1.     Introduction
Fetal akinesia deformation sequence syndrome (FADS)(OMIM 208150) with alternative nomenclature include multiple congenital contractures(MCC)and arthrogryposis multiplex congenital(AMC), is a recessive single gene disease with genetic heterogeneity and was  reported by Pena and Shokeir in 1974 for the first time[Pena & Shokeir, 1974]. The affected fetus appears a series of abnormal ultrasonographic manifestations, including reduced fetal motion (fetal akinesia), intrauterine growth restriction, joint flexion, and other deformities such as cystic edema disease, pulmonary hypoplasia, cleft palate, and cryptorchidism, which may be caused by exogenous (extra-fetal) or endogenous (fetal) disease. Extrinsic etiologies of FADS include uterine abnormalities, a maternal disease or multifetal pregnancy, and the inherent aetiology mainly is from the genetic factor. For FADS, the genetic factor is primarily caused by genetic variation associated with the neuromuscular junction (NMJ). It has been suggested FADS most often inherited as an autosomal recessive trait [Prontera et al.,2006], and X-linked or dominant inheritance [Tolmie et al.,1987; Mckeown,&Harris, 1988]. Several genes involved in the NMJ have been previously reported associated with FADS, such as DOK7 (OMIM 610285) [Vogt et al.,2009], RAPSN (OMIM601592)[Vogt et al.,2008], MuSK(OMIM601296)[Wilbe et al.,2015] and AGRN(OMIM103320 ) [Geremek et al.,2020].
Since two homozygous and a compound heterozygous mutations in MuSK (Muscle-specific tyrosine kinase receptor) have been reported to cause FADS: a homozygous mutation c.40dupA[Wilbe et al.,2015], a missense variant c.1724T4C; p. (Ile575Thr) [Tan-Sindhunata et al.,2015] and a compound heterozygous c.220C>T and c.421delC [Li et al.,2019], in this report, by using the whole exon sequencing upon the latest affected fetus and the couples from a family with thrice unfavourable pregnancy, we detected a novel compound heterozygous mutation in MuSK that caused a series clinical features of FADS in a fetus.
2. Medical Record
A 30-year-old Chinese pregnant woman, gravida 3, para 0, abortus 2, came to our centre for consultation due to twice adverse birth histories at the 23rd gestational week. The first pregnancy was in 2015, without any fetal movement at 24th gestational weeks yet. A detailed ultrasound examination revealed the fetal joint contracture, stomach unvisualized, fetal hydrops and left equinovarus. Karyotype analysis was performed on amniotic fluid cells, with a negative result. The second pregnancy was in 2017, ultrasound examination of the fetus at 20th week of gestation showed that the fetal stomach unvisualized, akinesia, pulmonary hypoplasia, double equinovarus and heart shifting to the left. Both of the last two pregnancies were terminated.
A detailed ultrasound examination was performed for this pregnancy, and the results were shown as follow: lack of limb movements, left pulmonary hypoplasia, right pleural effusion, atrial septal defects, small stomach, subcutaneous oedema, clenched fingers, all limbs contracture, and polyhydramnios (Figure 1). Then Amniocentesis was subjected to chromosome karyotype analysis and chromosomal microarray analysis, and the results were negative. Though, the couples chose to terminate the pregnancy, because of the fetus showing multiple abnormalities with poor prognosis. Furthermore, we carried out the whole exon sequencing on the family trio (maternal blood, paternal blood and fetal musculus gastrocnemius) (Figure 2).