Laterality Defects, Autosomal Dominant

Clinical Features

Heterotaxy results from failure to establish normal left-right (L-R) asymmetry during embryonic development. Other than X-linked visceral heterotaxy (306955), most familial cases are thought to be autosomal recessive. Casey et al. (1996) identified a family in which 4 individuals from 3 generations showed laterality defects. Two had complete reversal of normal laterality (situs inversus) (270100), while 2 others had asplenia, midline liver, and complex cardiac malformations (situs ambiguus). Two obligate gene carriers were anatomically normal (situs solitus). Male-to-male transmission confirmed autosomal inheritance.

Vitale et al. (2001) reported a 5-generation family with abnormality of laterality. Seven individuals were affected, with situs inversus present in 4 and situs ambiguus in 3. There was no male-to-male transmission, but males and females appeared to be similarly affected and linkage analysis excluded an X chromosome locus. Vitale et al. (2001) suggested that an autosomal dominant pattern of inheritance was likely; under this model, 4 apparently normal individuals were obligate gene carriers. Two additional family members had isolated cardiac defects without any other L/R abnormality: one had ventricular inversion in combination with transposition of the great arteries, whereas the other had hypoplastic left heart syndrome.

Maclean and Dunwoodie (2004) reviewed the evidence that mutations in genes and pathways critical for L-R patterning are involved in common isolated congenital malformations such as congenital heart disease, biliary tract anomalies, renal polycystic disease, and malrotation of the intestine, indicating that disorders of L-R development are far more common than a 1 in 10,000 incidence of heterotaxia might suggest. They reviewed data from mammalian (human and mouse) L-R patterning disorders to provide a clinically oriented perspective useful in this 'diagnostically challenging area.'

Wessels et al. (2008) described 9 affected members of a 3-generation family with a combination of cardiac abnormalities and left isomerism, inherited in an autosomal dominant pattern. The cardiac abnormalities included noncompaction of the ventricular myocardium, bradycardia, pulmonary valve stenosis, and secundum atrial septal defect; the laterality sequence anomalies included left bronchial isomerism, azygous continuation of the inferior vena cava, polysplenia, and intestinal malrotation. The common finding in all affected members was ventricular noncompaction with conduction abnormalities.

Inheritance

Male-to-male transmission of laterality defects in the family reported by Casey et al. (1996) confirmed autosomal dominant inheritance.

Mapping

Vitale et al. (2001) performed linkage analysis in a 5-generation family with abnormality of laterality and obtained a maximum lod score of 2.95 at theta = 0 for marker D6S426 on 6p21. Recombination events defined an interval of 32 cM bounded by markers D6S105 and D6S1960.

Wessels et al. (2008) performed linkage analysis in a 3-generation family with cardiac abnormalities and left isomerism and found linkage to chromosome 6p24.3-p21.2 between D6S470 (telomeric) and D6S1610 (centromeric), with a maximum lod score of 2.7 at D6S276. This linkage interval overlapped with that previously reported by Vitale et al. (2001) in a family with abnormality of laterality; the smallest region of overlap was a 9.4-cM (12-Mb) interval between D6S105 and D6S1610.