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

Springer Science and Business Media LLC - 2020
Gerhard Binder1, Julian Ziegler1, Roland Schweizer1, Wisam Habhab2, Tobias B. Haack2, T. Heinrich2, Thomas Eggermann3
1Pediatric Endocrinology, University Children’s Hospital, Hoppe-Seyler-Strasse 1, 72076, Tübingen, Germany
2Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
3Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany

Tóm tắt

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.

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