GENOTYPE-PHENOTYPE CORRELATION FOR NUCLEOTIDE SUBSTITUTIONS IN THE IGII-IGIII LINKER OF FGFR2

Dominantly acting, allelic mutations of the fibroblast growth factor r eceptor 2 (FGFR2) gene have been described in five craniosynostosis sy ndromes, In Apert syndrome, characterised by syndactyly of the hands a nd feet, recurrent mutations of a serine-proline dipeptide (either Ser 252Trp or Pro253Arg) in the linker between the IgII and IgIII extracel lular immunoglobulin-like domains, have been documented in more than 1 60 unrelated individuals. We have identified three novel mutations of this dipeptide, associated with distinct phenotypes. A C-->T mutation that predicts a Ser252Leu substitution, ascertained in a boy with mild Crouzon syndrome (craniosynostosis with normal limbs) is also present in three clinically normal members of his family, A CG-->TT mutation that predicts a Ser252Phe substitution results in a phenotype consiste nt with Apert syndrome, Finally, a CGC-->TCT mutation that predicts a double amino acid substitution (Ser252Phe and Pro253Ser) causes a Pfei ffer syndrome variant with mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous s yndactyly. The observation that the Ser252Phe mutation causes Apert sy ndrome, whereas the other single or double substitutions are associate d with milder or normal phenotypes, highlights the exquisitely specifi c molecular pathogenesis of the limb and craniofacial abnormalities as sociated with Apert syndrome. Ser252Phe is the first noncanonical muta tion to be identified in this disorder, its rarity being explained by the requirement for two residues of the serine codon to be mutated. Th e description of independent, complex nucleotide substitutions involvi ng identical nucleotides is unprecedented, and we speculate that this may result from functional selection of FGFR mutations in sperm.