There is also overlap between genes associated with situs ambiguus and primary ciliary dyskinesia, likely due to the important role of cilia is establishing left-right asymmetry. The planar cell polarity has an important role in positioning these cilia, and thus genes within this pathway are increasingly associated with situs ambiguus.Disrupted mitochondria function has also been recently linked to heterotaxy. Pathophysiology
Molecular and cellular mechanism
Several genes have been identified in normal development of the right-left axis. These genes have been extensively researched. Gene mutations that lead to atrial isomerism is a growing area of research. Mutations in genes that encode proteins in the TGF-beta pathway, including NODAL, NKX2-5, and ZIC3, have been linked to tetralogy of Fallot and hypoplastic left heart syndrome. Mutations in the ZIC3 gene, which encodes a zinc finger family transcription factor, is linked to a 50% risk of atrial isomerism in families. It is also an X-linked disorder, so testing for ZIC3 mutations is highly encouraged in male births.The most prevalent and best characterized genetic associations of heterotaxy include:

Classical pathology
Cardiac looping malformations:
Fallots tetralogy
transposition of the great vessels
Ventricular and atrial septal defects. Deranged abdominal organ asymmetry:
The stomach and spleen are prone to isolated reversal
The stomach, liver, and a single adrenal gland are occasionally found in the midline. Organ malformations:
asplenia and polysplenia often lead to sepsis
More rarely, the head of the pancreas fails to form
Horseshoe kidneys develop, which can lead to cancer, kidney stones, and/or infection. Malrotation errors cause volvulus and/or faulty peritoneal attachments, which completely obstruct the bowel.
Heart failure is often a concern because the inferior vena cava is disrupted due to the inappropriate morphology of the left ventricle to support the vena cava. Conductive nodes and tissues
Abnormal development of the heart results in impaired doubles of conductive nodes, as well as faulty electrical fibers throughout the ventricles. Individuals with right atrial isomerism develop two sinoatrial nodes, as they have 2 mirrored right atria, whereas those with left atrial isomerism fail to develop a sinus node at all. Thus, patients with left atrial isomerism are more likely to experience atrial fibrillation, or irregular rapid heart beat, and abnormal heart rhythm, known as atrial flutter. Development of the atrioventricular node and bundle of His largely depends on physiological looping of the ventricles. Abnormal looping of the ventricles contributes to arrhythmia and heart block in fetuses. Bronchial tree and lungs
Isomerism of the bronchial tree is not typically damaging and presents no significant clinical complications. Pulmonary valve stenosis results in issues of blood flow to the lungs. Abdominal organs
Abdominal organs, including the liver, stomach, intestinal tract, and spleen may be randomly arranged throughout the left-right axis of the body. Distribution of these organs largely dictates treatment, clinical outcomes, and further evaluation. The liver is typically symmetrical across the left-right axis in patients with situs ambiguus, which is abnormal. A majority of left atrial isomeric patients have defects throughout the biliary tree, which is responsible for bile production, even when the gall bladder is functional and morphologically normal.