Fig. 47.1
Cellular and molecular basis for normal and abnormal outflow tract development of the heart. The interaction of progenitor cells derived from the second heart field (SHF cells) and the cardiac neural crest (CNCC) that give rise to the outflow tract (OFT) myocardium and septum, respectively, plays a key role in the development of the OFT. TBX1, a major genetic determinant of the 22q11.2 deletion syndrome (22q11DS), is exclusively expressed in the SHF cells. TBX1 deletion in 22q11DS may affect not only the SHF cells but also the interaction of the SHF cells and CNCC and result in OFT defects ranging from tetralogy of Fallot, which is characterized by malalignment of the OFT septum, to truncus arteriosus, which results from aplasia of the OFT septum
The etiology of most patients with TA is usually unknown, and it is considered to be heterogenous and multifactorial in nature. Approximately 60 % of TA occurs as an isolated cardiovascular malformation, while the remainder has additional extracardiac anomalies and is frequently syndromic [2]. A diabetic mother has an increased risk of developing TA compared with the infant of a nondiabetic mother [2, 3]. A typical pattern of malformation was reported in embryos exposed to retinoic acid involving conotruncal and aortic arch anomalies including TA [2, 3].
Several genes encoding transcription factors and signaling proteins highlight the importance of the CNCC and SHF and their interaction [4]. Mice deficient for genes encoding these proteins result in TA. Syndromes with chromosome 22q11.2 microdeletion served as an entry to understanding the genetic basis for TA, and a gene encoding the transcription factor T-box 1 (TBX1) has been proposed as a major genetic determinant [5, 6]. To date, mutations of genes encoding NKX or GATA transcription factors have been reported in patients with TA without 22q11.2 deletion.
47.2 Genetics
TA has no striking gender difference in frequency. Several reports describe families with one proband with TA and several relatives with CHD although most cases of TA occur sporadically. A recurrence risk for siblings of probands with TA is reported as 1.2 % in a combined study [7] and 6.6 % in a consecutive study of 49 families [8]. In some families, the affected relatives have concordant defects, namely, conotruncal or cardiac outflow tract defects, whereas in other families, the defects are morphologically discordant, suggesting that the recurrence risk is highly variable and dependent on the specific etiology in each family. Syndromes and genes associated with TA are summarized in Table 47.1.
Table 47.1
Genetic etiology for truncus arteriosus (TA)
Genetic causes | Locus | Frequency |
|---|---|---|
Syndrome | ||
22q11.2 deletion syndrome (22q11DS) DiGeorge syndrome Velo-cardio-facial syndrome Conotruncal anomaly face syndrome | 22q11.2 (10p14-13) | Commona |
Single gene | ||
TBX1 (transcription factor) | 22q11.2 | Rare |
NKX2-5 (transcription factor) | 5q35.1 | Rare |
NKX2-6 (transcription factor) | 8p21.2 | Rare |
GATA4 (transcription factor) | 8p23.1 | Rare |
GATA6 (transcription factor) | 18q11.2 | Rare |
47.2.1 Syndromes and Chromosomal Anomalies
Approximately 40 % of patients with TA are syndromic. TA accounts for approximately 10 % of cardiovascular malformations associated with the 22q11.2 deletion syndrome. It was also reported that 2–3 % of TA patients have chromosomal anomalies other than 22q11.2 deletion [2].
47.2.2 22q11.2 Deletion Syndrome (22q11DS)
Monoallelic microdeletion of chromosome 22q11.2 results in the most common human genetic deletion syndrome with an incidence of 1 in 4000–5000 live births [5, 6, 9]. Recognition that DiGeorge syndrome (DGS), velo-cardio-facial syndrome (VCFS), and conotruncal anomaly face syndrome (CAFS) have overlapping clinical presentations and share 22q11.2 deletion revealed a common etiology of these clinical entities.
The clinical findings associated with 22q11DS are highly variable. Approximately 80 % of patients with 22q11DS are born with CHD. The types of CHD are variable, but characterized as conotruncal and aortic arch defects including tetralogy of Fallot (TOF) (~30 %) (see Chap. 32), interrupted aortic arch (IAA) type B (~15 %), ventricular septal defect (VSD) (~15 %), TA (~10 %), and others (~5 %) (Fig. 47.1). 22q11.2 deletion is the second most common genetic cause of CHD and is present in ~60 % of patients with IAA type B, ~35 % of patients with TA, and ~15 % of patients with TOF (~55 % of patients with TOF plus pulmonary atresia and major aortopulmonary collateral arteries) [10, 11].
As for the type of TA associated with 22q11.2 deletion, Momma et al. reported that three had type A1 and two had type A3 with no other in their five consecutive patient types, according to the Van Praagh classification [12], while Goldmuntz et al. reported all four types in their largest series of consecutive patients with TA and 22q11.2 deletion [10]. They also found that patients with the additional finding of an aortic arch anomaly (such as a right aortic arch or aberrant subclavian artery) were more likely to have a 22q11.2 deletion than those with a normal left aortic arch.
A genetic test for 22q11.2 deletion would be recommended to screen all infants who are newly diagnosed with TA because the syndromic feature might be difficult to identify in the neonatal period and the finding of the deletion could facilitate the clinician to carefully detect the associated extracardiac features. It is also important to provide accurate recurrence risk and comprehensive genetic counseling for the family.
47.2.3 Other Syndromes
CHARGE syndrome is an acronym characterized by a pattern of congenital anomalies including coloboma of the eye (C), heart anomaly (H), atresia of choanal (A), retardation of mental and somatic development (R), genital anomalies (G), and ear abnormalities and/or deafness (E). Mutations of CHD7 on 8q12.1-q12.2 are found in approximately 60 % of patients with CHARGE syndrome [13]. A mutation of SEMA3E on 7q21.11 encoding semaphorin 3E was also reported [14]. Approximately 30–40 % of CHD associated with CHARGE syndrome represents outflow tract defects including TA.
VACTERL association is an acronym for the nonrandom association of vertebral defects (V), anal atresia (A), cardiac malformations (C), tracheoesophageal fistula (T) with esophageal atresia (E), radial or renal dysplasia (R), and limb anomalies (L). A mutation of HOXD13 (homeobox D13) on 2q31.1 was reported in a patient with VACTERL association [15]. Up to 75 % of patients with VACTERL association have CHDs. VSD, atrial septal defects (ASD), and TOF are commonly seen, whereas TA and transposition of the great arteries (TGA) are less common.
DGS is highly associated with TA and the common 22q11.2 deletion as mentioned above, but some cases have no detectable molecular defect of this region. Relatively rare cases of DGS can be caused by heterozygous deletion of 10p14-13 (DGS2 locus) [16]. We reported a unique patient with a de novo deletion beginning in the intron between exons 5 and 6 of CDC (cell division cycle) 45L and deleting exons 1–3 of UFD (ubiquitin fusion degradation) 1L on 22q11.2 critical region and typical features of the DGS including TA [17]. The CDC45L gene is situated immediately telomeric of UFD1L and is transcribed in the opposite direction through a common cis-acting element [18].
Association between TA and the following rare syndromes has also been cited in Online Mendelian Inheritance in Man (OMIM): cleft-limb-heart malformation [19]; fibuloulnar aplasia/hypoplasia with renal abnormalities [20]; microcephaly, congenital heart disease, unilateral renal agenesis, and hyposegmented lungs [21]; and renal-hepatic-pancreatic dysplasia 2 implicated with mutation of NEK8 (nimA-related kinase 8) on 17q11.2 [22].
47.2.4 Gene Mutations
47.2.4.1 TBX1
Because of the high incidence and association with CHD, including TA, 22q11DS has attracted attention as a model for investigating the genetic and developmental basis for TA. Although extensive gene searches have been successful in identifying more than 30 genes in the critical 22q11.2 locus, direct sequencing has failed to detect a responsible gene [5, 6, 23]. Elegant efforts to model 22q11DS in mice by creating orthologous chromosomal deletions were successful in reproducing aortic arch defects of 22q11DS, leading to identification of a T-box transcription factor, TBX1, as a major genetic determinant of CHD associated with 22q11DS [24, 25].
We and other groups found that Tbx1 was expressed in the SHF, but not in the CNCC [26–28]. This finding was surprising because CHD associated with 22q11DS had been considered primarily to be a result of developmental defects of CNCC [5, 6, 9, 23]. Our Cre-mediated murine transgenic system suggested that Tbx1-expressing descendents representing a subset of cells derived from the SHF contribute predominantly to the pulmonary infundibulum [29]. Developmental defects of this subset of cardiac progenitor cells may cause hypoplasia of the pulmonary infundibulum, resulting in TOF. A more severe decrease in number or absence of this subset of cells may affect development and/or migration of CNCC, resulting in TA. This hypothetical model is supported by the observation that outflow tract defects ranging from TOF to TA are highly associated with 22q11DS (Fig. 47.1).
There is a report of TBX1 mutations in three unrelated patients with CHD without the common 22q11.2 deletion [30]. Yagi et al. identified mutations in the TBX1 gene in heterozygous state in three patients with phenotypes related to the 22q11.2 deletion syndrome, including the characteristic conotruncal anomaly face.
47.2.4.2 NKX Transcription Factors
Homeobox-containing genes regulate tissue-specific gene expression and play roles in differentiation and patterning of tissues during development [31]. NKX2–5/CSX and NKX2–6 were identified as vertebrate homologs of a Drosophila “tinman,” a homeobox-containing gene essential for development of the heart-like dorsal vessel [32, 33].
Schott et al. reported that heterozygous mutations of NKX2–5 caused familial ASD with atrioventricular block [34]. This was the first report clearly showing that a single gene mutation could cause a nonsyndromic CHD. McElhinney et al. examined the NKX2–5 gene in 474 patients with CHD and identified a heterozygous mutation in 1 (4 %) of 22 patients with TA [35]. A number of subsequent studies have indicated that mutations in the homeodomain of NKX2–5 are likely to cause ASD, whereas mutations located outside the homeodomain may be associated with outflow tract defects including TA [36, 37].
By mutation analyses for NKX2–6, Heathcote et al. identified homozygosity for a mutation (F151L) in the NKX2–6 gene in affected members of a large consanguineous Kuwaiti family with TA [38]. Ta-Shma et al. identified a homozygous truncating mutation in the NKX2–6 gene in three sibs, born of consanguineous Palestinian parents with TA [39]. These findings indicate that mutations of NKX2–5 or NKX2–6 are the genetic cause of a minority of cases of TA.
47.2.4.3 GATA Transcription Factors
GATA transcription factors are characterized as zinc finger proteins and play roles in the differentiation and survival of many cell types, including cardiomyocytes [40]. Among six GATA transcription factors, GATA4, GATA5, and GATA6 are expressed in the precardiac mesoderm and are thought to play essential roles during development of the heart.
Garg et al. reported that mutations in GATA4 caused ASD/VSD, probably as a result of disruptions to interactions with TBX5 [41]. A few reports have demonstrated an association between GATA4 mutations and outflow tract defects [42]. We identified a novel GATA4 sequence variants in a patient with TA [43]. This variant (p.Thr330Arg) was located in a common basic region of the GATA transcription factors and resulted in disruption of the synergistic activity between GATA4 and NKX2–5 or GATA6. It has been reported that a reciprocal regulation and a synergistic activity between GATA4 and NKX2-5 are essential for the expression of several cardiac-specific genes [44, 45]. Other studies have indicated that GATA4 plays a role in cardiovascular development in collaboration with GATA6 [46, 47] Taken together, a decrease in the synergistic and/or collaborative activity of GATA4 with NKX2-5 and/or GATA6 may be implicated in TA.
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