CDKN1C – Silver-Russell syndrome

Silver-Russell syndrome (SRS) is an imprinting disorder characterized by prenatal and postnatal growth restriction, relative macrocephaly, and typical facial features. A subset of SRS cases arises from maternally inherited gain-of-function alterations of CDKN1C on chromosome 11p15.5, which acts as a cyclin-dependent kinase inhibitor (Silver-Russell syndrome).

Multiple independent families have been reported with maternally transmitted CDKN1C missense variants affecting the PCNA-binding domain (codons 268–279), notably c.803G>T (p.Arg268Leu) and c.802C>A (p.Arg268Ser), in at least 11 affected individuals across 7 pedigrees, with segregation in mother-to-child transmissions ([PMID:33076988], [PMID:25427884]). Additionally, three Japanese patients from two families with maternally inherited duplications encompassing CDKN1C presented with classical SRS without hemihypotrophy ([PMID:25427884]).

Inheritance is autosomal dominant with maternal expression due to imprinting. Segregation analysis identified 7 additional affected relatives harboring these variants. The variant spectrum in SRS includes 2 recurrent missense substitutions in the PCNA-binding motif and multi-megabase 11p15.5 duplications restricted to the ICR2 domain.

Functional studies demonstrate that PCNA-binding hotspot variants destabilize the CDKN1C–PCNA interaction and markedly increase protein stability, consistent with a gain-of-function mechanism. Cycloheximide chase and proteasome inhibitor assays confirmed that p.Ile261Ser and p.Asp263Asn mutants resist proteasomal degradation ([PMID:24098681]). These findings concord with the growth-restrictive phenotype.

Negative screening of larger SRS and fetal growth restriction cohorts did not reveal pathogenic CDKN1C variants outside the PCNA-binding hotspot, supporting locus specificity ([PMID:15234339], [PMID:31497289]). No conflicting reports have been documented.

In summary, maternally inherited CDKN1C gain-of-function missense variants and domain-restricted duplications provide strong genetic and functional evidence for CDKN1C as a cause of SRS. Inclusion of CDKN1C hotspot sequencing and copy-number analysis is clinically actionable for molecular diagnosis of Silver-Russell syndrome.

Key take-home: CDKN1C gain-of-function alterations constitute a validated, diagnostically relevant cause of SRS, meriting their incorporation into genetic testing panels.

References

• Molecular epigenetics • 2020 • Novel mutation points to a hot spot in CDKN1C causing Silver-Russell syndrome PMID:33076988
• Journal of human genetics • 2015 • Silver-Russell syndrome without body asymmetry in three patients with duplications of maternally derived chromosome 11p15 involving CDKN1C PMID:25427884
• PloS One • 2013 • Increased protein stability of CDKN1C causes a gain-of-function phenotype in patients with IMAGe syndrome PMID:24098681
• Molecular Genetics and Metabolism • 2004 • Searching for genomic variants in IGF2 and CDKN1C in Silver-Russell syndrome patients PMID:15234339
• F1000Research • 2019 • Analysis of CDKN1C in fetal growth restriction and pregnancy loss PMID:31497289

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