ArticlePLoS genetics2011
Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice.
Article in PLoS genetics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 94 citations in OpenAlex.
- A novel homozygous splicing variant in FREM1 expands the phenotypic spectrum of BNAR syndrome: functional validation and successful PGT-M.BMC medical genomics · 2026Article
- Using a new analytic approach for genotyping and phenotyping chromosome 9p deletion syndrome.European journal of human genetics : EJHG · 2024Article
- Two novel mutations within FREM1 gene in patients with bifid nose.BMC pediatrics · 2023Article
- Joint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape.Nature communications · 2023Review
- Clinical interest of molecular study in cases of isolated midline craniosynostosis.European journal of human genetics : EJHG · 2023Article
- Frem1 activity is regulated by Sonic hedgehog signaling in the cranial neural crest mesenchyme during midfacial morphogenesis.Developmental dynamics : an official publication of the American Association of Anatomists · 2023Article
- Review
- Retroperitoneal liposarcoma and craniosynostosis: possible genomic relationship, case report, and literature review.Functional & integrative genomics · 2022Review
- Snrpb is required in murine neural crest cells for proper splicing and craniofacial morphogenesis.Disease models & mechanisms · 2022Article
- Article
- Incidence of persistent metopic suture in Australia: findings from 1034 three-dimensional computed tomography scans.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2021Article
- The Potential Role of FREM1 and Its Isoform TILRR in HIV-1 Acquisition through Mediating Inflammation.International journal of molecular sciences · 2021Review
- Facial cleft? The first case of manitoba-oculo-tricho-anal syndrome with novel mutations in China: a case report.BMC pediatrics · 2021Article
- Elevated expression of FREM1 in breast cancer indicates favorable prognosis and high-level immune infiltration status.Cancer medicine · 2020Article
- Article
- Integrated Transcriptome and Network Analysis Reveals Spatiotemporal Dynamics of Calvarial Suturogenesis.Cell reports · 2020Article
- Exome sequencing reveals a novel splice site variant in HUWE1 gene in patients with suspected Say-Meyer syndrome.European journal of medical genetics · 2020Article
- Comprehensive genetic analysis of 57 families with clinically suspected Cornelia de Lange syndrome.Journal of human genetics · 2019Article
- Mouse Models of Syndromic Craniosynostosis.Molecular syndromology · 2019Review
- Structural Genome Variations Related to Craniosynostosis.Molecular syndromology · 2019Review
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Authors and funding
22 authors at 9 institutions in 5 countries.
Funding
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.
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