Complete Transposition of the Great Arteries

Patterns of Congenital Heart Disease in Familial Precurrence

Maria Cristina Digilio, MD; Brett Casey, MD; Alessandra Toscano, MD; Raffaele
Calabrò, MD;
Giuseppe Pacileo, MD; Maurizio Marasini, MD; Elena Banaudi, MD; Aldo Giannotti,
MD;
Bruno Dallapiccola, MD; Bruno Marino, MD
Background—Transposition of the great arteries (TGA) is considered to be associated
only rarely with genetic syndromes
and to have a low risk of precurrence among relatives of affected patients. Because most
family studies have involved
a relatively small number of patients and evaluated all types of TGA as a single group,
we performed a large, prospective
study investigating the precurrence of congenital heart disease in families of children
with complete, nonsyndromic
TGA.
Methods and Results—From January 1997 through December 2000, 370 patients with
nonsyndromic, complete TGA were
consecutively evaluated and enrolled in the study. The occurrence of cardiac and
noncardiac anomalies among relatives
of the probands was investigated. Relatives with congenital heart disease were found in
37 of 370 families (10%),
including 5 of 37 families (13.5%) with more than one affected relative. TGA itself was
the most common precurrent
malformation: complete TGA occurred in 6 families and congenitally corrected TGA
occurred in 5 families. Precurrence
risks for congenital heart disease were calculated at 1.8% (8 of 436) for siblings, 0.5% (4
of 740) for parents, 0.5% (16
of 3261) for first cousins, 0.2% (4 of 2101) for uncles/aunts, and 0.06% (1 of 1480) for
grandparents.
Conclusions—The present study shows that TGA is not always sporadic in families.
Precurrence of concordant cardiac
defects within affected family members supports monogenic or oligogenic inheritance of
TGA in certain kindreds.
Moreover, the occurrence of complete TGA and congenitally corrected TGA among first-
degree relatives in several
different families strongly suggests an underlying pathogenetic link between these 2
malformations that has been
previously unrecognized. (Circulation. 2001;104:2809-2814.)
Key Words: heart defects, congenital transposition of great vessels genetics
T
ransposition of the great arteries (TGA) accounts for 5%
to 7% of all congenital heart defects (CHDs),
1–3
with a
prevalence rate of 0.2 per 1000 live births.
4
TGA is the most
frequent cyanotic CHD5
and the most frequent CHD diagnosed in the neonatal period.
1
The genetic contribution to the pathogenesis of TGA is not
considered to be strong given that very few familial cases
have been described
6,7
and that genetic syndromes or extracardiac malformations are uncommonly associated
with
TGA.
1,8
Currently, the mean precurrence risk for CHD
among siblings of patients affected with any type of TGA is
considered to be 1.4%,
7,9 –17
and a recent large population
study failed to identify any familial precurrence among 20
offspring of adult patients with TGA.
16
Information about precurrence risks among different subgroups of TGA have been
provided in only one study,
17
which reported that patients with complete TGA (ie, situs
solitus, D-loop ventricle, and TGA with or without a ventricular septal defect [VSD])
have the lowest precurrence rate of
CHD among siblings (0.27%), whereas a precurrence risk of
2% has been calculated for siblings of patients with complex
TGA (with or without a single ventricle, tricuspid atresia, or
double outlet right ventricle) or with TGA with the asplenia
syndrome/right isomerism form of heterotaxy. Correspondingly, the results of the
Baltimore-Washington Infant Study
8
showed that complete TGA also has a lower percentage of
associated extracardiac defects in comparison with complex
TGA.
Anecdotal clinical experience suggested that the occurrence of familial CHD among
index cases of TGA might be
higher than previously reported, particularly among the subgroup of patients with
complete TGA. This study was
Received June 14, 2001; revision received September 26, 2001; accepted September 26,
2001.
From the Departments of Medical Genetics and Pediatric Cardiology, Bambino Gesù
Hospital, Rome (M.C.D., A.T., A.G.); the Department of
Pathology, Baylor College of Medicine and Texas Children’s Hospital, Houston (B.C.);
the Department of Pediatric Cardiology, Monaldi Hospital,
Napoli, Italy (R.C., G.P.); the Department of Pediatric Cardiology, G. Gaslini Hospital,
Genova, Italy (M.M.); the Department of Pediatric Cardiology,
Regina Margherita Hospital, Torino, Italy (E.B.); the Department of Medical Genetics,
La Sapienza University and Mendel-CSS Institute, Rome, Italy
(B.D.); and the Division of Pediatric Cardiology, Department of Pediatrics, La Sapienza
University, Rome, Italy (B.M.).
Correspondence to B. Marino, Cardiologia Pediatrica, Istituto di Pediatria, Università La
Sapienza, Viale Regina Elena 324, 00161, Roma, Italia. E-mail
bruno.marino@uniroma1.it
© 2001 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
Downloaded from circ.ahajournals.org 2809 by on April 11, 2011 designed specifically
to investigate this hypothesis and to
determine whether any particular CHD occurred more commonly than others among
relatives of index cases.
Considering that most previous familial studies have involved a relatively small number
of patients and evaluated all
types of TGA as a single group, we performed a prospective
investigation of familial precurrence of CHD in families of
children with complete TGA evaluated in 5 Italian departments of pediatric cardiology
over 4 years. The study was
designed to verify if the familial analysis of a large series of
patients could help in the identification of pedigrees at high
risk for CHD and to study the types of CHD occurring in
relatives of patients with complete TGA.
Methods
From January 1997 to December 2000, 370 consecutive patients with
nonsyndromic, complete TGA were evaluated and enrolled in this
Italian multicenter study, which was coordinated by the Bambino
Gesù Hospital in Rome. Five pediatric cardiology institutions participated to this study:
the Bambino Gesù Hospital in Rome (179
patients), the Gaslini Hospital in Genova (87 patients), the Monaldi
Hospital in Naples (67 patients), the Regina Margherita Hospital in
Torino (23 patients), and the La Sapienza University in Rome (14
patients). There were 260 male (70.3%) and 110 female (29.7%)
patients. Mean age was 5.95 4.62 years (range, newborn to 17.7
years). The majority of the patients (347 of 370, 93.8%) were
enrolled at the time of a routine postoperative appointment. The
remaining patients (23 of 370,6.2%) were enrolled at the time of
initial presentation. In all patients, the cardiac diagnosis was confirmed by one or more of
the following: echocardiography, cardiac
catheterization, surgical intervention, and/or autopsy. The study was
restricted to patients with TGA and discordant ventriculoarterial
connections (patent semilunar valves), with or without a VSD and/or
outflow tract obstructions. All had situs solitus of the atria, levocardia, D-loop of the
ventricle, and concordant atrioventricular connections (patent atrioventricular valves).
Patients with any type of single
ventricle and/or classic findings of heterotaxy (41 patients) were
excluded.
Clinical and phenotypical evaluations were performed in all
patients by a geneticist to detect extracardiac anomalies. The
definition of nonsyndromic was based on an examination at the time
of the enrollment in the study. Standard karyotype on peripheral
lymphocytes and fluorescent in situ hybridization with Sc11.1 probe
for 22q11.2 microdeletion were performed in all cases. Patients with
major extracardiac malformations and/or with facial dysmorphisms
in the setting of chromosome anomalies, mendelian syndromes, or
associations (28 patients) and one patient with a 22q11.2 microdeletion were excluded.
Information about family history was obtained by an interview
with the parents of the index cases. The precurrence of cardiac and
noncardiac congenital anomalies in relatives of the probands was
investigated. Family pedigrees were constructed to include siblings,
parents, grandparents, aunts/uncles, and first cousins. Information
about more distant relatives was volunteered by some families. The
study was approved by our ethics committee. All living first-degree
relatives underwent clinical and electrocardiographic examination.
In families in which CHD occurred in more than one member, a
complete echocardiographic study was performed on all living firstand second-degree
relatives.
Results
TGA with intact ventricular septum (IVS) was diagnosed in
246 of 370 cases (66.5%), and TGA with a VSD was
diagnosed in 124 of the 370 cases (33.5%). Of the 246
patients with TGA and IVS, 184 (74.8%) were male and 62
(25.2%) were female; in the 124 patients with TGA and VSD,
there were 76 (61.3%) males and 48 (38.7%) females. The
difference in sex distribution between the 2 groups (TGA
with IVS and TGA with VSD), using
2
analysis (with
P0.05 accepted as significant), is statistically significant
(P0.01).
One or more relatives with CHD were found in 37 of the
370 families (10%). In particular, familial precurrence of
CHD was detected in 22 of 246 families (8.9%) of probands
with TGA and IVS and in 15 of 124 families (12.1%) of
probands with TGA and VSD (P0.441). The affected
relatives had complete TGA in 6 families (Figure 1) and
congenitally corrected TGA (situs solitus, L-loop ventricle
with discordant atrioventricular connections, and TGA with
discordant ventriculoarterial connections) in 5 families (Figure 2). Different types of
CHD were also found among
relatives of 2 of the families included in Figure 1. In the
remaining 26 families, the affected relatives had CHDs
different from TGA (Table 1). Some pedigrees with familial
aggregation of TGA included in the present study were also
previously reported.
18,19
Precurrence risks for CHD among
relatives in our series of patients with TGA are shown in
Table 2. Considering the occurrence of CHD in first-degree
relatives of our probands, the heritability of TGA can be
estimated as 10% .
Noncardiac anomalies in relatives of the probands were
identified in 36 families. The type of noncardiac anomaly is
shown in Table 3. The risk rates for noncardiac anomalies in
relatives of our probands were 0.7% (3 of 436) for siblings,
0.5% (4 of 740) for parents, 0.8% (26 of 3261) for first
cousins, and 0.3% (7 of 2101) for uncles/aunts.
Consanguinity was identified in the parents of 5 probands
(second cousins in 4 cases and first cousins in one). Eight
probands with TGA (6 with TGA and IVS and 2 with TGA
and VSD, P0.89) had an unaffected twin sibling (dizygotic
in 5 cases, monozygotic in 3). The ethnicity of the families
was Italian in 369 of the 370 families; the ethnicity of the
remaining family (pedigree 2 in Figure 1) was Slavic gypsy.
Discussion
We analyzed familial precurrence of CHD in a large series of
patients with complete TGA from an Italian multicenter
study. The results obtained from the investigation of 370
families show a precurrence risk for CHD in siblings of 1.8%
(Table 2). Six families with precurrence of concordant TGA
(Figure 1) were identified and, surprisingly, in 5 other
families, congenitally corrected L-TGA was identified in
relatives of index cases (Figure 2).
According to previous literature reports, the mean precurrence rate in siblings of patients
with TGA is considered to be
1.4%,
7,9 –17
which is just lower than that in our results. In this
regard, it is important to consider that most of the studies
investigating familial TGA are referring to all types of TGA
as a single group. The only exception is the article by Becker
et al,
17
which showed that the study group of complete TGA
(168 patients) had a precurrence rate of only 0.27%. The
recent population study published by Burn et al,
16
which
investigated vertical transmission of TGA, found no cases of
CHD among 20 offspring of 104 probands with TGA. In the
2810 Circulation December 4, 2001
Downloaded from circ.ahajournals.org by on April 11, 2011 same study, the precurrence
of CHD in siblings of patients
with TGA was 0.97% (one case among 103 siblings).
The variety of recurrence risk rates found among different
studies may reflect different genetic and geographic backgrounds in populations. The
finding of more families with
precurrent TGA than previously expected could mean that a
study of large numbers of patients may identify pedigrees at high
risk for CHD. A combination of chance, decreased penetrance,
and nondominant transmission may account for the absence of
vertical transmission of CHD found in the study performed by
Burn et al.
16
Ascertainment bias may also affect the study
results, because different anatomic types of TGA allowing
survival to adulthood could have a possible different genetic
impact in comparison with more severe TGA.
The rate of consanguinity in our series is 1.4% (5 of 370
families). Only few data are available from the literature, but
first-cousin matings among parents of patients with TGA
have been occasionally reported.
20
The higher proportion of male patients affected by TGA
reported in previous series
1,21,22
was confirmed in our experience. In addition, a statistically significant male
preponderance in patients with TGA and IVS in comparison with those
with TGA and VSD was also found in our study, similar to
the observations reported in the Baltimore-Washington Infant
Study.
21
The segregation of an X-linked gene could be
suspected in families with precurrent TGA in males (Figures
1 and 2), but this type of transmission can be excluded in
most of our families because of apparent male-to-male
segregation of a putative disease gene (Figures 1 and 2).
Kindreds with familial TGA show that both TGA with VSD
and TGA with IVS can occur in the same family. No significant
difference was found in precurrence risk rates in families of
patients with TGA and IVS in comparison with those of patients
with TGA and VSD. Discordant CHDs precurring more often in
our pedigrees include tetralogy of Fallot and VSD (Table 1); a
multifactorial mode of inheritance of predisposition to familial
CHD can be hypothesized in these cases.
Some patterns of familial precurrence observed in our
study suggest that the recent pathogenetic classification of
CHD is not completely adequate to account for all cases of
TGA. In fact, according to the pathogenetic classification
proposed by Clark,
23,24
complete TGA is grouped among
Figure 1. Pedigree of 6 families with concordant TGA in affected members. TF indicates
tetralogy of Fallot; ASD, atrial septal defect.
Arrow indicates propositus; f, male affected; , male unaffected; , female affected; ,
female unaffected; slashes, deceased.
Figure 2. Pedigree of 5 families of probands with TGA and
additional family member with congenitally corrected L-TGA.
CCTGA indicates congenitally corrected transposition of the
great arteries. For symbols, see Figure 1.
Digilio et al Familial Transposition of the Great Arteries 2811
Downloaded from circ.ahajournals.org by on April 11, 2011 conotruncal heart defects
due to abnormalities of ectomesenchymal tissue migration, which are frequently
associated with
chromosomal deletion 22q11.2 in the setting of DiGeorge/
velocardiofacial syndrome. Actually, only a few cases of
TGA and deletion 22q11.2 have been reported,
25–27
suggesting that in only a small percentage of cases can TGA be
definitively explained on the basis of a defect in neural crest
cell migration. An interesting observation in our series is the
occurrence of tetralogy of Fallot related to deletion 22q11.2
in a sister of a male proband with TGA without chromosomal
abnormalities (Table 1). The occurrence of CHD in siblings
with discordant karyotypes supports the existence of additional genetic predisposing
factors, which could play a role in
the pathogenesis of familial aggregation of CHDs.
28
TABLE 1. Cardiac Defects in Relatives of Patients With Complete TGA
Cardiac Defect Relationship No. of relatives
Complete TGA Sister 1
Uncle 1
First cousin 1
Second cousin 3
Congenitally corrected L-TGA Sister 2
Brother 1
Mother 1
First cousin 1
Tetralogy of Fallot Sister (with deletion 22q11.2) 1
Aunt 1
First cousin 1
Second cousin 5
VSD Aunt 1
First cousin 4
Second cousin 3
Aortic stenosis (valvular) Brother 1
Father 1
First cousin 2
Second cousin 2
Pulmonary stenosis (valvular) Brother 1
Father 1
First cousin 1
Second cousin 1
Aortic coarctation First cousin 2
Uncle 1
Atrial septal defect (os) Mother 1
Grandfather 1
Single ventricle First cousin 1
Total anomalous pulmonary venous return First cousin 1
Partial anomalous pulmonary venous return First cousin 1
Persistent left superior vena cava First cousin 1
Left ventricle noncompaction Brother 1
TABLE 2. Empirical Risk for Cardiac Defects Obtained in the Present Series of
Patients With Complete TGA
Relationship
No. of Family Members
With Complete TGA
(Risk)
No. of Family Members
With Congenitally
Corrected L-TGA (Risk)
No. of Family Members
With CHD (Risk)
Siblings 1/436 (0.2%) 3/436 (0.7%) 8/436 (1.8%)
Parents 0/740 (0) 1/740 (0.1%) 4/740 (0.5%)
First cousins 1/3261 (0.03%) 1/3261 (0.03%) 16/3261 (0.5%)
Uncles/aunts 1/2101 (0.05%) 0/2101 (0) 4/2101 (0.2%)
Grandparents 0/1480 (0) 0/1480 (0) 1/1480 (0.06%)
2812 Circulation December 4, 2001
Downloaded from circ.ahajournals.org by on April 11, 2011 Ferencz et al,
21
however, classified TGA with the group of
conotruncal anomalies, but separated this malformation from
those with “normally related great arteries,” ie, tetralogy of
Fallot, truncus arteriosus, and interrupted aortic arch. In fact,
TGA seems to differ from the other types of conotruncal
defects: it presents with a lower percentage of associated
extracardiac anomalies,
1,8
a lower risk of familial precurrence
of CHD,
6,7
and a lower prevalence of deletion 22q11.2.
25–27
According to general consent, congenitally corrected
L-TGA is not included in the group of conotruncal defects,
but is classified among the situs and looping abnormalities.
21,23,24
The presence of congenitally corrected L-TGA in 5
first-degree relatives of our patients with TGA is quite
surprising (Figure 2). Aggregation of complete TGA and
L-TGA in the same family suggests a possible genetic and
causative connection between the 2 defects. Considering the
high prevalence of TGA in patients with heterotaxy
29
and
based on these cases of familial aggregation, the pathogenetic
group of situs and loop abnormalities might include at least
some cases of complete TGA.
In this regard, it is interesting to note that a relationship
between complete TGA and laterality defects is corroborated by
molecular studies investigating some new genes. In fact, mice
trans-heterozygous for both SMAD2 and nodal mutations can
have TGA, which is associated with right pulmonary isomerism
in some cases.
30
Mutations of the EGF-CFC gene, CRYPTIC, in
humans have been found to be associated with heterotaxic
phenotypes
31
as well as with some cases of complete TGA.
32
In addition, a mutation in the ZIC3 gene, an X-linked gene
related to sporadic and familial situs abnormalities, has been
detected in a family in which affected males have TGA and
midline anomalies but no obvious left-right malformations.
33
Familial segregation of both laterality defects and isolated
TGA has been also recently observed in one family.
34
All
these data support the hypothesis that TGA could be included
within the spectrum of laterality defects in some cases.
Data from animal studies support the suggestion that TGA
and situs/looping abnormalities may be related pathogenetically. Although TGA is the
most difficult cardiac malformation to reproduce experimentally, a consistent model of
TGA
was recently obtained by all-trans retinoic acid administration
during mouse pregnancy.
35,36
In this animal model, TGA
could be found in the presence of both D- and L-loops of the
ventricles (ie, complete TGA and congenitally corrected
TGA),
35
and treatment with retinoic acid in mouse embryos
also could induce looping anomalies with right isomerism.
37
Moreover, complete TGA (ie, with situs solitus and D-loop
ventricle) can be present among heart defects of homozygous
iv/iv mice presenting with a high prevalence of visceral
heterotaxy and lateralization anomalies.
38
Animal models,
therefore, support a common pathogenetic mechanism involved in causing some cases of
complete TGA along with
congenitally corrected TGA and other laterality defects.
Complete TGA could be considered a less severe manifestation than typically
encountered.
Noncardiac heritable disorders in relatives of patients with
complete TGA include a great variety of conditions. Previous
observations from the literature report a preferential occurrence of heritable blood
disorders in parents of children with
TGA,
1,39
and this association was also noted in one of the
families from our series (Table 3). The rarity of TGA and of
hemophilia in the population suggests that the co-occurrence
of these diseases in a family could be causally related. Also,
in our series (Table 3) as in previous epidemiological studies,
1
congenital hypothyroidism was found in relatives of
patients with TGA.
In the present study, some limitations concerning the
methods of ascertainment of the cases can be pointed out. In
fact, our study is not a population-based analysis, considering
that our series consists of patients with TGA enrolled at time
of hospital admission. In addition, the great majority of the
patients were collected when seen for a postoperative appointment. This could constitute
a bias in data evaluation,
TABLE 3. Noncardiac Anomalies in Relatives of Patients With
Complete TGA
Type of Noncardiac Anomaly Relationship No. of Relatives
Neurological disorders
Mental retardation First cousin 9
Aunt 2
Epilepsy Uncle 1
Hydrocephalus First cousin 1
Sensorineural deafness First cousin 4
Mother 1
Aunt 1
Chromosomal anomalies
47,XXY Father 1
Trisomy 21 First cousin 4
Blood disorders
Hemophilia, factor X Mother 1
Urogenital anomalies
Vesicoureteral reflux First cousin 1
Hypospadias Second cousin 1
Gastrointestinal malformations
Esophageal atresia Second cousin 1
Intestinal malformation Brother 1
Aunt 1
First cousin 1
Skeletal defects
Hip defects Uncle 1
Osteogenesis imperfecta First cousin 1
Cutaneous disorders
Epidermolysis bullosa Sister 1
Xeroderma pigmentosum First cousin 1
Miscellaneous
Cleft lip/palate First cousin 2
Aunt 1
Hypothyroidism Mother 1
Sister 1
Cystic fibrosis First cousin 1
X-linked combined immunodeficiency Second cousin 1
Duchenne muscular dystrophy First cousin 1
Digilio et al Familial Transposition of the Great Arteries 2813
Downloaded from circ.ahajournals.org by on April 11, 2011 particularly considering that
TGA has high preoperative and
intraoperative mortality.
20
An additional limitation could be
due to the fact that imaging tests for CHD were performed
routinely only in the first degree relatives of the probands,
whereas the presence of CHD in more distant relatives was
investigated by interview.
Conclusions
The present study shows that TGA is not always a sporadic
occurrence in families. Familial precurrence of concordant
cardiac defects within affected family members supports
monogenic or oligogenic inheritance of TGA in selected
pedigrees. This observation has practical implications in
genetic counseling for TGA. It is remarkable that TGA and
congenitally corrected TGA can segregate in the same family
due to a probable monogenic transmission supporting a
pathogenetic link between some cases of complete TGA and
the situs and looping abnormalities.
The complexity of these observations suggests a multigenic origin of TGA, probably with
the involvement of
multiple or even unrecognized causative and pathogenetic
mechanisms. Large families with multiple members affected
by CHD are fundamental for the identification of the genes
related to the specific malformations using genetic techniques
such as linkage analysis and positional cloning. The collection of pedigrees segregating
the gene(s) of interest will
provide an important aid for the delineation of the human
gene map of CHDs.
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