Heterotaxy, Visceral, 1, X-Linked

A number sign (#) is used with this entry because X-linked heterotaxy-1 (HTX1) and multiple types of congenital heart defects-1 (CHTD1) are caused by mutation in the ZIC3 gene (300265) on chromosome Xq26.

Mutation in the ZIC3 gene can also cause VACTERL with or without hydrocephalus (VACTERLX; 314390), a disorder with overlapping features.

Description

Heterotaxy

Heterotaxy ('heter' meaning 'other' and 'taxy' meaning 'arrangement'), or situs ambiguus, is a developmental condition characterized by randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another (Srivastava, 1997). Heterotaxy is a clinically and genetically heterogeneous disorder.

Multiple Types of Congenital Heart Defects

Congenital heart defects (CHTD) are among the most common congenital defects, occurring with an incidence of 8/1,000 live births. The etiology of CHTD is complex, with contributions from environmental exposure, chromosomal abnormalities, and gene defects. Some patients with CHTD also have cardiac arrhythmias, which may be due to the anatomic defect itself or to surgical interventions (summary by van de Meerakker et al., 2011).

Reviews

Obler et al. (2008) reviewed published cases of double-outlet right ventricle and discussed etiology and associations.

Genetic Heterogeneity of Visceral Heterotaxy

See also HTX2 (605376), caused by mutation in the CFC1 gene (605194) on chromosome 2q21; HTX3 (606325), which maps to chromosome 6q21; HTX4 (613751), caused by mutation in the ACVR2B gene (602730) on chromosome 3p22; HTX5 (270100), caused by mutation in the NODAL gene (601265) on chromosome 10q22; HTX6 (614779), caused by mutation in the CCDC11 gene (614759) on chromosome 18q21; HTX7 (616749), caused by mutation in the MMP21 gene (608416) on chromosome 10q26; and HTX8 (617205), caused by mutation in the PKD1L1 gene (609721) on chromosome 7p12.

Genetic Heterogeneity of Multiple Types of Congenital Heart Defects

An X-linked form of CHTD, CHTD1, is caused by mutation in the ZIC3 gene on chromosome Xq26. CHTD2 (614980) is caused by mutation in the TAB2 gene (605101) on chromosome 6q25. A form of nonsyndromic congenital heart defects associated with cardiac rhythm and conduction disturbances (CHTD3; 614954) has been mapped to chromosome 9q31. CHTD4 (615779) is caused by mutation in the NR2F2 gene (107773) on chromosome 15q26. CHTD5 (617912) is caused by mutation in the GATA5 gene (611496) on chromosome 20q13. CHTD6 (613854) is caused by mutation in the GDF1 gene (602880) on chromosome 19p13.

Clinical Features

Mathias et al. (1987) described a black family in which 9 males in 2 generations had variable expression of altered laterality of visceral organs inherited in an X-linked recessive pattern. Eight males had complex congenital heart defects, including various manifestations of dextrocardia, ventricular septal defect (VSD), atrial septal defect (ASD), patent ductus arteriosus (PDA), transposition of the great arteries (TGA), valvular stenosis, and pulmonary artery hypoplasia. Four patients were reported as having complete situs inversus affecting the heart and visceral organs. Two patients had polysplenia and 2 had asplenia. Other less common features included sacral agenesis, extrahepatic biliary atresia, duodenal atresia, and posteriorly placed anus. In the preceding generation, 4 males were said to have been similarly affected. Eleven of the affected individuals died before age 2 years. Mathias et al. (1987) concluded that the anomalies resulted from an inability of the embryo to establish normal left-right axis asymmetry during development. In a follow-up of the family reported by Mathias et al. (1987), Casey et al. (1993) reported that 3 of the affected males were living, whereas the remainder died by 3 years of age, usually due to complications of cardiac malformations. Ciliary structure and function were normal, as were chromosome studies. All but one of the affected males had congenital heart disease, and all but one of the affected males manifested alterations of visceral situs, including asplenia or polysplenia, symmetric liver, intestinal malrotation, and abnormal lung lobation. Other midline malformations identified were sacral agenesis, posteriorly placed anus, rectal stenosis, meningomyelocele, cerebellar hypoplasia, and arhinencephaly. None of the 8 living obligate carrier females and none of their 7 presumably unaffected sons exhibited signs or symptoms of heterotaxy.

Soltan and Li (1974) reported a large kindred in which 4 males in 3 sibships had dextrocardia. One had corrected transposition of great arteries, ventricular septal defect and patent ductus arteriosus. A second had corrected transposition of the great arteries and VSD that closed spontaneously; a third had situs inversus viscerum, VSD, and pulmonic stenosis. The pedigree suggested X-linked recessive inheritance.

Mikkila et al. (1994) described X-linked laterality defects in 2 male cousins. One infant had a large atrial septal defect, anomalous inferior vena cava, and atresia of the extrahepatic bile ducts. He died at age 7.5 months due to cardiac and hepatic insufficiency. Postmortem examination showed nonrotation of the intestines, polysplenia, and absence of the coccyx. The cousin showed oligohydramnios at 21 weeks' gestation and the pregnancy was terminated. Postmortem examination showed bilobed right lung, atrial septal defect, agenesis of both kidneys and ureters, malrotation of the intestines, and imperforate anus. Both mothers, who were sisters, and the grandmother had a uterine septum and mild hypertelorism, which the authors suggested may have represented gene carrier manifestations.

Chhin et al. (2007) reported a brother and sister with X-linked visceral heterotaxy. The brother had dextro-looped transposition of the great arteries (D-TGA), single ventricle, pulmonary atresia, and polysplenia, whereas his affected sister had D-TGA, pulmonary and mitral atresia, and asplenia. Molecular analysis identified a mutation in the ZIC3 gene (300265.0009). The unaffected mother was a carrier. X-inactivation studies showed that the affected sister had skewed X-inactivation favoring expression of the mutant allele.

Mapping

Casey et al. (1993, 1993) performed linkage studies in a large family with X-linked heterotaxy reported by Mathias et al. (1987). All carrier females were heterozygous for marker DXS994 at Xq25-q26, which showed no recombinants with the disease locus, termed HTX1, and yielded a maximum lod score of 6.37 at theta = 0.0. Using microsatellite markers, they found that DXS994 showed no recombination in 20 informative meioses; flanking markers showed one or more recombinants. Multipoint linkage analysis resulted in a maximum lod score of 5.77 at 0.00 recombination frequency.

Ferrero et al. (1997) conducted further studies of the family reported by Casey et al. (1993) and found 2 recombinations that placed HTX1 between DXS300 and DXS1062, an interval spanning approximately 1.3 Mb on Xq26.2. To provide independent confirmation of HTX1 localization, they conducted a PCR-based search for submicroscopic deletions in this region in unrelated males with sporadic or familial heterotaxy. A cluster of sequence tagged sites failed to amplify in an individual who also had a deceased, affected brother. Fluorescence in situ hybridization identified the mother as a carrier of the deletion, which arose as a new mutation from the maternal grandfather. The deletion interval spanned 600 to 1,100 kb and lay wholly within the 1.3-Mb region identified by recombination.

Cytogenetics

In an Italian family in which affected males had a clinical phenotype ranging from VACTERL-H (314390) to X-linked visceral heterotaxy, Chung et al. (2011) identified a 1.3-Mb deletion of chromosome Xq26.3 including the ZIC3 gene. One male fetus had complex cardiac anomalies, including atrial isomerism, atrioventricular septal defect, double-outlet right ventricle, transposition of the great arteries, and subvalvular pulmonary stenosis. He also had enlarged kidneys, imperforate anus, right-sided stomach and pancreas, bilateral trilobed lungs, and asplenia, consistent with heterotaxy. Neuropathology was normal. Family history revealed 2 additional male family members who had died soon after birth. Both had imperforate anus, and postmortem examination of 1 showed hydrocephalus, vertebral defects, limb deformities, fused kidneys, complex cardiac anomalies, and duplication of the descending colon, but no heterotaxy. The mother of the first fetus, her mother, sister, grandmother, and daughter also carried the deletion. None of the females were affected, except perhaps the daughter, who had a small ventricular septal defect. The report demonstrated the wide intrafamilial phenotypic variability resulting from ZIC3 mutations.

Molecular Genetics

In affected members of the family with X-linked heterotaxy originally reported by Mathias et al. (1987), Gebbia et al. (1997) identified a heterozygous mutation in the ZIC3 gene (300265.0001). They identified 4 different mutations in the ZIC3 (see, e.g., 300265.0002 and 300265.0008) in 4 other families with X-linked heterotaxy.

Ware et al. (2004) screened the coding region of the ZIC3 gene in 194 unrelated patients, including 61 patients with classic heterotaxy, 93 patients with heart defects characteristic of heterotaxy, and 11 patients with situs inversus totalis. They identified 5 novel ZIC3 mutations in 3 classic heterotaxy kindreds (see, e.g., 300365.0004-300365.0005). They also identified a ZIC3 mutation in a female patient with sporadic heterotaxy limited to the heart (300265.0006) as well as in a patient with atrial septal defect and pulmonic stenosis, but no other heterotaxic malformations (300265.0007). Ware et al. (2004) concluded that the phenotypic spectrum of ZIC3 mutations should be expanded to include affected females and congenital heart defects not typical for heterotaxy. Screening of a cohort of patients with sporadic heterotaxy indicated that ZIC3 mutations account for approximately 1% of affected individuals.

Associations Pending Confirmation

For discussion of a possible association between variation in the SMAD2 gene and heterotaxy, see 601366.0001-601366.0002.

For discussion of a possible association between variation in the ANKS3 gene and heterotaxy, see 617310.0001.

Genotype/Phenotype Correlations

Megarbane et al. (2000) reported a Lebanese family in which 2 maternal cousins died very early in life from transposition of the great arteries associated with 1 or several other cardiac defects. Various minor midline defects were also observed, including hypertelorism and broad nasal base, but there were no situs abnormalities other than a persistent left superior vena cava in 1 cousin. Specifically, there were no spleen, lung, or cerebromeningeal defects. A maternal uncle of these 2 babies was born cyanotic and died on the third postnatal day. Both infants were found to have a mutation in the ZIC3 gene (300265.0003) which was predicted to have some residual activity. Another unaffected maternal uncle was found to have the mutation, suggesting incomplete penetrance. The authors noted that this was the first case of incomplete penetrance in a male carrier of a chromosome X mutation ever reported. Megarbane et al. (2000) suggested that the TGA observed in these infants was a left-right body axis defect confined to the heart and noted that previous reports indicated intrafamilial variability of the situs defect.