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Objective  The IGF/IGF1R axis is involved in the regulation of human growth. Both IGF1 and IGF2 can bind to the IGF1R in order to promote growth via the downstream PI3K/AKT pathway. Pathogenic mutations in  IGF1  and  IGF1R  determine intrauterine growth restriction and affect postnatal body growth. However, to date, there are only few reports of pathogenic  IGF2  mutations causing severe prenatal, as well as postnatal growth retardation.    Results  Here we describe a  de novo  c.195delC  IGF2  variant (NM_000612, p.(Ile66Ser fs *93)) in a 4-year-old patient with severe pre- and post-natal growth retardation in combination with dystrophy, facial dimorphism, finger deformities, as well as a patent ductus. Cloning and sequencing of a long-range PCR product harboring the deletion and a SNP informative site chr11:2153634 (rs680, NC_000011.9:g.2153634T&gt;C) demonstrated that the variant resided on the paternal allele. This finding is consistent with the known maternal imprinting of  IGF2 . 3D protein structure prediction and overexpression studies demonstrated that the p.(Ile66Ser fs *93)  IGF2  gene variation resulted in an altered protein structure that impaired ligand/receptor binding and thus prevents IGF1R activation.    Conclusion  The severity of the phenotype in combination with the dominant mode of transmission provides further evidence for the involvement of IGF2 in growth disorders.

A new p.(Ile66Serfs*93) IGF2 variant is associated with pre- and postnatal growth retardation