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

M.B. Tan-Sindhunata, I.B. Matthijssen, M. Smit, F. Baas, J.I.P. de Vries, J.P. van der Voorn, I. Kluijt, M.A. Hagen, E.W. Blom, E.A. Sistermans, J.E. Heijboer-Meijers, Q. Waisfisz, M.M. Weiss, A.J.A. Groffen

Research output: Contribution to JournalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)1151-1157
JournalEuropean Journal of Human Genetics
Issue number9
Publication statusPublished - 2015


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