Conotruncal Heart Malformations

A number sign (#) is used with this entry because of evidence that various conotruncal heart malformations can be caused by mutation in one of several genes. A mutation in the TBX1 gene (602054) has been found in individuals with conotruncal anomaly face syndrome (CAFS). Mutation in the NKX2-6 gene (611770) has been identified in 2 consanguineous families with conotruncal heart malformations, including persistent truncus arteriosus (PTA). Mutation in the NKX2-5 gene (600584) has been found in a patient with interrupted aortic arch and in a patient with PTA. Mutation in the GATA6 gene (601656) has been found in patients with PTA. Mutation in the ZFPM2 gene (603693) has been identified in patients with DORV.

Clinical Features

In a study of the families of children with cardiac malformations, Pierpont et al. (1988) found that conotruncal malformations carry a higher recurrence risk than other cardiac defects and proposed a monogenic mode of inheritance. Rein et al. (1990) described a large kindred in which 2 sibs had truncus arteriosus communis, a first cousin once removed had transposition of the great arteries (TGA; see 608808), and a second cousin had double-outlet right ventricle. Rein and Sheffer (1994) reported 2 additional sibs with conotruncal malformations born into the consanguineous kindred they had previously reported. Le Marec et al. (1989) had raised the question of autosomal recessive inheritance of truncus arteriosus.

Typical facial features of conotruncal anomaly face syndrome (CAFS) are ocular hypertelorism (with increased interpupillary distance due to increased separation of the inner canthi), short palpebral fissures, 'bloated' eyelids, a low nasal bridge, a small mouth, and minor ear lobe anomalies. These features are almost always associated with nasal voice (often associated with cleft palate/submucosal cleft palate/bifid uvula) and mild mental retardation (frequently associated with developmental retardation and, occasionally, dwarfism), and often associated with cardiovascular anomalies. The cardiovascular anomalies in patients with the conotruncal anomaly face syndrome mainly consist of cardiac outflow tract defects, such as tetralogy of Fallot (TOF; 187500), pulmonary atresia, double-outlet right ventricle, truncus arteriosus communis, and aortic arch anomalies. Some patients also have hypocalcemia, especially in the neonatal period (sometimes associated with hypoparathyroidism), and thymic aplasia or hypoplasia (Matsuoka et al., 1998).

Cytogenetics

Conotruncal heart malformations may be components of certain syndromes, e.g., DiGeorge syndrome (188400), the velocardiofacial syndrome (192430), and genitopalatocardiac syndrome (231060). Using DNA markers, Emanuel et al. (1992) found loss of heterozygosity indicating microdeletions of chromosome 22q11.2 in 30% of isolated conotruncal anomalies. These results were confirmed by fluorescence in situ hybridization (FISH).

Matsuoka et al. (1994) performed FISH analysis using the D22S75 DiGeorge critical region probe (DCGR) in 50 CAFS patients, 11 parent couples, and 10 mothers of CAFS patients. Monosomy for the region 22q11.2 was found in 42 CAFS patients and in 4 mothers and 1 father who had CAFS without congenital heart disease. No deletion of 22q11.2 was found in 60 patients who had congenital heart disease without CAFS.

Conotruncal defects (CTD) account for a fourth to a third of all nonsyndromic congenital heart defects. Debrus et al. (1996) searched for a 22q11 microdeletion in familial cases of nonsyndromic CTD. The study involved 36 cases of various isolated conotruncal defects, that is, without history of hypocalcemia, immune deficiency, absent thymus, or dysmorphic appearance. With 48F8, a cosmid probe localized in the smallest deleted region of the DiGeorge critical region, they found no deletions by FISH in these 36 affected individuals from 16 families. The second marker, D22S264, a microsatellite localized at the distal part of the largest deleted region, showed heterozygosity in 32 of 37 patients and hence was not related at this locus, whereas 5 markers were uninformative.

To investigate molecular and clinical aspects of CAFS, Matsuoka et al. (1998) studied the correlation between deletion size and phenotype and the mode of inheritance in 183 CAFS patients. Hemizygosity for a region of 22q11.2 was found in 180 (98%) of the patients by FISH analysis using the D22S75 (N25) DGCR probe. No hemizygosity was found in 3 (2%) of the patients with CAFS by FISH using 9 DCGR probes and another probe from a related region. None of these 3 patients had mental retardation and only 1 had nasal speech, which was observed in almost all of the 180 CAFS patients who carried identified deletions (mental retardation in 92%; nasal voice in 88%). Familial CAFS was found in 19 (13%) of 143 families and 16 affected parents (84%) were mothers. Although only 2 of the affected parents had cardiovascular anomalies, the deletion size in the 16 affected parents and their affected family members, who were studied by FISH analysis, was the same. This indicated that extragenic factors may play a role in the genesis of phenotypic variability, especially in relation to cardiovascular anomalies. No familial cases were found among CAFS patients with absent thymus/DiGeorge anomaly (DGA). Also, in all 18 CAFS patients with completely absent thymus/DGA and in all 6 CAFS patients with schizophrenia, the deletion was found to be longer distally. In a study of the origin of the deletion using microsatellite analyses in 48 de novo patients, the mother was shown to be the source in 65% of CAFS patients, while the father was the source in 64% of DGA patients. In addition to the major features of CAFS, other notable extracardiac anomalies were susceptibility to infection, schizophrenia, atrophy or dysmorphism of the brain, thrombocytopenia, short stature, facial palsy, anal atresia, and mild limb abnormalities.

Takahashi et al. (1995) found a submicroscopic deletion in 22q11 in 5 of 64 patients with a conotruncal heart malformation. Devriendt et al. (1996) prospectively analyzed 150 patients with a conotruncal heart disease for the presence of a del22q11 by means of FISH, using the probe DO832. Patients with a transposition of the great arteries were not included in this study. The main diagnoses were tetralogy of Fallot (105 patients), tetralogy of Fallot with additional cardiopathies (18 patients), and truncus arteriosus (6 patients). Among the 140 patients in whom blood culture was successful, 18 had a deletion (12.8%). All patients with the deletion showed additional clinical features of the velocardiofacial syndrome. In 7 of the 150 patients (4.6%), the family history was positive for the presence of a conotruncal heart defect.

Saitta et al. (1999) identified a patient with CAFS who had a novel deletion of 22q11.2. His deletion was distal to the usual 3-Mb deletion found in most patients with velocardiofacial syndrome. The deletion did not overlap with any of the previously described 'minimal critical regions' for velocardiofacial syndrome/DiGeorge syndrome. The patient showed hypertelorism, posteriorly rotated ears, micrognathia, a loud cardiac murmur, hypospadias, descended testes, single palmar creases, and bilateral fifth-finger clinodactyly. The cardiac defect was truncus arteriosus type II and a ventricular septal defect. Borderline hypocalcemia was found. The deletion was found to exclude UFD1L (601754), raising questions about the role of this gene in the CATCH22 syndrome. The CDC45L gene (603465) was also excluded from the deletion.

Molecular Genetics

Yagi et al. (2003) identified mutations in the TBX1 gene (602054.0001 and 602054.0003) in heterozygous state in 3 patients with phenotypes related to the 22q11.2 deletion syndrome (see 188400), including CAFS.

In 1 (4%) of 23 patients with interrupted aortic arch and 1 (4%) of 22 patients with truncus arteriosus, McElhinney et al. (2003) identified heterozygosity for a missense mutation in the NKX2-5 gene (R25C; 600584.0004).

Heathcote et al. (2005) used autozygosity mapping of a large consanguineous Kuwaiti family segregating PTA to map the causative locus to chromosome 8p21. They subsequently identified homozygosity for a missense mutation in the NKX2-6 gene (611770.0001) in all affected individuals.

In 3 sibs, born of consanguineous Palestinian parents, with conotruncal heart malformations, Ta-Shma et al. (2014) identified a homozygous truncating mutation in the NKX2-6 gene (611770.0002). The mutation was found by exome sequencing. Two patients had truncus arteriosus and 1 had a complex conotruncal defect with malalignment ventricular septal defect and aortic arch hypoplasia, as well as asymptomatic athymia.

Kodo et al. (2009) screened the genomes of 21 unrelated Japanese patients with nonsyndromic persistent truncus arteriosus and identified heterozygosity for a 2-bp deletion (601656.0001) and a missense mutation (601656.0002) in the GATA6 gene, respectively, in 2 probands. The 2-bp deletion was also present in the first proband's father and sister, both of whom had pulmonary stenosis. The sister also had patent ductus arteriosus and atrial septal defect. Atrial septal defect was also present in the first proband. The second proband's mutation occurred de novo, and neither was found in 182 Japanese controls.

In 2 (15.4%) of 13 Italian patients with DORV, De Luca et al. (2011) identified heterozygosity for 2 different missense mutations in the ZFPM2 gene, E30G (603693.0002) and I227V (603693.0006).

In a 10-year-old Chinese boy with Langer-Giedion syndrome (150230) and DORV, Tan et al. (2012) identified a de novo balanced chromosomal translocation t(8; 18)(q22;q21) that appeared to disrupt the ZFPM2 gene on chromosome 8q23. Analysis of the ZFPM2 gene in 145 Chinese patients with conotruncal defects, including 95 with tetralogy of Fallot, 38 with sporadic DORV, and 12 with transposition of the great arteries, revealed 5 heterozygous missense mutations in patients with DORV (see, e.g., 603693.0004 and 603693.0008) that were not found in 250 Chinese controls in whom conotruncal heart disease had been excluded by echocardiography. No mutations were identified in the patients with TOF or TGA. Tan et al. (2012) suggested that ZFPM2 variants might be a common cause of DORV.

Associations Pending Confirmation

For discussion of a possible relationship between variation in the NRP1 gene and truncus arteriosus, see 602069.0001.

For discussion of a possible relationship between variation in the PRKD1 gene and truncus arteriosus, see 605435.0001.

Ta-Shma et al. (2013) studied the consanguineous Iranian Jewish family in which 4 sisters had isolated truncus arteriosus, previously reported by Rein et al. (1990) and Rein and Sheffer (1994). Exome sequencing in the 1 surviving sister revealed homozygosity for a missense mutation in the PLXND1 gene (R1299C). The mutation was not detected in a first-cousin once-removed male with transposition of the great arteries; DNA was not available from a second cousin with double-outlet right ventricle and an unbalanced atrioventricular septal defect, or from her parents. The mutation was not found in 60 Iranian Jewish controls or in the Exome Variant Server or dbSNP (build 137) databases.

Animal Model

Patterson et al. (1993) studied the inheritance and embryology of conotruncal defects in the Keeshond breed of dogs. Defects in related Keeshonds included the same variety of conotruncal malformations found in man: conal ventricular septal defects, tetralogy of Fallot, and persistent truncus arteriosus type 1. In addition, some closely related dogs that were clinically normal had minor defects of the right ventricular outlet septum on postmortem examination. In initial breeding experiments inheritance of conotruncal defects was nonmendelian, but after selective inbreeding, results were consistent with a single gene defect. Penetrance was complete in homozygotes (conotruncal malformation of some degree present). Subclinical defects were present in 8% of heterozygotes. Embryologic studies showed that in affected embryos myocardial growth in the conotruncal region was retarded during the critical window when the conotruncal cushions fuse to form the conotruncal septum.