4. Discussion
MuSKis located in Cytogenetic location:9q31.3, Genomic coordinates(GRCh38): chr9:110,668,188-110,806,632. A mutation in MuSK associated with autosomal recessive FADS was firstly reported in 2015, which presented a family trio in inheritance mode with an insertion mutation in exon 1 of MuSK . It resulted in prematurely terminate translation [Wilbe et al.,2015]. MuSK is a receptor tyrosine kinase expressed on the muscle cell membrane [DeChiara et al.,1996; Glass et al.,1996]. Acetylcholine(ACh) is a medium for signal transmission. The combination of ACh and acetylcholine receptors (AChR) can cause muscle contractions. MuSK is a component of the AChR pathway and a major regulator of neuromuscular connection formation and maintenance[Wilbe et al.,2015]. The mutation of MuSK gene can lead to the decreased expression of mRNA level and stability of Musk protein level. When AChR was decreased, it led to muscle contractility disorder. Up to December 31, 2019, four families with 24 patients with FADS had been reported carrying MuSK  mutation(Table1). Two families carried homozygous mutations, and one carried a compound heterozygous mutation [Wilbe et al.,2015; Tan-Sindhunata et al.,2015; Li et al.,2019]. Of the 24 patients, 45.8% (11/24) selected termination of pregnancy, 4.1%(1/24) developed intrauterine fetal death, one was stillborn, and 45.8% (11/24) died after birth. The longest survival time was five days. No survival cases were reported. These pregnancy outcomes were consistent with previous studies. Wible et al. knocked out the Mouse MuSKgene and conducted animal experiments. They identified that loss of function mutations occur in MuSK is lethal. In this case, the nonsense mutation(NM-005592.3) c.790C > T is expected to cause the encoded protein to truncate and lose its normal function. The missense mutation (NM-005592.3) c.296G >T is expected to change the amino acid at position 99 of the encoded protein from Cys to Phe. Various bioinformatics tools predict this amino acid change with potential pathogenic effects. MuSK has an important biological function, and it is highly conserved across most species. MuSK protein contains IgG-like domains, extracellular domain,Frizzled-like cysteine-rich domain,atransmembrane domain and a cytoplasmic domain[Stiegler et al.,2009]. In this case, the two mutations located in Ig-like1/3 in an extracellular domain. The extracellular domain of MuSK plays an important role in AChR cluster, which can lead to muscle contractility disorder. Based on the fetus’ ultrasound examination, we identified the two mutations are pathogenic variation. The fetal ultrasound manifestations of the previous twice pregnancies of this patient were very similar to this one, so we speculated that the previous twice fetuses perhaps carried the same pathogenic MuSKgene.