Abstract：
Noonan syndrome is a so-called \"RASopathy,\" that is characterized by short stature, distinctive facial features, congenital heart defects, and developmental delay. Of individuals with a clinical diagnosis of Noonan syndrome, 80%-90% have pathogenic variants in the known genes implicated in the disorder, but the molecular mechanism is unknown in the remaining cases. Heterozygous pathogenic variants of ETS2 repressor factor (ERF), which functions as a repressor in the RAS/MAPK signaling pathway, cause syndromic craniosynostosis. Here, we report an ERF frameshift variant cosegregating with a Noonan syndrome-like phenotype in a family. The proband was a 3-year-old female who presented with dysmorphic facial features, including proptosis, hypertelorism, slightly down slanted palpebral fissures, low-set posteriorly rotated ears, depressed nasal bridge, short stature, and developmental delay. Exome sequencing of the proband identified a heterozygous ERF variant [NM_006494.4: c.185del p.(Glu62Glyfs*15)]. Her mother and sister showed a similar phenotype and had the same heterozygous ERF variant. A large proportion of the previously reported patients with syndromic craniosynostosis and pathogenic ERF variants also showed characteristic features that overlap with those of Noonan syndrome. The present finding supports an association between heterozygous ERF variants and a Noonan syndrome-like phenotype.
摘要：
Noonan综合征是一种所谓的“放射病”，“这是以身材矮小为特征的，独特的面部特征，先天性心脏缺陷,和发育迟缓。在临床诊断为努南综合征的个体中，80％-90％在与该疾病有关的已知基因中有致病变异，但其余病例的分子机制尚不清楚。ETS2抑制因子（ERF）的杂合致病变体，作为RAS/MAPK信号通路的阻遏物，引起综合征性颅骨融合。这里,我们报道了一个ERF移码变异体,其与Noonan综合征样表型在一个家族中共分离.先证者是一名3岁女性，面部特征畸形，包括突起,超端粒,稍微向下倾斜的睑裂，低设置后旋转的耳朵，鼻梁凹陷,身材矮小,和发育迟缓。先证者的外显子组测序鉴定了杂合ERF变体[NM_006494.4:c.185delp.(Glu62Glyfs*15)]。她的母亲和姐姐表现出相似的表型，并且具有相同的杂合ERF变体。先前报道的大部分患有综合征性颅骨融合和致病性ERF变异的患者也显示出与Noonan综合征重叠的特征性特征。本发现支持杂合ERF变体与Noonan综合征样表型之间的关联。
