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. 2020 Oct 19;12(1):152.
doi: 10.1186/s13148-020-00945-y.

Novel mutation points to a hot spot in CDKN1C causing Silver-Russell syndrome

Gerhard Binder  1 , Julian Ziegler  2 , Roland Schweizer  2 , Wisam Habhab  3 , Tobias B Haack  3 , Tilman Heinrich  3 , Thomas Eggermann  4
Affiliations

Novel mutation points to a hot spot in CDKN1C causing Silver-Russell syndrome

Gerhard Binder et al. Clin Epigenetics. .

Abstract

Background: 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. 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.

Results: Here, 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.

Conclusions: In 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.

Keywords: CDKN1C; Growth retardation; Silver–Russell syndrome.

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Conflict of interest statement

GB has received honoraria for lectures from Ferring, Ipsen, Lilly, Merck Serono, Novo Nordisk, Pfizer and Sandoz and for membership in advisory boards from Ferring, Ipsen, Novo Nordisk and Pfizer. The other authors have nothing to declare.

Figures

Fig. 1
Fig. 1
Pedigree of the family. The two affected family members (index IV,1 and mother III,2) carry the mutation c.835C > A as well as the unaffected maternal grandmother (II,2) who is likely to have the mutation de novo. The arrow indicates the index patient
Fig. 2
Fig. 2
Photographs of index patient, his affected mother and his unaffected maternal grandmother
Fig. 3
Fig. 3
Growth charts of index patient and his affected mother. The percentiles shown are according to Prader et al. [18]. The “rhGH” arrows indicate the start and the cessation of treatment with recombinant GH. The “LHRHa” arrows indicate the start and the cessation of treatment with an LHRH agonist. The “TH” arrow indicates the target height of the mother. The index patient’s target height could not be determined, because his mother is affected
See this image and copyright information in PMC

References

    1. Eggermann T, Binder G, Brioude F, Maher ER, Lapunzina P, Cubellis MV, et al. CDKN1C mutations: two sides of the same coin. Trends Mol Med. 2014;20(11):614–622. doi: 10.1016/j.molmed.2014.09.001. - DOI - PubMed
    1. Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, et al. Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith–Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14(4):229–249. doi: 10.1038/nrendo.2017.166. - DOI - PMC - PubMed
    1. Arboleda VA, Lee H, Parnaik R, Fleming A, Banerjee A, Ferraz-de-Souza B, et al. Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet. 2012;44(7):788–792. doi: 10.1038/ng.2275. - DOI - PMC - PubMed
    1. Brioude F, Oliver-Petit I, Blaise A, Praz F, Rossignol S, Le Jule M, et al. CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome. J Med Genet. 2013;50(12):823–830. doi: 10.1136/jmedgenet-2013-101691. - DOI - PubMed
    1. Sabir AH, Ryan G, Mohammed Z, Kirk J, Kiely N, Thyagarajan M, et al. Familial Russell–Silver syndrome like phenotype in the PCNA domain of the CDKN1C gene, a further case. Case Rep Genet. 2019 doi: 10.1155/2019/1398250. - DOI - PMC - PubMed

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