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. 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. 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.

中文翻译：

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新突变指向 CDKN1C 中的一个热点，导致银罗素综合征

母体等位基因上的致病性 CDKN1C 功能获得变异最初被报道为 IMAGe 综合征的原因，其特征是宫内发育迟缓、干骺端发育不良、原发性肾上腺功能不全和生殖器异常。最近，在临床诊断为 Silver-Russell 综合征（SRS）但没有肾上腺功能不全的一个家族的几个成员中发现了母系遗传的 CDKN1C 错义突变（p.Arg279Leu）。此后，来自英国的两个患有家族性 SRS 的同父异母兄弟姐妹被描述为携带相同的突变。这种特定的氨基酸变化位于一个狭窄的功能区域内，该区域包含以前与 IMAGe 综合征相关的突变。这里，我们描述了第三个具有母系遗传 SRS 的家族性病例，这是由于错义变异影响了相同的氨基酸位置 279 但导致了不同的氨基酸取代（p. (Arg279Ser)）。两名受影响的家庭成员（母亲和儿子）表现出完整的 SRS 表型（Netchine-Harbison CSS 得分均为 5，共 6 分），但没有身体不对称或肾上腺功能不全。与功能丧失基因组 IGF2 突变相比，CDKN1C 功能获得性突变是 SRS 不太常见的原因，似乎影响少数氨基酸的簇。