PEG10 loss of function causes Silver-Russell syndrome: a familial case with paternal deletion

Background: Silver-Russell syndrome (SRS, MIM#180860) is an imprinting disorder characterized by pre-natal and post-natal growth retardation, relative macrocephaly at birth, prominent forehead, feedingdifficulties, and body asymmetry. Clinical diagnosis is based on at least 4 out of 6 clinical signs (Netchine-Harbison clinical scoring system). The main molecular mechanisms are loss of methylation at the paternalH19/IGF2:IG-DMR (30-60%) at the 11p15 chromosomal region and maternal uniparental disomy of chromosome 7 (5-10%). While it is well known that deregulation of 11p15 imprinted genes (IGF2, H19, andCDKN1C) contributes to the SRS phenotype, those on chromosome 7 (GRB10, PEG10, and MEST) are still indiscussion.Methods and Results: We report two brothers clinically diagnosed with SRS (postnatal growth delay,relative macrocephaly at birth, feeding difficulties, and SRS facies). One proband also has distal tremors anda treated growth hormone deficiency.CGH-array revealed a deletion of 109 Kb including PEG10 and SGCE genes, inherited from their unaffectedfather. Whole Exome Sequencing did not disclose other causative variants. PEG10 functions as atranscriptional repressor of cyclin-dependent kinase inhibitors, including CDKN1C, for which maternal gain-of-function variants are linked to SRS and IMAGe syndrome. Real-time PCR studies showed adownregulation of PEG10 and an upregulation of CDKN1C expression only in the brothers. Interestingly,IGF2 was upregulated in the treated proband.Conclusion: Our findings provide the first evidence supporting the role of PEG10 in the pathogenesis ofSilver-Russell Syndrome, mediated by a gain-of-function effect on the CDKN1C expression, offering newinsights into the molecular mechanisms underlying this condition.