title: Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence.
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.
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: M Brigita
authors.initials: MB
authors.lastname: Tan-Sindhunata
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Inge B
authors.initials: IB
authors.lastname: Mathijssen
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Margriet
authors.initials: M
authors.lastname: Smit
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.affiliation: Department of Obstetrics and Gynaecology, Research Institute MOVE, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Johanna I
authors.initials: JI
authors.lastname: de Vries
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: J Patrick
authors.initials: JP
authors.lastname: van der Voorn
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Irma
authors.initials: I
authors.lastname: Kluijt
authors.affiliation: Department of Obstetrics and Gynaecology, Research Institute MOVE, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Marleen A
authors.initials: MA
authors.lastname: Hagen
authors.affiliation: Department of Clinical Genetics, MUMC, Maastricht, The Netherlands.
authors.forename: Eveline W
authors.initials: EW
authors.lastname: Blom
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Sistermans
authors.affiliation: 1] Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands [2] Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Quinten
authors.initials: Q
authors.lastname: Waisfisz
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Weiss
authors.affiliation: 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.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Groffen
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001176:Arthrogryposis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D005260:Female; D005333:Fetus; D018703:Founder Effect; D015870:Gene Expression; D005787:Gene Frequency; D005804:Genes, Lethal; D005820:Genetic Testing; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009045:Motor Endplate / Q000235:genetics* / Q000473:pathology; D032342:Muscle Cells / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009426:Netherlands; D010375:Pedigree; D011296:Prenatal Diagnosis; D061251:Primary Cell Culture; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000235:genetics*
chemical_list: D011950:Receptors, Cholinergic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases