Rapid detection of de novo P253R mutation in FGFR2 using uncultured amniocytes in a pregnancy affected by polyhydramnios, Blake's pouch cyst, and Apert syndrome.
In Apert syndrome, characterised by syndactyly of the hands and feet, recurrent mutations of a serine-proline dipeptide (either Ser252Trp or Pro253Arg) in the linker between the IgII and IgIII extracellular immunoglobulin-like domains, have been documented in more than 160 unrelated individuals.
Unlike the majority of FGFR2 mutations, S252W and P253RAS mutations and a D321A PS mutation retain ligand-dependency and are also associated with severe limb pathology.
The arginine residue at position 253 in the linker region between the Ig-like domains D2 and D3 in the wild type fly and worm sequences is particularly striking, as the Pro253Arg mutation in humans is responsible for Apert syndrome.
Interestingly, two FGFR2 mutations creating cysteine residues (W290C and Y340C) caused severe forms of PS while conversion of the same residues into another amino-acid (W290G/R, Y340H) resulted in Crouzon phenotype exclusively.
FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing.
A genotype-specific surgical approach for patients with Pfeiffer syndrome due to W290C pathogenic variant in FGFR2 is associated with improved developmental outcomes and reduced mortality.
Five different mutations were found including two novel (W290G, C342W) and two previously reported, recurrent mutations for Crouzon syndrome (A344A, S354C), and one new mutation for Jackson-Weiss syndrome (C342R).