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.

M Brigita Tan-Sindhunata ¹, Inge B Mathijssen ², Margriet Smit ¹, Frank Baas ³, Johanna I de Vries ⁴, J Patrick van der Voorn ⁵, Irma Kluijt ², Marleen A Hagen ⁴, Eveline W Blom ⁶, Erik Sistermans ¹, Hanne Meijers-Heijboer ⁷, Quinten Waisfisz ¹, Marjan M Weiss ¹, Alexander J Groffen ⁸

Affiliations

1 Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
2 Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
3 Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
4 Department of Obstetrics and Gynaecology, Research Institute MOVE, VU University Medical Center, Amsterdam, The Netherlands.
5 Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
6 Department of Clinical Genetics, MUMC, Maastricht, The Netherlands.
7 1] Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands [2] Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
8 1] Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands [2] Department of Functional Genomics, Center for Neurogenomics and Cognition Research, VU University, Amsterdam, The Netherlands.

PMID: 25537362 DOI: 10.1038/ejhg.2014.273

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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