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

MB Tan-Sindhunata, IB Mathijssen, M Smit… - European Journal of …, 2015 - nature.com
MB Tan-Sindhunata, IB Mathijssen, M Smit, F Baas, JI De Vries, JP Van Der Voorn, I Kluijt…
European Journal of Human Genetics, 2015nature.com
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 …
Abstract
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.
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