Genetics of craniosynostosis: genes, syndromes, mutations and genotype-phenotype correlations

Craniosynostosis is a very heterogeneous group of disorders, in the etiology of which genetics play an important role. Chromosomal alterations are important causative mechanisms of the syndromic forms of craniosynostosis accounting for at least 10% of the cases. Mutations in 7 genes are unequivocally associated with mendelian forms of syndromic craniosynostosis: FGFR1, FGFR2, FGFR3, TWIST1, EFNB1, MSX2 and RAB23. Mutations in 4 other genes, FBN1, POR, TGFBR1 and TGFBR2, are also associated with craniosynostosis, but not causing the major clinical feature of the phenotype or with an apparently low penetrance. The identification of these genes represented a great advance in the dissection of the genetics of craniosynostosis in the last 15 years, and today they explain the etiology of about 30% of the syndromic cases. The paucity in the identification of genes associated with this defect has partly been due to the rarity of familial cases. In contrast, very little is known about the molecular and cellular factors leading to nonsyndromic forms of craniosynostosis. Revealing the molecular pathology of craniosynostosis is also of great value for diagnosis, prognosis and genetic counseling. This chapter will review (1) the chromosomal regions associated with syndromic forms of the malformation, (2) the genes in which a large number of mutations have been reported by independent studies (FGFR1, FGFR2, FGFR3, TWIST1 and EFNB1) and (3) the molecular mechanisms and genotype-phenotype correlations of such mutations.