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

Silver-Russell syndrome (SRS, MIM#180860) is an imprinting disorder characterized by prenatal and postnatal growth retardation, relative macrocephaly at birth, prominent forehead, feeding difficulties, 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 paternal H19/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, and CDKN1C) contributes to the SRS phenotype, those on chromosome 7 (GRB10, PEG10, and MEST) are still in discussion. We report two brothers clinically diagnosed with SRS (postnatal growth delay, relative macrocephaly at birth, feeding difficulties, and SRS facies). One patient also has distal tremors and a treated growth hormone deficiency. CGH-array revealed a deletion of 109 Kb including PEG10 and SGCE genes, inherited from their unaffected father. Whole Exome Sequencing did not disclose other causative variants. PEG10 functions as a transcriptional repressor of cyclin-dependent kinase inhibitors, including CDKN1C, for which maternal gain-of-function variants are linked to SRS. Real-time PCR studies showed a downregulation of PEG10 and an upregulation of CDKN1C expression only in the affected brothers. Interestingly, IGF2 was upregulated in the patient 1 under GH administration. Our findings provide the first evidence supporting the role of PEG10 in the pathogenesis of Silver-Russell Syndrome, mediated by a gain-of-function effect on the CDKN1C expression, offering new insights into the molecular mechanisms underlying this condition.