title: Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice.
abstract: The premature fusion of the paired frontal bones results in metopic craniosynostosis (MC) and gives rise to the clinical phenotype of trigonocephaly. Deletions of chromosome 9p22.3 are well described as a cause of MC with variably penetrant midface hypoplasia. In order to identify the gene responsible for the trigonocephaly component of the 9p22.3 syndrome, a cohort of 109 patients were assessed by high-resolution arrays and MLPA for copy number variations (CNVs) involving 9p22. Five CNVs involving FREM1, all of which were de novo variants, were identified by array-based analyses. The remaining 104 patients with MC were then subjected to targeted FREM1 gene re-sequencing, which identified 3 further mutant alleles, one of which was de novo. Consistent with a pathogenic role, mouse Frem1 mRNA and protein expression was demonstrated in the metopic suture as well as in the pericranium and dura mater. Micro-computed tomography based analyses of the mouse posterior frontal (PF) suture, the human metopic suture equivalent, revealed advanced fusion in all mice homozygous for either of two different Frem1 mutant alleles, while heterozygotes exhibited variably penetrant PF suture anomalies. Gene dosage-related penetrance of midfacial hypoplasia was also evident in the Frem1 mutants. These data suggest that CNVs and mutations involving FREM1 can be identified in a significant percentage of people with MC with or without midface hypoplasia. Furthermore, we present Frem1 mutant mice as the first bona fide mouse model of human metopic craniosynostosis and a new model for midfacial hypoplasia.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Cox
authors.forename: A Murat
authors.initials: AM
authors.lastname: Maga
authors.forename: Kieran M
authors.initials: KM
authors.lastname: Short
authors.forename: Fenny
authors.initials: F
authors.lastname: Wiradjaja
authors.forename: Irene M
authors.initials: IM
authors.lastname: Janssen
authors.forename: Fernanda
authors.initials: F
authors.lastname: Jehee
authors.forename: Debora
authors.initials: D
authors.lastname: Bertola
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Garima
authors.initials: G
authors.lastname: Yagnik
authors.forename: Kiyotoshi
authors.initials: K
authors.lastname: Sekiguchi
authors.forename: Daiji
authors.initials: D
authors.lastname: Kiyozumi
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Carlo
authors.initials: C
authors.lastname: Marcelis
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cunningham
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Anderson
authors.forename: Simeon A
authors.initials: SA
authors.lastname: Boyadjiev
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Passos-Bueno
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Ian
authors.initials: I
authors.lastname: Smyth
authors.forename: Michael F
authors.initials: MF
authors.lastname: Buckley
authors.forename: Tony
authors.initials: T
authors.lastname: Roscioli
mesh_terms: D000818:Animals; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D003393:Cranial Sutures / Q000002:abnormalities / Q000473:pathology; D003398:Craniosynostoses / Q000235:genetics*; D016207:Cytokines / Q000235:genetics; D056915:DNA Copy Number Variations; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010641:Phenotype; D018123:Receptors, Interleukin / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: C514249:CER1 protein, human; D016207:Cytokines; D016326:Extracellular Matrix Proteins; C548979:Frem1 protein, human; C492585:Frem1 protein, mouse; D018123:Receptors, Interleukin