Defects in the determination of left-right asymmetry.

Left and right in the embryo is automatically defined by the formation of the anteroposterior and dorsoventral axes. In an asymmetrical organism, specification of the left-right axis must incorporate two distinct processes, the generation of asymmetry and its orientation or handedness. The orientation of the heart and abdominal organs in vertebrates is non-random and highly conserved both across and within species.' Reversal of orientation may occur without concomitant defects in the generation of asymmetry. However, failure to generate asymmetry is almost always combined with abnormal orientation. The first overt breaking of symmetry across the midline of the embryo occurs when the primitive heart tube loops to the right but subtle asymmetries are evident as early as the primitive streak stage.2 A spectrum of malformations, ranging from complete reversed situs to complete failure to establish asymmetry, is seen in man and it is likely that their aetiology and genetic basis will turn out to be extremely heterogeneous. Nevertheless, genetic animal models indicate that a spectrum of lateralisation defects can be produced by a single defective gene. In man most cases of disturbed laterality are sporadic but there are several well recognised syndromes which occur in families. The usual orientation of the heart and abdominal organs is known as situs solitus. Situs inversus refers to a perfect reversal of situs solitus with a left heart loop. Any arrangement other than situs solitus or situs inversus, that is, random orientation of different organs, is known as heterotaxy or situs ambiguus. The estimated prevalence of complete situs inversus is around 1 in 10 OOO.3 An increased incidence of parental consanguinity has been found, suggesting that a proportion of cases are autosomal recessive.`5 The incidence ofheterotaxy is generally much lower,34 but interestingly was found to be equal to that of situs interversus in an inbred Bedouin population (1 in 4000).6 Cardiac anomalies are found in between 3 and 9% of cases of complete situs inversus. Heterotaxy, on the other hand, is almost invariably associated with complex cardiovascular malformation as well as splenic and a variety of gastrointestinal anomalies. In the present state of knowledge, the most logical way to categorise defects in laterality is on the basis of ciliary function. (JtMed Genet 1996;33:498-503)