Abstract
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 ( Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia and Genital 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.
Highlights
Cyclin-dependent kinase inhibitor 1C (CDKN1C, known as P57/kip2) (OMIM 600856) is a key negative regulator of cell proliferation that is encoded by a paternally imprinted gene on the short arm of chromosome 11 (11p15.4) in humans (Stampone et al, 2018).Consistent with its role in growth and development, maternallyinherited loss-of-function variants in CDKN1C are found in approximately 5–10% of individuals with the “overgrowth” condition, Beckwith-Wiedemann Syndrome (BWS) (OMIM 130650) (Eggermann et al, 2014)
intrauterine growth restriction (IMAGe) syndrome is characterised by fetal/ Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia and Genital anomalies as well as additional features such as hearing loss and hypercalciuria (Bennett et al, 1993; Vilain et al, 1999)
Chr11p15.5 imprinting clusters, including several individuals with maternal duplication of the locus containing CDKN1C (Bonaldi et al, 2011; Boonen et al, 2016; Schönherr et al, 2007). These findings suggest that the growth restriction phenotype associated with CDKN1C may be more variable and adrenal insufficiency is not always present
Summary
Cyclin-dependent kinase inhibitor 1C (CDKN1C, known as P57/kip2) (OMIM 600856) is a key negative regulator of cell proliferation that is encoded by a paternally imprinted (maternally expressed) gene on the short arm of chromosome 11 (11p15.4) in humans (Stampone et al, 2018).Consistent with its role in growth and development, maternallyinherited loss-of-function variants in CDKN1C are found in approximately 5–10% of individuals with the “overgrowth” condition, Beckwith-Wiedemann Syndrome (BWS) (OMIM 130650) (Eggermann et al, 2014). Children with IMAGe syndrome have all been found to harbour pathogenic single nucleotide variants (SNVs) in a very specific region of the PCNA-binding domain of CDKN1C (Arboleda et al, 2012; Cabrera-Salcedo et al, 2017). These changes potentially lead to increased activity through increasing protein stability, thereby preventing cell cycle progression into S phase (Borges et al, 2015; Hamajima et al, 2013).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
