Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence

Eur J Hum Genet. 2015 Sep;23(9):1151-7. doi: 10.1038/ejhg.2014.273. Epub 2014 Dec 24.


Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Arthrogryposis / diagnosis
  • Arthrogryposis / genetics*
  • Arthrogryposis / pathology
  • Base Sequence
  • Female
  • Fetus
  • Founder Effect*
  • Gene Expression
  • Gene Frequency
  • Genes, Lethal
  • Genetic Testing
  • Homozygote
  • Humans
  • Male
  • Molecular Sequence Data
  • Motor Endplate / genetics*
  • Motor Endplate / pathology
  • Muscle Cells / metabolism
  • Muscle Cells / pathology
  • Mutation*
  • Netherlands
  • Pedigree
  • Prenatal Diagnosis
  • Primary Cell Culture
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptors, Cholinergic / chemistry
  • Receptors, Cholinergic / genetics*


  • Receptors, Cholinergic
  • MUSK protein, human
  • Receptor Protein-Tyrosine Kinases

Supplementary concepts

  • Pena Shokeir syndrome, type 1