title: MuSK: a new target for lethal fetal akinesia deformation sequence (FADS).
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Wilbe
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Ekvall
authors.affiliation: Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Eurenius
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden Department of Pathology and Cytology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Katharina
authors.initials: K
authors.lastname: Ericson
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden Department of Pathology and Cytology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Olivera
authors.initials: O
authors.lastname: Casar-Borota
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Klar
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Adam
authors.initials: A
authors.lastname: Ameur
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Annerén
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Bondeson
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology; D001176:Arthrogryposis / Q000235:genetics* / Q000503:physiopathology; D059472:Exome / Q000235:genetics; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000503:physiopathology; D005333:Fetus / Q000503:physiopathology; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D009469:Neuromuscular Junction / Q000235:genetics* / Q000254:growth & development / Q000503:physiopathology; D010375:Pedigree; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011950:Receptors, Cholinergic / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D011950:Receptors, Cholinergic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases
keywords: Clinical genetics