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Background:  Cyclin-dependent kinase inhibitor 1C (CDKN1C) is a key negative regulator of cell growth encoded by a paternally imprinted/maternally expressed gene in humans. Loss-of-function variants in  CDKN1C  are associated with an overgrowth condition (Beckwith-Wiedemann Syndrome) whereas “gain-of-function” variants in  CDKN1C  that increase protein stability cause growth restriction as part of IMAGe syndrome (  I ntrauterine growth restriction,  M etaphyseal dysplasia,  A drenal hypoplasia and  Ge nital anomalies). As three families have been reported with  CDKN1C  mutations who have fetal growth restriction (FGR)/Silver-Russell syndrome (SRS)  without  adrenal insufficiency, we investigated whether pathogenic variants in  CDKN1C  could be associated with isolated growth restriction or recurrent loss of pregnancy.    Methods:  Analysis of published literature was undertaken to review the localisation of variants in  CDKN1C  associated with IMAGe syndrome or fetal growth restriction.  CDKN1C  expression in different tissues was analysed in available RNA-Seq data (Human Protein Atlas). Targeted sequencing was used to investigate the critical region of  CDKN1C  for potential pathogenic variants in SRS (n=66), FGR (n=37), DNA from spontaneous loss of pregnancy (n= 22) and women with recurrent miscarriages (n=78) (total n=203).    Results:  All published single nucleotide variants associated with IMAGe syndrome are located in a highly-conserved “hot-spot” within the PCNA-binding domain of CDKN1C between codons 272-279. Variants associated with familial growth restriction but normal adrenal function currently affect codons 279 and 281.  CDKN1C  is highly expressed in the placenta compared to adult tissues, which may contribute to the FGR phenotype and supports a role in pregnancy maintenance. In the patient cohorts studied no pathogenic variants were identified in the PCNA-binding domain of CDKN1C.    Conclusion:  CDKN1C is a key negative regulator of growth. Variants in a very localised “hot-spot” cause growth restriction, with or without adrenal insufficiency. However, pathogenic variants in this region are not a common cause of isolated fetal growth restriction phenotypes or loss-of-pregnancy/recurrent miscarriages.

Analysis of CDKN1C in fetal growth restriction and pregnancy loss