Fetal Akinesia Deformation Sequence 3

A number sign (#) is used with this entry because of evidence that fetal akinesia deformation sequence-3 (FADS3) is caused by homozygous mutation in the DOK7 gene (610285) on chromosome 4p16. One such family has been reported.

Mutation in the DOK7 gene can also cause a form of congenital myasthenic syndrome (CMS10; 254300).

Description

The fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous constellation of features including fetal akinesia, intrauterine growth retardation, arthrogryposis, and developmental anomalies, including lung hypoplasia, cleft palate, and cryptorchidism (Vogt et al., 2009). It shows phenotypic overlap with the lethal form of multiple pterygium syndrome (see 253290).

For a general phenotypic description and a discussion of genetic heterogeneity of FADS, see 208150.

Clinical Features

Vogt et al. (2009) reported 3 sibs from a consanguineous Bengali family with a severe lethal form of myasthenia and a mutation in the DOK7 gene. The first fetus was stillborn at 32 weeks' gestation and had signs of a neuromuscular developmental abnormality. The second fetus miscarried spontaneously at 22 weeks' gestation. Postmortem examination showed downslanting palpebral fissures, short neck, small jaw, overlapping fingers, and rocker-bottom feet. The third fetus showed no fetal movements at 24 weeks' gestation. None had evidence of pterygia. Muscle biopsy in 1 fetus showed muscle denervation with immature irregularly shaped muscle cells. The findings were consistent with a clinical diagnosis of FADS. Vogt et al. (2009) concluded that complete loss of DOK7 results in a lethal fetal akinesia phenotype that is at the more severe end of a spectrum of disorders involving acetylcholine receptors.

Molecular Genetics

In 3 sibs from a consanguineous Bengali family with a severe form of myasthenia resulting in fetal death, Vogt et al. (2009) identified a homozygous truncating mutation in the DOK7 gene (610285.0009).