Alternative titles; symbols
ORPHA: 3366;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9p22.3 | Trigonocephaly 2 | 614485 | Autosomal dominant | 3 | FREM1 | 608944 |
A number sign (#) is used with this entry because of evidence that trigonocephaly-2 (TRIGNO2) is caused by heterozygous mutation in the FREM1 gene (608944) on chromosome 9p22.
Trigonocephaly occurs predominantly as a nonsyndromic craniosynostosis and has an estimated prevalence of between 1:15,000 and 1:68,000 live births (summary by Vissers et al., 2011).
For a discussion of genetic heterogeneity of isolated trigonocephaly, see TRIGNO1 (190440).
A syndromic form of trigonocephaly is associated with monosomy for an 8-Mb interval of chromosome 9p22.3 (see 158170).
Using high-density chromosome 9-specific arrays, Vissers et al. (2011) reanalyzed the deletion breakpoints of 4 patients with syndromic metopic craniosynostosis and de novo copy number variation involving chromosome 9p22.3 (see 158170), 3 of whom were previously studied by Swinkels et al. (2008). Two of the patients' rearrangements contained deletion breakpoints within the FREM1 gene (608944), deleting exons 7 to 37 and 10 to 37, respectively; in the remaining 2 patients, the FREM1 gene was entirely deleted. Vissers et al. (2011) concluded that the CNV data were consistent with a model in which haploinsufficiency of FREM1 is associated with trigonocephaly.
Vissers et al. (2011) analyzed the FREM1 gene in 104 patients with nonsyndromic metopic craniosynostosis and identified heterozygous missense mutations in 3 patients (608944.0008 and 608944.0009) that were not found in control chromosomes. Incomplete penetrance was demonstrated in 2 of the families, in which family members who also carried the mutation in heterozygosity displayed minimal or no craniofacial abnormalities.
Vissers et al. (2011) studied C57BL/6J mice carrying the ENU-generated Frem1(bat) mutation, which is thought to represent a hypomorphic allele rather than a null allele. Morphometric analysis of skulls from homozygous and heterozygous mutant mice demonstrated craniofacial malformations consistent with the craniofacial features seen in the 9p22 deletion syndrome (158170), in particular metopic craniosynostosis and midface asymmetry and/or hypoplasia. The penetrance of the phenotypes in mice correlated to mutant gene dosage.
Swinkels, M. E. M., Simons, A., Smeets, D. F., Vissers, L. E., Veltman, J. A., Pfundt, R., de Vries, B. B. A., Faas, B. H. W., Schrander-Stumpe l, C. T. R. M., McCann, E., Sweeney, E., May, P., Draaisma, J. M., Knoers, N. V., van Kessel, A. G., van Ravenswaaij-Arts, C. M. A. Clinical and cytogenetic characterization of 13 Dutch patients with deletion 9p syndrome: delineation of the critical region for a consensus phenotype. Am. J. Med. Genet. 146A: 1430-1438, 2008. [PubMed: 18452192] [Full Text: https://doi.org/10.1002/ajmg.a.32310]
Vissers, L. E. L. M., Cox, T. C., Maga, A. M., Short, K. M., Wiradjaja, F., Janssen, I. M., Jehee, F., Bertola, D., Liu, J., Yagnik, G., Sekiguchi, K., Kiyozumi, D., and 10 others. Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. PLoS Genet. 7: e1002278, 2011. Note: Electronic Article. [PubMed: 21931569] [Full Text: https://doi.org/10.1371/journal.pgen.1002278]