Most cases of Moebius syndrome are spontaneous, with no family history and no known genetic cause. In certain rare cases, the disorder has been associated with defects in chromosomes 3, 10, and 13. The Online Mendelian Inheritance in Man (OMIM) database lists the gene map locus 13q12.2-q13 as having significance for Moebius syndrome.

Mutations of the genes PLXND1 and REV3L have also been pinpointed as being associated with Moebius syndrome, based on animal studies showing nerve deficits typical of the syndrome when mutations of those genes are introduced in animals.

The significance of the genes PLXND1 and REV3L is as yet unknown, and their involvement sheds little light on the origins of the disease, since they regulate different pathways. PLXND1 is connected to neural migration during hindbrain development and REV3L plays a role in DNA translesion synthesis, a process which repairs damaged DNA.

PLXND1 has been mapped to chromosome 3q22.1. A novel mutation of PLXND1 was found in a patient diagnosed with Moebius syndrome in 2015. Sequencing in 103 patients with Moebius syndrome identified one additional patient with a mutation of PLXND1.

Conflicting studies have mapped REV3L to 1p33-32 and chromosome 6q21. A variant of REV3L leading to decreased levels of the normal REV3L transcript was found in a patient diagnosed with Moebius syndrome in 2015. That same variant was found in sequencing studies in 6 other unrelated patients with Moebius syndrome. In another study 103 patients with Moebius syndrome were sequenced and 2 were identified with a new variant of the REV3L gene.

In rare cases where Moebius syndrome shows a familial inheritance pattern, it is inherited as an autosomal dominant trait. That means a single copy of the abnormal gene results in the manifestation of the disease and there is a 50% chance of passing it on to the offspring.

In one family, six people in two generations had palsy of cranial nerves VI and/or VII with skeletal or digital malformations. Nine others had digital anomalies without the cranial nerve involvement. Another family had three members with features of Moebius syndrome with mental retardation. However, these cases of inheritance are very rare.

Defects of chromosomes 1p34 and 13q13 were found in one family which had facial diplegia and flexion finger contractures in 7 members across 3 generations. In another case, a two-year-old girl with Moebius syndrome had a deletion of 13q12.2. These cases suggest that chromosome 13q12.2-q13 is of significance.

One boy with symptoms of Moebius syndrome had a reciprocal translocation on chromosomes 1 and 2. The locus a 1p22 was switched with 2q21.1.

In another case, Moebius syndrome with cleft palate, dextrocardia, mandibular hypoplasia, brain volume loss, and Poland syndrome was associated with another translocation involving 1p22. In that case, it was switched with 11p13. These cases may implicate 1p22 as a genetic cause of Moebius syndrome.

Thus genetic mutation, or a combination of one or more mutations and environmental factors, may cause a developmental defect of the hindbrain. This may occur through mechanisms such as disruption of blood flow to the brain during fetal development, leading to the manifestation of Moebius syndrome at birth.

Reviewed by Liji Thomas, MD

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