants born from 1994 through 2005 to mothers residing in metropolitan Atlanta, GA.
Methods Data Source Information on CHDs and chromosomal abnormalities was obtained from the Metropolitan Atlanta Congenital Defects Program (MACDP), an ongoing population-based birthdefects surveillance system in operation since 1967. For this analysis, we reviewed data on infants delivered from January 1, 1994 through December 31, 2005. Detailed methods of MACDP are described elsewhere [7]. Briefly, MACDP ascertains deliveries affected by major birth defects to mothers whose residence is in the five central counties of the metropolitan Atlanta area at the time of delivery. Trained abstractors actively ascertain information on major structural and genetic birth defects identified among live-born infants before the sixth birthday, among fetal deaths occurring at C20 weeks’ gestation, and among pregnancy terminations. Because of concern for the reliability of CHD diagnoses made prenatally, for this analysis, pregnancy terminations were excluded, and live-born infants and fetal deaths with CHDs that were confirmed postnatally were included. MACDP data sources include medical records from birth and pediatric hospitals, cytogenetic laboratories (one academic and one commercial laboratory), and a major referral center for pediatric cardiology. Abstracted information is reviewed by MACDP staff, which includes pediatricians and clinical geneticists. Up to 24 individual defects can be coded per infant using a modified version of the International Classification of Disease, Ninth Revision, Clinical Modification and British Paediatric Association (modified ICD9/BPA) coding classification systems. CHDs: Classification, Inclusion, and Exclusion Criteria Clinical information on infants with CHDs in MACDP (ICD9/BPA codes 745.000 to 747.499, 747.640, 759.040, and 759.300 to 759.399) was reviewed by physicians with expertise in pediatric cardiology to classify the structural heart defects using a modified nomenclature from the Society of Thoracic Surgeons [27]. Individual CHDs and
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aggregates based on presumed morphogenetically similar developmental mechanisms have been described elsewhere [27]. Patent ductus arteriosus (PDA) is abstracted only if another major birth defect is present and was not classified as a CHD if the infant was\36 weeks’ gestational age; if a term infant had a PDA identified and closed before 6 weeks of life; or if the PDA was necessary to sustain life due to the presence of other CHDs. Bicuspid aortic valve was only counted if it occurred as an isolated CHD. This classification system excludes patent foramen ovale and other isolated minor conditions, such as valve insufficiency. An infant could be classified as having B4 CHDs; however, infants with a single ventricle (e.g., tricuspid atresia or double-inlet ventricle) or heterotaxy were classified as having only one major CHD, regardless of the presence of other CHDs. For this analysis, cases of isolated cardiomyopathy and nonstructural heart defects (e.g., isolated neonatal arrhythmias or persistent fetal circulation) were excluded. Ascertainment of Cytogenetic Abnormalities After identifying infants with CHDs, we selected those who had been identified as having a chromosomal abnormality by using the modified ICD9/BPA codes for chromosomal abnormalities (758.000 to 758.999) (including any cytogenetic results other than 46,XX, 46,XY, or variants believed to be benign). During the time period included in this analysis, fluorescence in situ hybridization (FISH) testing for 22q11.2 deletion was widely available. Of note, the decision to perform cytogenetic testing was at the discretion of the health care providers caring for the infants; thus, not all infants with CHDs were tested. Infants with chromosomal abnormality codes that are used only for specific cytogenetically confirmed diagnoses were included as having a chromosomal abnormality without further review. These included infants with a code for trisomy 21 (758.000, 758.010, 758.020, or 758.030), mosaic trisomy 21 (758.040), trisomy 13 (758.100, 758.110, 758.120, or 758.130), trisomy 18 (758.200, 758.210, 758.220, or 758.230), 22q11.2 deletion (758.370), 45,X (758.600), or Klinefelter syndrome (758.700). In addition, abstracted results of chromosome analyses or FISH studies on infants who had nonspecific codes for any other chromosomal abnormality were reviewed to ensure that the child had a documented chromosomal abnormality and to allow classification into an appropriate category. Altogether, infants were classified into 22 mutually exclusive categories of chromosomal abnormalities (see Table 3). Results were reviewed by a cytogeneticist (C.L.M.) to ensure appropriate classification. If an apparently balanced translocation was present, the case was considered to have a chromosomal abnormality only if the translocation was de novo or
Echocardiogram reports, cardiac catheterization, surgery, and postmortem reports International Society of Cardiology Codes; only CBDMP mentions that diagnoses confirmed by echocardiography, cardiac catheterization, surgery, and/or autopsy Clinical evaluation, echocardiography, cardiac catheterization, surgery, autopsy
Not stated
Not stated
Yes
Clinic-based
Regional population– based cardiovascularspecific birth-defects registry Hospital-based
France and CBDMP: regional populationbased registries; Sweden: national population-based birthdefects registry Regional population– based birth-defects registry Clinic-based
Population-based registry of congenital anomalies
New South Wales and the Australian Capital Territory (Australia; 1981–1984)
Baltimore-Washington Infant Study (1981–1989)
The country of Malta (1990–1994)
Combination of the Central-Eastern France Registry (France; 1983–1992), Swedish national population-based system for registration of congenital malformations (Sweden; 1981–1992), and CBDMP (1985–1992)
Emilia-Romagana birth-defects registry [1980–2000]
Germany (not stated)
Northern England (1985–2003)
Kidd et al. 1993 [16]
Ferencz et al. 1997 [10]
Grech & Gatt 1999 [13]
Harris et al. 2003 [14]
Bosi et al. 2003 [3]
Schellberg et al. 2004 [29]
Dadvand et al. 2009 [9]
Echocardiography, cardiac catheterization, surgery, or autopsy
11.3
12.9
13
9.5
12.1
9
Total: 18
Infants \26 weeks gestation
Pregnancy terminations, fetal deaths, diagnosis occurred after first year of life
Infants \28 weeks gestation
Pregnancy terminations, fetal deaths, diagnosis occurred after first year of life
Pregnancy terminations, fetal deaths, diagnosis occurred after first year of life
Pregnancy termination, fetal deaths, diagnosis occurred after first year of life
France and Sweden: \28 weeks gestation, CBDMP: \20 weeks gestation; heart conditions excluded: cardiomegaly, cardiomyopathy, fibroelastosis, rate or rhythm anomalies, cardiac valve insufficiency, and patent ductus
9.10
16
11.6
\28 weeks gestation, stillbirths, spontaneous and/or induced abortions, diagnosis occurred after the second year of life Pregnancy terminations, fetal deaths
EUROCAT exclusion list, \20 weeks gestation
CBDMP: 20.3
Sweden: 12.8
France:12.6
Individual registry:
Percentage of CHD attributed to chromosomal abnormalities (%)
Excluded infants
EUROCAT European Registers of Congenital Anomalies and Twins, MRI magnetic resonance imaging, CT computed tomography, CBDMP California Birth Defects Monitoring Program
Not stated
Clinical evaluation, electrocardiography, chest radiography, echocardiography, cardiac catheterization, MRI, or CT
Echocardiography, cardiac catheterization, surgical inspection, or autopsy
No
Yes
Pediatric cardiologists, echocardiography, cardiac catheterization, surgery, or autopsy
No
Echocardiography, cardiac catheterization, surgery, or necropsy
No
Population-based birth defects registry
The Registry of Congenital Malformations and The Child Cardiology Registry (Sweden; 1981–1986)
Pradat 1992 [24]
Echocardiography, cardiac catheterization, surgical inspection, or autopsy
No
Regional populationbased cardiovascular specific birth defects registry
Baltimore-Washington Infant Study (1981–1986)
Ferencz et al. 1989 [11]
Echocardiography, cardiac catheterization, surgery, or autopsy
No
Hospital-based, consecutive-births casecontrol study
Departement du Bas-Rhin (France; 1979–1986)
Stoll et al. 1989 [31]
Source of data on CHD
Study design
Study site (years in study)
Reference
22q11.2 deletion included in analysis (yes/no/not stated)
Table 1 Epidemiological studies of the abnormal chromosomal contribution to CHDs during the last 20 years
Pediatr Cardiol (2011) 32:1147–1157 1149
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if parental results were not available. When a chromosomal abnormality was suspected but not documented by cytogenetic testing, the infant was assumed to not have a chromosomal abnormality. Data Analysis To calculate the birth prevalence of CHDs, we used as the denominator the number of live infants born to residents of the MACDP surveillance area for the years 1994 to 2005 as obtained from vital records of the state of Georgia. We calculated the proportion of infants with CHDs who had chromosomal abnormalities for all CHDs and by CHD type. The infant was only counted once for all types of CHDs if there were multiple types of CHDs present. Risk ratios (RRs) and 95% confidence intervals (CI) were used to compare the proportion of infants with CHDs who have chromosomal abnormalities by infant sex, gestational age (for live-born singletons only: preterm [\37 completed weeks], term [C37 completed weeks]), maternal race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, other), maternal age at birth (\35 years, C35 years), one or more than one CHD type, and birth status (live-born infants, fetal deaths). RRs and 95% CI were generated using SABER [6]. Results were considered statistically significant if P was B0.05 and 95% CI did not include 1.0.
Results We identified 4430 infants with CHDs, for a birth prevalence of 7.9/1000 live births. Among infants with CHDs, 547 (12.3%) had a chromosomal abnormality, and most of these infants (77.1%) had only 1 type of CHD. CHDs most likely to be associated with a chromosomal abnormality were interrupted aortic arch (IAA), type B and not otherwise specified (69.2%); atrioventricular septal defect (AVSD) (67.2%); double-outlet right ventricle (DORV) (33.3%); partial anomalous pulmonary venous return (33.3%); and truncus arteriosus (32.3%). CHDs that were least likely to have had a chromosomal abnormality diagnosed were heterotaxy (2.2%), Ebstein anomaly (2.6%), and pulmonary valve stenosis (3.3%) (Table 2). The most commonly observed chromosomal abnormalities among infants with CHDs were trisomy 21 (52.8%), trisomy 18 (12.8%), 22q11.2 deletion (12.2%), and trisomy 13 (5.7%) (Table 3). Deletion 22q11.2 was the largest single type of chromosomal abnormality among many infants with conotruncal CHDs, but a variety of other chromosomal abnormalities were observed in these infants as well. Trisomy 21 was observed most often in infants with an AVSD or a secundum atrial septal defect (ASD). Most of the infants with ventricular septal defect, not otherwise
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specified (VSD NOS), with a chromosomal abnormality had trisomy 18, 21, or 13 (Table 4). The proportion of infants with CHDs who had a chromosomal abnormality did not differ by infant sex or gestational age (Table 5). Infants with more than one CHD diagnosis were more likely to have a chromosomal abnormality (RR = 2.2, 95% CI 1.8–2.6) than those with only one CHD diagnosis. Infants with CHDs born to nonHispanic black mothers were slightly more likely to have a chromosomal abnormality diagnosed compared with those born to non-Hispanic white mothers (RR = 1.3, 95% CI 1.1–1.5). Fetal deaths with CHDs were nearly three times as likely to have a chromosomal abnormality diagnosed (33.9%) as live-born infants (12.1%) (RR = 2.8, 95% CI 2.0–4.1). Infants with CHDs born to mothers who were C35 years old were more likely to have a chromosomal abnormality than infants with CHDs born to mothers \35 years of age (RR = 2.1, 95% CI 1.8–2.5) (Table 5). However, when infants with CHDs and trisomy 21, 18, or 13 were excluded from the maternal age analysis, there was no longer a statistically significant association (data not shown).
Discussion This study provides an updated estimate of the contribution of chromosomal abnormalities to the etiology of CHDs overall and by type of CHD, and suggests that a chromosomal abnormality detected by G-banding analysis or targeted FISH is responsible for CHDs in approximately one in eight live born infants and fetal deaths. Despite the addition of targeted FISH analyses, the contribution is similar to previous estimates. The lack of change could be related to the increasing prevalence in recent years of mild heart defects, such as muscular VSDs, which are less likely to be associated with chromosomal abnormalities. Trisomies 21, 18, and 13 and 22q11.2 deletion comprise the majority of chromosomal abnormalities seen in infants with CHDs in our study. It is important to note that laboratory testing for chromosomal abnormalities continues to improve. Array comparative genomic hybridization (chromosomal microarray) testing has recently become clinically available and can be used to identify chromosomal imbalances not detectable by previous technologies [1, 30]. Our study uses data from a time period when chromosomal microarray testing was not routinely available; thus, these results underestimate the contribution of chromosomal abnormalities to the etiology of CHDs [18]. However, this study will be useful as a comparison to future studies that use microarray testing to better understand the proportion of chromosomal imbalances among infants with CHDs [21].
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Table 2 Proportion of infants (live births and fetal deaths) with CHDs who have chromosomal abnormalities by CHD classification (MACDP 1994–2005) CHD classification
All infants with CHD
Infants with single CHD
Chromosomal abnormality and CHDa
Any CHD
Chromosomal abnormality and CHD
n
n
%
n
n
%
4430
547
12.3
3903
422
10.8
Any CHD
All types of CHD
a
Conotruncal Interrupted aortic arch, type B or NOS
26
18
69.2
17
12
70.6
DORV
27
9
33.3
21
7
33.3
Truncus arteriosus
31
10
32.3
21
6
28.6
Tetralogy of Fallot
263
52
19.8
242
48
19.8
Vascular rings
70
9
12.9
51
1
2.0
VSD, Conotruncal
22
2
9.1
15
0
N/A
d-TGA
132
6
4.5
113
5
4.4
220
148
67.2
153
108
70.6
AVSD Abnormal cell growth Partial anomalous pulmonary venous return
6
2
33.3
1
0
N/A
Total anomalous pulmonary venous return
41
3
7.3
34
2
5.9
ASD, sinus venosus
19
1
5.3
15
0
N/A
VSD, NOS
181
37
20.4
159
29
18.2
VSD, perimembranous
593
92
15.5
407
51
12.5
VSD, muscular
1,356
59
4.4
1,212
40
3.3
VSD
ASD ASD secundum
517
102
19.7
274
38
13.9
ASD OS/NOS
127
21
16.5
89
11
12.4
123
12
9.8
116
12
10.3
Left-sided obstructive defects HLHS Mitral valve stenosis
11
2
18.2
10
2
20.0
Coarctation of the aorta Aortic stenosis
249 59
30 5
12.0 8.5
120 46
10 2
8.3 4.3
Bicuspid aortic valve PDA
45
3
6.7
45
3
6.7
170
28
16.5
121
11
9.1
Right-sided obstructive defects Tricuspid valve stenosis
13
1
7.7
12
1
8.3
Pulmonary atresia
31
3
9.7
31
3
9.7
Pulmonary stenosis, other
23
1
4.3
23
1
4.3
Pulmonary stenosis, valvar
304
10
3.3
215
3
1.4
56
5
8.9
56
5
8.9
Single ventricle/complex CHDb Ebstein anomaly
38
1
2.6
37
1
2.7
Heterotaxy
91
2
2.2
91
2
2.2
Coronary artery anomaly
19
2
10.5
18
2
11.1
Other vascular anomalies
58
5
8.6
57
5
8.8
Other CHDs
OS otherwise specified, N/A not applicable, TGA transposition of the great arteries, HLHS hypoplastic left heart syndrome a
CHD type is not mutually exclusive, but infants were only counted once for all types of CHD
b
Includes the CHD types double-inlet single ventricle, single ventricle OS/NOS, unbalanced AVSD, and mitral or tricuspid atresia
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1152 Table 3 Frequencies of chromosomal abnormalities among infants with CHDs (MACDP 1994–2005)
Pediatr Cardiol (2011) 32:1147–1157
Chromosomal abnormality category Numerical
%
428
78.2
409
74.8
289
52.8
9
1.6
Mosaic trisomy 21
4
0.7
46,XX,der(21;21)(q10;q10)
1
0.2
45,XX,-21[11]/46,XX,?21,der(21;21)(q10;q10)[8]
1
0.2
47,XY,t(4;13)(p15.2;q21.2),?21
1
0.2
Autosomal Trisomy 21 Trisomy 21, other
47,XY,?21[36]/47,XY,?i(8)(p10)[14]
1
0.2
‘‘Mosaic Down syndrome/trisomy X’’a
1
0.2
70
12.8
Trisomy 18 Trisomy 18, other
3
0.5
48,XXY,?18
1
0.2
48,XXX,?18
1
0.2
1 31
0.2 5.7
Trisomy 22
3
0.5
Trisomy 22, other
3
0.5
47,XX,?22[2]/46,XX[48]
1
0.2
47,XY?22[3]/46,XY[13]
1
0.2
47,XX,?22[5]/46,XX[15]
1
0.2
47,XY,?18[24]/46,XY[6] Trisomy 13
Triploidy
1
0.2
69,XXX
1
0.2
1
0.2
Other 45,XY,-21[4]/46,XY[46] Sex chromosome
1
0.2
19
3.5
Turner syndrome
6
1.1
Turner syndrome, other
7
1.3
45,X,t(8;13)(q21.1;q22)[16]/46,XX,t(8;13)(q21.1;q22)[14]
1
0.2
46,X,i(X)(q10)
1
0.2
46,X,idic(X)(q22.1) 45,X[26]/46,XY[4]
1 1
0.2 0.2
45,X[19]/46,X,idic(X)(qter ? p11.2)[11]
1
0.2
45,X[35]/46,X,idic(Y)(p11.32)[15]
1
0.2
45,X[23]/47,X,??dic r(Y)[10]
1
0.2
Klinefelter syndrome
2
0.4
Klinefelter syndrome, other
2
0.4
48, XXYY
1
0.2
47,XXY[16]/46,XY[14]
1
0.2
47, XXX
1
0.2
47, XYY
1
0.2
115
21.0
Structural
123
n = 547
Unbalanced
110
20.1
Deletion
84
15.4
22q11.2
67
12.2
46,XX,del(11)(q24.2) 46,XX,der(1)(pter ? 36.3305::p36.3205 ? p36.2300::p36.3100 ? qter)
2 1
0.4 0.2
46,XY,del(1)(q42.13q42.3)
1
0.2
46,XX,del(2)(p25.1)
1
0.2
Pediatr Cardiol (2011) 32:1147–1157 Table 3 continued
1153
Chromosomal abnormality category
n = 547
%
46,XX,del(4)(p15.32)
1
0.2
46,XY,del(4)(q28.2q31.3)
1
0.2
46, XY,del(5)(q11.2q13.1)
1
0.2
‘‘Deletion of the short arm of the sixth chromosome’’a
1
0.2
46,XX,del(6)(p25)
1
0.2
46,XX,add(7)(p21) or del(7)(p21p22)
1
0.2
46,XX,del(9)(p22.1)
1
0.2
46,XX,del(9)(p23)
1
0.2
46,XY,del(10)(p15.1)
1
0.2
46,XY,del(17)(p11.2p11.2)
1
0.2
46,XX,del(18)(q21.31)
1
0.2
46,XY,del(18)(q23)
1
0.2
9
1.6
Duplication 46,XY,dup(3)(q26.2q27.1)mat
1
0.2
46,XY,add(4)(p14) 46,XY,add(5)(p15.1)
1 1
0.2 0.2
46,XX,dup(6)(pter ? q25.3::q25.1 ? qter)
1
0.2
46,XX,add(9)(p24.1)
1
0.2
47,XX,?der(11)(q11).ish der(11)(wcp11?,D11Z1?)
1
0.2
46,XX,dup(17)(q23.3q24.2)
1
0.2
46,XX,dup(20)(q11.2q13.1) OR 46,XX,ins(20;?)(q13.1;?)
1
0.2
46,XY,add(21)(q22.3)
1
0.2
9
1.6
Unbalanced translocation 46,XX,der(4)t(4;?)(q31.1;?)
1
0.2
47,XY,der(6)t(6;17)(p25.1;q25.2)mat,?mar.ish der(7)
1
0.2
46,XY,add(12)(p13.3).ish der(12)t(4;12)(wcp4?)
1
0.2
47,XY,?der(15)t(15;16)(q14;q13)mat
1
0.2
46,XY,der(15)t(15;17)(q26.3;p13.1).ish der(15)t(15;17) (wcp15?,D15Z?,FES?,15qsubtel?,D1752199?,LIS1?)
1
0.2
46,XY,der(21)t(3;21)(q21;q22.3)
1
0.2
46,XX,der(22)t(1;22)(q32.1;q13.3)
1
0.2
46,X,der(X)t(X;12)(p11.23;q22)mat
1
0.2
46,X,der(Y)t(X;Y)(p11.4;p11.2)
1
0.2
Recombinant chromosome from inversion
1
0.2
46,XX,rec(3)dup(3q)inv(3)(p25q25.1)mat
1
0.2
Other 46,XX,i(8)(q10)
9
1.6
1
0.2
47,XY,?del(8)p21/46,XY
1
0.2
46,XX,der(17)(pter?p13.1::p1205?p11.2::p1205?qter)
1
0.2
46,XX,der(18)(pter?q21.32::q21.32?q11.2::qter)
1
0.2
46,XY,idic(20)(p11.1)[14]/46,XY[16]
1
0.2
46,XX,r(21)(p13q22.2)
1
0.2
46,X,dir dup(X)(q13q24) 46,X,del(Y)(q11.2)
1 1
0.2 0.2
47,XX, ?mar de novo.ish der(14/22) (D14Z1?/D22Z1?,wcp14-, wcp22-,rDNA??)
1
0.2
123
1154 Table 3 continued
Pediatr Cardiol (2011) 32:1147–1157
Chromosomal abnormality category
n = 547
Apparently balanced
6
1.1
3
0.5
46,XY,t(1;6)(q44;q23.3)
1
0.2
45,XX,der(13;22)(q10;q10)
1
0.2
45,XX,der(13;14)(q10;q10)[7]/46,XX[13]
1
0.2
3
0.5
Translocation
a
Chromosomal abnormalities listed in quotes were shown when the cytogenetic analysis report was not available in the abstracted records
Inversion 46,XY,2qs pat,inv(5)(q13.3q23.2)mat
1
0.2
46,XY,inv(7)(p22q11.23)
1
0.2
46,XX,inv(11)(q21q23.3)mat
1
0.2
Our estimated frequency of chromosomal abnormalities among infants with CHDs was 12.3%, similar to that reported in most previous studies estimating the contribution between 11.3% and 13% [9–11, 24, 31]. Several studies showed a lower frequency of chromosomal abnormalities among infants with CHDs (9% to 9.5%), but these studies included live-born infants only [3, 13, 16]. A greater frequency of chromosomal abnormalities was found in a study by Harris et al. that combined data from three population-based birth-defects registries. These investigators attributed their greater proportion (18%) to different inclusion criteria in California’s birth-defects monitoring system (20.3% of infants with CHDs from California had chromosomal abnormalities compared with 12.6% in infants from France and 12.8% in infants from Sweden) [14]. Schellberg et al. estimated that 16% of infants with CHDs had chromosomal abnormalities; however, their study was clinic-based and used a stepwise approach to obtaining different cytogenetic tests in living infants that presented to their clinic [29]. Similar to our findings, the association between CHDs and trisomies 21, 18, and 13 has long been recognized [3, 9–11, 13, 14, 16, 24, 29, 31]. We found that many infants with conotruncal CHDs are also frequently observed to have 22q11.2 deletions, a phenomenon that has previously been reported [4, 15, 17, 29]. Our study extends our previous study of 22q11.2 deletions using data from MACDP [4] and provides data on the frequency of 22q11.2 deletion in relation to other common chromosomal abnormalities among infants with CHDs. Among all of the infants with CHDs in our study, 22q11.2 deletions were detected in a similar proportion of CHD infants as trisomy 18 and were observed more frequently than trisomy 13, which has not previously been reported. Our analysis showed more than two thirds of infants with AVSDs had a chromosomal abnormality, and most had trisomy 21. This supports the well-known association between AVSDs and chromosomal abnormalities, in particular, trisomy 21 [10, 12, 19, 34]. chromosomal abnormalities were also frequently seen in infants with DORV. In our study, one-
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%
third of infants with DORV had a chromosomal abnormality. Obler et al. showed a greater estimate of 40%; however, their study included infants that did not have confirmed chromosomal abnormalities [22]. The large number of infants with a VSD, NOS or ASD who had a chromosomal abnormality is likely due to the finding of additional CHD types in infants with these defects (e.g., AVSD and ASD). Our results support the hypothesis that genetic loci on many different chromosomes are involved in the causation of CHDs [23]. Van Karnebeek and Hennekam performed a search in the Human Cytogenetics DataBase looking for unbalanced structural chromosomal abnormalities that had been listed in at least three individuals with CHDs [35]: they identified unbalanced structural abnormalities involving all chromosomes except 12, 14, 19, 21, and X. In our study, there were three infants with CHDs and trisomy 22; most infants with trisomy 22 are known to have CHDs [33]. The association between Turner syndrome and CHDs has been well established [2], and in our analysis, there were eight infants with Turner syndrome and CHD. We also observed infants with CHDs in our study with other sex chromosomal abnormalities, such as Klinefelter syndrome (XXY), XXX, and XYY; these chromosomal abnormalities were also observed in infants with conotruncal CHDs in a recent study [17]. Our study has many strengths. Infants were classified using a clinically standard nomenclature and morphogenetically-based aggregation system for CHDs. This system differentiated subtle but important types of CHDs and minimized misclassification [32]. Data on chromosomal abnormalities were reviewed by a cytogeneticist to ensure that infants were classified into appropriate categories. Such systematic classifications may allow for comparisons with other population-based studies using similar systematic classifications. We used a population-based study design to ensure that all infants born with CHDs, not just those seen at a particular referral center, were included in the analysis. In addition, because our study used data from a birth-defects surveillance system, we were able to include
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Table 4 Chromosomal abnormalities observed with specific CHDs listed by CHD type (MACDP 1994–2005) n Conotruncal IAA (type B or NOS) 22q11.2 deletion Unbalanced deletiona DORV Trisomy 18 Trisomy 13 22q11.2 deletion Truncus arteriosus 22q11.2 deletion Trisomy 13 Tetralogy of Fallot 22q11.2 deletion Trisomy 21 Trisomy 18 Trisomy 13 Unbalanced deletiona Trisomy 21, other Trisomy 22, other Unbalanced, other Unbalanced Translocation 47, XXX Balanced translocation AVSD Trisomy 21 Trisomy 18 Trisomy 13 Trisomy 21, other Unbalanced, other Triploidy VSD, NOS Trisomy 18 Trisomy 21 Trisomy 13 Trisomy 22 Turner syndrome Trisomy 18, other 22q11.2 deletion Unbalanced duplication Unbalanced deletiona ASD, Secundum Trisomy 21 Trisomy 13 22q11.2 deletion Trisomy 18 Unbalanced duplication Unbalanced translocation Trisomy 18, other a
18 17 1 9 6 2 1 10 9 1 52 23 9 7 5 2 1 1 1 1 1 1 148 131 11 2 2 1 1 37 17 8 4 2 2 1 1 1 1 102 80 7 7 3 2 2 1
Infants with unbalanced deletions other than 22q11.2 deletion
%
94.4 5.6 66.7 22.2 11.1 90.0 10.0 44.2 17.3 13.5 9.6 3.8 1.9 1.9 1.9 1.9 1.9 1.9 88.5 7.4 1.4 1.4 0.7 0.7 45.9 21.6 10.8 5.4 5.4 2.7 2.7 2.7 2.7 78.4 6.9 6.9 2.9 2.0 2.0 1.0
fetal deaths with CHDs in our analysis to give a more complete picture of the contribution of chromosomal abnormalities to CHDs. The population-based design and inclusion of fetal deaths help minimize potential selection bias and allow for more reliable estimation of the contribution of chromosomal abnormalities to CHDs. For example, approximately 5% of infants with tetralogy of Fallot in our analysis had trisomy 18 or trisomy 13, associations that might not be observed in clinic- or hospitalbased analyses of tetralogy of Fallot [25]. However, our study also has several limitations. Although most infants with CHDs exhibit symptoms and have them detected early in life, for some defects with limited clinical manifestations in infancy and childhood (e.g., isolated coronary artery anomalies, bicuspid aortic valve, mild coarctation), ascertainment is likely to be incomplete; thus, our estimate of the contribution of chromosomal abnormalities applies to CHDs diagnosed in infancy or early childhood. Decisions about cytogenetic testing were made by clinicians caring for the infant. Based on our data, chromosomal analyses were performed in 38.9% of the infants with CHD. Therefore, our results are likely to underestimate the true contribution of chromosomal abnormalities to CHDs. In addition, only infants on whom cytogenetic testing had been performed before the child’s sixth birthday and documented as abnormal were considered to have a chromosomal abnormality. If cytogenetic studies were never performed or were performed at an age [6 years, then the chromosomal abnormality would have been missed. MACDP does not ascertain all cytogenetic testing results from all sources, so there is a possibility that some infants with CHDs could have an undocumented chromosomal abnormality. Because of concern for the reliability of CHD diagnoses made prenatally, our study did not include pregnancy terminations, many of which might have had chromosomal abnormalities because severe birth defects are found more often among fetal deaths and terminations [8]. Finally, we assumed that chromosomal abnormalities were responsible for the CHDs with which they were observed; however, it is possible that some chromosomal abnormalities (e.g., apparently balanced rearrangements) were not causative but rather were chance observations. Based on our analysis, approximately one in eight live births and fetal deaths with CHDs have a chromosomal abnormality, and a much greater frequency was observed with certain types of CHDs. The 22q11.2 deletion was observed nearly as often among infants with CHDs as those with trisomy 18 and more frequently than those with trisomy 13. Clinicians should maintain a low threshold at which to obtain testing for chromosomal abnormalities in infants with CHDs, especially in infants with specific types of CHDs or multiple CHDs. A consensus group has
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Table 5 Clinical and demographic characteristics of infants with CHDs and chromosomal abnormalities (MACDP 1994–2005)
All CHDs
Infants with CHDs and chromosomal abnormalities
RR (95% CI)
n
n
%
Male
2170
241
11.1
Ref
Female
2255
305
13.5
1.2 (1.0–1.4)
Infant sex
Gestational agea (week) C37
3,137
371
11.8
Ref
\37
895
128
14.3
1.2 (1.0–1.5)
4371
527
12.1
Ref
20
33.9
2.8 (2.0–4.1)
Birth outcome Live born Fetal death
59
Frequency of CHD types Only 1 CHD
3903
422
10.8
Ref
[1 CHD
527
125
23.7
2.2 (1.8–2.6)
Non-Hispanic white
1960
215
11.0
Ref
Non-Hispanic black
1,564
222
14.2
1.3 (1.1–1.5)
Hispanic
664
81
12.2
1.1 (0.9–1.4)
Other
188
22
11.7
1.1 (0.7–1.6)
Maternal race/ethnicity
Maternal age (y)
a
Live-born singletons only
\35
3482
347
10.0
Ref
C35
939
198
21.1
2.1 (1.8–2.5)
recently recommended chromosomal microarray as the first-tier diagnostic test for infants with developmental disabilities, autism spectrum disorders, or multiple congenital anomalies [21]. Inclusion of chromosomal microarray analysis in future studies of CHDs will allow development of evidence-based guidelines about its utility in the evaluation of isolated heart defects. Acknowledgments We thank Cheryl Broussard, Suzanne Gilboa, Assia Miller, and Sarah Tinker for their assistance with the statistical analyses. The authors acknowledge the dedication and contributions of the abstractors, staff, and scientists who contribute to the MACDP. This research was supported in part by an appointment to the Research Participation Program at the CDC administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the United States Department of Energy and the CDC. Disclaimer The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC).
References 1. Baldwin EL, Lee JY, Blake DM, Bunke BP, Alexander CR, Kogan AL et al (2008) Enhanced detection of clinically relevant genomic imbalances using a targeted plus whole genome oligonucleotide microarray. Genet Med 10:415–429
123
2. Bondy CA (2007) Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 92:10–25 3. Bosi G, Garani G, Scorrano M, Calzolari E (2003) Temporal variability in birth prevalence of congenital heart defects as recorded by a general birth defects registry. J Pediatr 142:690–698 4. Botto LD, May K, Fernhoff PM, Correa A, Coleman K, Rasmussen SA et al (2003) A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112:101–107 5. Centers for Disease Control (2007) Hospital stays, hospital charges, and in-hospital deaths among infants with selected birth defects— United States, 2003. MMWR Morbid Mortal Wkly Rep 56:25–29 6. Centers for Disease Control (2010) Statistical analysis battery for epidemiologic research (SABER). Available at: www.cdc.gov/ nceh/publications/saber/saber.htm. Accessed 31 Mar 2010 7. Correa A, Cragan JD, Kucik JE, Alverson CJ, Gilboa SM, Balakrishnan R et al (2007) Reporting birth defects surveillance data 1968–2003. Birth Defects Res A Clin Mol Teratol 79:65–186 8. Cragan JD, Gilboa SM (2009) Including prenatal diagnoses in birth defects monitoring: experience of the Metropolitan Atlanta Congenital Defects Program. Birth Defects Res A Clin Mol Teratol 85:20–29 9. Dadvand P, Rankin J, Shirley MD, Rushton S, Pless-Mulloli T (2009) Descriptive epidemiology of congenital heart disease in Northern England. Paediatr Perinat Epidemiol 23:58–65 10. Ferencz C, Loffredo CA, Correa-Villasenor A, Wilson PD (eds) (1997) Genetic and environmental risk factors of major cardiovascular malformations: the Baltimore-Washington Infant Study 1981–1989. Futura Publishing Armonk, NY 11. Ferencz C, Neill CA, Boughman JA, Rubin JD, Brenner JI, Perry LW (1989) Congenital cardiovascular malformations associated
Pediatr Cardiol (2011) 32:1147–1157
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
with chromosome abnormalities: an epidemiologic study. J Pediatr 114:79–86 Freeman SB, Bean LH, Allen EG, Tinker SW, Locke AE, Druschel C et al (2008) Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project. Genet Med 10:173–180 Grech V, Gatt M (1999) Syndromes and malformations associated with congenital heart disease in a population-based study. Int J Cardiol 68:151–156 Harris JA, Francannet C, Pradat P, Robert E (2003) The epidemiology of cardiovascular defects, part 2: a study based on data from three large registries of congenital malformations. Pediatr Cardiol 24:222–235 Johnson MC, Hing A, Wood MK, Watson MS (1997) Chromosome abnormalities in congenital heart disease. Am J Med Genet 70:292–298 Kidd SA, Lancaster PA, McCredie RM (1993) The incidence of congenital heart defects in the first year of life. J Paediatr Child Health 29:344–349 Lammer EJ, Chak JS, Iovannisci DM, Schultz K, Osoegawa K, Yang W et al (2009) Chromosomal abnormalities among children born with conotruncal cardiac defects. Birth Defects Res A Clin Mol Teratol 85:30–35 Lu XY, Phung MT, Shaw CA, Pham K, Neil SE, Patel A et al (2008) Genomic imbalances in neonates with birth defects: high detection rates by using chromosomal microarray analysis. Pediatrics 122:1310–1318 Marino B, Digilio MC (2000) Congenital heart disease and genetic syndromes: specific correlation between cardiac phenotype and genotype. Cardiovasc Pathol 9:303–315 Mathews TJ, MacDorman MF (2008) Infant mortality statistics from the 2005 period linked birth/infant death data set. Natl Vital Stat Rep 57:1–32 Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP et al (2010) Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 86:749–764 Obler D, Juraszek AL, Smoot LB, Natowicz MR (2008) Double outlet right ventricle: aetiologies and associations. J Med Genet 45:481–497 Pierpont ME, Basson CT, Benson DW Jr, Gelb BD, Giglia TM, Goldmuntz E et al (2007) Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 115:3015–3038
1157 24. Pradat P (1992) Epidemiology of major congenital heart defects in Sweden, 1981–1986. J Epidemiol Community Health 46: 211–215 25. Rauch R, Hofbeck M, Zweier C, Koch A, Zink S, Trautmann U et al (2010) Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot. J Med Genet 47:321–331 26. Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A (2008) Prevalence of congenital heart defects in metropolitan Atlanta, 1998–2005. J Pediatr 153:807–813 27. Riehle-Colarusso T, Strickland MJ, Reller MD, Mahle WT, Botto LD, Siffel C et al (2007) Improving the quality of surveillance data on congenital heart defects in the metropolitan Atlanta congenital defects program. Birth Defects Res A Clin Mol Teratol 79:743–753 28. Roskes EJ, Boughman JA, Schwartz S, Cohen MM (1990) Congenital cardiovascular malformations (CCVM) and structural chromosome abnormalities: a report of 9 cases and literature review. Clin Genet 38:198–210 29. Schellberg R, Schwanitz G, Gravinghoff L, Kallenberg R, Trost D, Raff R et al (2004) New trends in chromosomal investigation in children with cardiovascular malformations. Cardiol Young 14:622–629 30. Shaffer LG, Kashork CD, Saleki R, Rorem E, Sundin K, Ballif BC et al (2006) Targeted genomic microarray analysis for identification of chromosome abnormalities in 1500 consecutive clinical cases. J Pediatr 149:98–102 31. Stoll C, Alembik Y, Roth MP, Dott B, De Geeter B (1989) Risk factors in congenital heart disease. Eur J Epidemiol 5:382–391 32. Strickland MJ, Riehle-Colarusso TJ, Jacobs JP, Reller MD, Mahle WT, Botto LD et al (2008) The importance of nomenclature for congenital cardiac disease: implications for research and evaluation. Cardiol Young 18(Suppl 2):92–100 33. Tinkle BT, Walker ME, Blough-Pfau RI, Saal HM, Hopkin RJ (2003) Unexpected survival in a case of prenatally diagnosed non-mosaic trisomy 22: clinical report and review of the natural history. Am J Med Genet A 118A:90–95 34. Torfs CP, Christianson RE (1998) Anomalies in Down syndrome individuals in a large population-based registry. Am J Med Genet 77:431–438 35. van Karnebeek CD, Hennekam RC (1999) Associations between chromosomal anomalies and congenital heart defects: a database search. Am J Med Genet 84:158–166 36. Waitzman NJ, Romano PS, Scheffler RM (1994) Estimates of the economic costs of birth defects. Inquiry 31:188–205 37. Yang Q, Chen H, Correa A, Devine O, Mathews TJ, Honein MA (2006) Racial differences in infant mortality attributable to birth defects in the United States, 1989–2002. Birth Defects Res A Clin Mol Teratol 76:706–713
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