Heterotaxy arises from a failure of the embryo to establish normal left-right asymmetry and is known to affect 3% of infants with congenital heart disease. A recessive mutation causing heterotaxy was recovered in a mouse mutagenesis screen focused on congenital heart defects. Homozygote mutants exhibit abnormal situs in the thoracic and abdominal cavities. Dextrocardia, levocardia, or mesocardia was seen together with right pulmonary isomerism and complex structural heart defects in the single ventricle spectrum. A dominant chamber of left ventricular morphology positioned on the left or right is seen together with transposition of the great arteries. Right atrial isomerism with or without total anomalous pulmonary venous connection was observed in half of the mutants. Because ciliary motion at the embryonic node is required for the specification of laterality, we examined the tracheal epithelia of newborn mice as a proxy for the nodal cilia. However, videomicroscopy showed no defect in ciliary motion. Genome scanning using polymorphic microsatellite markers mapped the mutation to a 3.3 Mb interval on mouse chromosome 7. None of the genes previously described for familial heterotaxy were found in this interval, indicating a novel mutation in this mouse model of heterotaxy. (Pediatr Res 63: 9-14, 2008) T he specification of laterality is essential for survival of air breathing mammals because left-right asymmetry associated with the four chamber heart and great vessels is required for the normal separation of pulmonary and systemic circulation. Heterotaxy syndromes involve birth defects in which organ situs in the thoracic and abdominal cavity are altered in a discordant manner. They are associated with 3% of all congenital heart defects (CHD) (1), with the prevalence estimated at 1.4/10,000 births (2). Because a wide spectrum of complex structural heart malformations are frequently seen in conjunction with heterotaxy, the overall prognosis is often poor. Some of the cardiovascular malformations associated with heterotaxy syndromes include transposition of the great arteries, single ventricle defects, anomalous pulmonary venous connection, atrial septal defects, ventricular septal defects, and right ventricular outflow tract obstruction (3). Other associated findings include left-sided or bilobed liver, rightsided stomach with gut malrotation, and a high incidence of midline associated defects such as cleft lip/palate, encephalocele, and renal abnormalities (1,3,4).Despite detailed knowledge of the clinical presentations, the cause(s) of heterotaxy remains largely unknown. Data collected from the Baltimore-Washington Infant Study from 1980 to 1989 showed a potential association with a familial history of malformations (odds ratio ϭ 5.1, 95% confidence interval ϭ 2.0 -12.9), maternal diabetes, and geographic location, suggesting both environmental and genetic contributions to heterotaxy syndromes (5). In addition, it has been reported that approximately 10% of infants with heterotaxy have a family histor...

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