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, M
etaphyseal 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