Abstract
Heterozygous mutations of the homeobox genes ALX4 and MSX2 cause skull defects termed enlarged parietal foramina (PFM) and cranium bifidum (CB); a single MSX2 mutation has been documented in a unique craniosynostosis (CRS) family. However, the relative mutational contribution of these genes to PFM/CB and CRS is not known and information on genotype–phenotype correlations is incomplete. We analysed ALX4 and MSX2 in 11 new unrelated cases or families with PFM/CB, 181 cases of CRS, and a single family segregating a submicroscopic deletion of 11p11.2, including ALX4. We explored the correlations between skull defect size and age, gene, and mutation type, and reviewed additional phenotypic manifestations. Four PFM cases had mutations in either ALX4 or MSX2; including previous families, we have identified six ALX4 and six MSX2 mutations, accounting for 11/13 familial, but only 1/6 sporadic cases. The deletion family confirms the delineation of a mental retardation locus to within 1.1 Mb region of 11p11.2. Overall, no significant size difference was found between ALX4- and MSX2-related skull defects, but the ALX4 mutation p.R218Q tends to result in persistent CB and is associated with anatomical abnormalities of the posterior fossa. We conclude that PFM caused by mutations in ALX4 and MSX2 have a similar prevalence and are usually clinically indistinguishable. Mutation screening has a high pickup rate in PFM, especially in familial cases, but is not indicated in CRS.
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Acknowledgements
We thank all the individuals and families who participated in this study; L Ades, D Bonthron, I Bueno, K Chrzanowska, CA Kim, T Letteboer, H Urbach, S Wall, and J Zschocke for patient referral; L Shaffer and L Potocki for sharing skull radiographs; N Elanko and S Twigg for general technical and DHPLC support; L Kearney and J Leach for assistance with FISH analysis; and K Clarke for DNA sequencing. This work was funded by the Alexander S Onassis Foundation and the Medical Research Council (LA Mavrogiannis), the Ministerio de Sanidad of Spain, Programa de Redes Temáticas de Investigación Cooperativa, FIS-ISCIII (Grants: C03/07 to FJ Ramos and JL Olivares; G03/098 to FJ Ramos), and the Wellcome Trust (AOM Wilkie). LA Mavrogiannis wishes to dedicate this work to the memory of his father, Anastasios.
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Mavrogiannis, L., Taylor, I., Davies, S. et al. Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype. Eur J Hum Genet 14, 151–158 (2006). https://doi.org/10.1038/sj.ejhg.5201526
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DOI: https://doi.org/10.1038/sj.ejhg.5201526
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