Background Fraser syndrome (FS) is a autosomal recessive malformation syndrome characterised by cryptophthalmos, syndactyly and urogenital defects. FS is a genetically heterogeneous condition. Thus far, mutations in FRAS1 and FREM2 have been identified as cause of FS. Both FRAS1 and FREM2 encode extracellular matrix proteins that are essential for the adhesion between epidermal basement membrane and the underlying dermal connective tissues during embryonic development. Mutations in murine Grip1, which encodes a scaffolding protein that interacts with Fras1/Frem proteins, result in FS-like defects in mice.

Objective To test GRIP1 for genetic variants in FS families that do not have mutations in FRAS1 and FREM2.

Methods and results In three unrelated families with parental consanguinity, GRIP1 mutations were found to segregate with the disease in an autosomal recessive manner (donor splice site mutation NM_021150.3:c.2113+1G→C in two families and a 4-bp deletion, NM_021150.3:c.1181_1184del in the third). RT-PCR analysis of the GRIP1 mRNA showed that the c.2113+1G→C splice mutation causes skipping of exon 17, leading to a frame shift and a premature stop of translation.

Conclusion Mutations in GRIP1 cause classic FS in humans.