Wilbe Maria, Ekvall Sara, Eurenius Karin, Ericson Katharina, Casar-Borota Olivera, Klar Joakim, Dahl Niklas, Ameur Adam, Annerén Göran, Bondeson Marie-Louise
Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
J Med Genet. 2015 Mar;52(3):195-202. doi: 10.1136/jmedgenet-2014-102730. Epub 2015 Jan 22.
Fetal akinesia deformation sequence syndrome (FADS, OMIM 208150) is characterised by decreased fetal movement (fetal akinesia) as well as intrauterine growth restriction, arthrogryposis, and developmental anomalies (eg, cystic hygroma, pulmonary hypoplasia, cleft palate, and cryptorchidism). Mutations in components of the acetylcholine receptor (AChR) pathway have previously been associated with FADS.
We report on a family with recurrent fetal loss, where the parents had five affected fetuses/children with FADS and one healthy child. The fetuses displayed no fetal movements from the gestational age of 17 weeks, extended knee joints, flexed hips and elbows, and clenched hands. Whole exome sequencing of one affected fetus and the parents was performed. A novel homozygous frameshift mutation was identified in muscle, skeletal receptor tyrosine kinase (MuSK), c.40dupA, which segregated with FADS in the family. Haplotype analysis revealed a conserved haplotype block suggesting a founder mutation. MuSK (muscle-specific tyrosine kinase receptor), a component of the AChR pathway, is a main regulator of neuromuscular junction formation and maintenance. Missense mutations in MuSK have previously been reported to cause congenital myasthenic syndrome (CMS) associated with AChR deficiency.
To our knowledge, this is the first report showing that a mutation in MuSK is associated with FADS. The results support previous findings that CMS and/or FADS are caused by complete or severe functional disruption of components located in the AChR pathway. We propose that whereas milder mutations of MuSK will cause a CMS phenotype, a complete loss is lethal and will cause FADS.
胎儿运动减少变形序列综合征（FADS，OMIM 208150）的特征是胎儿运动减少（胎儿运动不能）以及子宫内生长受限、关节挛缩和发育异常（如颈部水囊瘤、肺发育不全、腭裂和隐睾）。乙酰胆碱受体（AChR）途径成分的突变先前已与FADS相关。
我们报告了一个反复发生胎儿丢失的家庭，该家庭中父母有5个患有FADS的患病胎儿/儿童和1个健康儿童。这些胎儿从孕17周起就没有胎动，膝关节伸直，髋关节和肘关节屈曲，双手紧握。对一名患病胎儿及其父母进行了全外显子组测序。在肌肉骨骼受体酪氨酸激酶（MuSK）中鉴定出一种新的纯合移码突变，c.40dupA，该突变在家族中与FADS共分离。单倍型分析揭示了一个保守的单倍型块，提示为奠基者突变。MuSK（肌肉特异性酪氨酸激酶受体）是AChR途径的一个成分，是神经肌肉接头形成和维持的主要调节因子。先前有报道称MuSK中的错义突变会导致与AChR缺乏相关的先天性肌无力综合征（CMS）。
据我们所知，这是首次报道MuSK突变与FADS相关。这些结果支持了先前的发现，即CMS和/或FADS是由AChR途径中成分的完全或严重功能破坏引起的。我们提出，虽然MuSK的轻度突变会导致CMS表型，但完全缺失是致命的，会导致FADS。
