Novel mutation points to a hot spot in CDKN1C causing Silver\u2013Russell syndrome

Gerhard Binder,Roland Schweizer,Tilman Heinrich,Thomas Eggermann,Julian Ziegler,Wisam Habhab,Tobias B Haack

doi:10.1186/s13148-020-00945-y

Gerhard Binder, Roland Schweizer + Show 5 more

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https://doi.org/10.1186/s13148-020-00945-y

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Abstract

BackgroundPathogenic CDKN1C gain-of-function variants on the maternal allele were initially reported as a cause of IMAGe syndrome characterized by intrauterine growth retardation, metaphyseal dysplasia, primary adrenal insufficiency and genital anomalies. Recently, a maternally inherited CDKN1C missense mutation (p.Arg279Leu) was identified in several members of a single family clinically diagnosed with Silver–Russell syndrome (SRS) but without adrenal insufficiency. Thereafter, two half siblings from UK with familial SRS were described who carried the same mutation. This specific amino acid change is located within a narrow functional region containing the mutations previously associated with IMAGe syndrome.ResultsHere, we describe a third familial case with maternally inherited SRS due to a missense variant affecting the same amino acid position 279 but leading to a different amino acid substitution (p. (Arg279Ser)). The two affected family members (mother and son) presented with the complete SRS phenotype (both Netchine–Harbison CSS score 5 of 6) but without body asymmetry or adrenal insufficiency.ConclusionsIn comparison with loss-of-function genomic IGF2 mutations, CDKN1C gain-of-function mutations are a less frequent cause of SRS and seem to affect a cluster of few amino acids.

Highlights

Pathogenic Cyclin-dependent kinase inhibitor 1C (CDKN1C) gain-of-function variants on the maternal allele were initially reported as a cause of IMAGe syndrome characterized by intrauterine growth retardation, metaphyseal dysplasia, primary adrenal insufficiency and genital anomalies
The cyclin-dependent kinase inhibitor 1C (CDKN1C) is a down-regulator of cell proliferation; CDKN1C inhibits the cyclin/CDK complexes of the G1 phase. It is encoded by the imprinted CDKN1C gene on 11p15.5 which is expressed from the maternal allele only [1]
The gene product binds to the cyclin/CDK complex by its C-terminal PCNA-binding domain and exhibits activity by the N-terminal CDK inhibitor domain which is linked to the binding domain by the central PAPA domain [1]

Summary

Introduction

Pathogenic CDKN1C gain-of-function variants on the maternal allele were initially reported as a cause of IMAGe syndrome characterized by intrauterine growth retardation, metaphyseal dysplasia, primary adrenal insufficiency and genital anomalies. Thereafter, two half siblings from UK with familial SRS were described who carried the same mutation This specific amino acid change is located within a narrow functional region containing the mutations previously associated with IMAGe syndrome. The cyclin-dependent kinase inhibitor 1C (CDKN1C) is a down-regulator of cell proliferation; CDKN1C inhibits the cyclin/CDK complexes of the G1 phase (for review: [1]) It is encoded by the imprinted CDKN1C gene on 11p15.5 which is expressed from the maternal allele only [1]. BWSp is characterized by a congenital overgrowth phenotype with additional features including macroglossia, exomphalos, lateralized overgrowth and hyperinsulinism It is an imprinting disorder caused by diverse genetic and epigenetic defects within the two imprinting centers (IC1, IC2) in 11p15.5 encompassing the coding genes IGF2, H19, CDKN1C and KCNQ1. In 5% of sporadic and 20% of familial BWS cases, genomic CDKN1C variants are detected that are distributed over the whole coding region and are predicted to cause loss of function [2]

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