In heterotaxy without cilia dysfunction, gene mutations have been found in six genes in patients with d-TGA: ACVR2B (activin receptor type II B), CFC1 (CRYPTIC), GDF1 (growth differentiation factor 1), LEFTY2 (left-right determination factor 2), MYH6 (alpha-cardiac myosin heavy chain), NODAL (nodal growth differentiation factor), and ZIC3 (Zic family member 3) (see Chap.38). The causality of ACVR2B is dubious in d-TGA because the two studies reporting variants [1, 2] found the same variant (p.Arg40His), which is found relatively frequently (0.5 %) in the world population. The two mutations found in CFC1 in d-TGA patients are strong candidates for disease-causing mutations because they change the reading frame [3] or alter a splicing site [4]. The frameshift mutation (c.522delC, p.Gly174del) is associated with heterotaxic anomalies including one case of right and one of left lung isomerism but also was found in a normal mother. In the study of Goldmuntz et al. [4], the CFC1 gene was screened in a series of 58 patients with d-TGA, and only the mutation causing abnormal splicing was found, yielding a prevalence of 2 % for CFC1 mutations in patients with d-TGA. Three GDF1 mutations were found in patients with d-TGA: two in a systematic screen (p.Cys227X and p.Ala318Thr) [6] and compound heterozygous mutations in a family with autosomal recessive inheritance and heterotaxy including right atrial isomerism [5]. Interestingly, one of the compound mutations is the p.Cys227X mutation. This mutation was found in controls suggesting that alone this mutation has either no impact or that it can predispose to isolated d-TGA, a phenotype less severe than heterotaxy, as observed when this mutation is associated with another mutation in trans.

The gene encoding the alpha-cardiac myosin heavy chain gene (MYH6) was found with a mutation in a girl with a d-TGA. This mutation changed a highly conserved histine to a glutamine (p.His252Gln). Her mother with a patent foramen ovale and her unaffected grandmother carried the mutation [20]. No other of the 49 TGA cases had a MYH6 mutation. Four putative heterozygous mutations were found in d-TGA patients in the NODAL gene (p.Glu203Lys, p.Gly260Arg, p.Arg275Cys, and a deletion/insertion) with demonstrated experimental deleterious consequence [8]. Surprisingly, the p.Gly260Arg mutation was found in five cases of Hispanic origin. This latter mutation and the p.Arg275Cys were also found in unaffected parents.

ZIC3 is the most studied gene in this series. It initially was identified through a positional cloning effort in families suffering from heterotaxy with X-linked inheritance [9]. At least nine additional ZIC3 mutations have been found in d-TGA patients [11–15, 21]. ZIC3 mutations have several specificities. They often are associated with midline anomalies (anal stenosis or imperforation, sacral agenesis, horseshoe kidney), extrahepatic biliary atresia, club feet, and mild facial dysmorphy. The inheritance is X-linked affecting boys, but there were examples of non-penetrance in males [11, 22] and on the contrary variable expression in females due to biased X-inactivation either revealing a recessive mutation (by inactivation of the normal allele) [13] or switching off a dominant mutation (by inactivation of the mutant allele) [1]. In this latter family, affected children had heterotaxy and CHD but no d-TGA. In addition to these nucleotide mutations, a cryptic chromosomal deletion was instrumental for the discovery of the role of ZIC3 gene in heterotaxy [10].