The majority of Duane syndrome cases are sporadic in origin, with only approximately 10% of patients showing a familial pattern (running in families). Both dominant (most common) and recessive forms of DS have been documented. In some families with dominant DS, it has skipped a generation (shown reduced penetrance) and ranged in severity within the same family (shown variable expressivity). Most familial cases are not associated with other anomalies.

Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.

DS is a congenital cranial dysinnervation disorder (CCDD). Genetic, and possibly environmental factors, are known to play a role.

Data to support abnormal development of cranial nerve VI (abducens nerve) in DS come from neuropathological, neuroradiological and neurophysiological evidence. Neuropathological evidence comes from autopsies of individuals with DS. These autopsies show abnormal innervation of the lateral rectus muscle (the muscle that moves the eye outward toward the ear) and an absence / failure to develop normally of the abducens nerve (cranial nerve VI) which normally supplies the lateral rectus muscle. In place of the abducens nerve is a nerve branch from the oculomotor nerve (cranial nerve III) which normally supplies other ocular muscles. Recent neuroradiological studies in DS support the postmortem findings and also show, by magnetic resonance imaging (MRI) studies, an absence / failure to develop normally of the abducens nerve (cranial nerve VI).

Neurophysiological evidence for neuronal involvement in DS comes from electromyographic (EMG) studies which show that the medial and lateral recti muscles are electrically active in individuals with DS. When individuals with DS attempt to move their eyes inward, both of these muscles contract at the same time, resulting in the eyeball retracting inward (pulling in) and the eye opening narrowing.

In familial DS cases both eyes are more likely to be affected. DS type 2 is not seen in those with a positive family history nor in those patients where mutations in genes have been found to cause DS; suggesting a different cause.

Genetic linkage studies of two large DS families (with affected members having type 1 and/or type 3 DS inherited autosomal dominantly) without associated abnormalities established the location of a DS gene on chromosome 2. Mutations in the CHN1 gene are the cause, hyperactivating the a2-chimaerin protein. Mutations in the CHN1 gene have also been found in other families.

Autosomal dominant DS can also be due to mutations in the MAFB gene on chromosome 20, either as a loss of function or as a dominant negative mutation causing deafness and DS. The combination of focal segmental glomerulosclerosis (FSGS), DS and deafness has been shown to be due to a rare MAFB mutation.

A genetic cause for individuals with DRRS (Duane radial ray syndrome; Okihiro syndrome), that is Duane syndrome (unilateral or bilateral) with a skeletal change of radial dysplasia (unilateral or bilateral) ranging from most commonly thumb hypoplasia to most severely a phocomelic limb (similar to that seen in thalidomide cases), has been found. Other features include deafness, renal and ocular manifestations. Inheritance is autosomal dominant. Truncating mutations and SALL4 gene deletions have been identified in DRRS families and there is haploinsufficiency (the level of the protein is not sufficient for normal functioning). No SALL4 gene mutations were found in 25 sporadic cases of isolated DS.

DS can also be found as part of a complex autosomal recessive disorder that can include deafness, facial weakness, vascular malformations and leaning difficulties due to two mutations in the HOXA1 gene.

DS is also associated with mutations in the CDH2 gene which encodes for the N-cadherin protein. These mutations cause a syndromic neurodevelopmental disorder with global developmental delay and/or intellectual disability, axonal pathfinding defects including corpus callosum agenesis or hypoplasia, associated with ocular, cardiac and genital anomalies.

Cytogenetic results (a study of chromosomes) of individuals with Duane syndrome and other abnormalities have, in rare cases, shown abnormalities that suggest other locations for genes responsible for causing DS. Deletions of chromosomal material on chromosomes 1, 4, 5 and 8, and the presence of an extra marker chromosome thought to be derived from chromosome 22, have been documented in DS individuals. In addition, DS has been reported with chromosomal duplications.

Given the evidence that DS results from an absence / failure to develop normally of the abducens nerve (cranial nerve VI) and aberrant innervation, and that DS is associated with other anomalies in some patients, it is thought that DS results from a disturbance of normal embryonic development by either a genetic or an environmental factor at the time when the cranial nerves and ocular muscles are developing (between the third and sixth week of pregnancy).