The RREB1 is a zinc finger transcription factor that plays a role in regulating gene expression and inactivating MAPK signalling components. To date, no pathogenic variant in the RREB1 gene has been associated with any disease, but several cases of 6p terminal deletions affecting the RREB1 gene have been reported. In this study, we report the first case of RREB1-associated Noonan-like RASopathy caused by a pathogenic variant within this gene. Genetic testing included whole-genome sequencing (WGS) of the proband and Sanger sequencing of the proband, his parents, and his sibling. The proband had a de novo c.2677del, p.(Ala893Argfs*20) variant, likely resulting in RREB1 haploinsufficiency. Comparative analysis of patients with microdeletions, including in the RREB1 gene, confirmed shared clinical traits while highlighting unique features, such as blue sclerae and absence of cardiac anomalies. This study reinforces previous data on RREB1 haploinsufficiency as the driver of a new Noonan-like RASopathy variant, which includes intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms as key clinical indicators. These findings shed light on this RREB1-related syndrome and underscore the necessity for further investigation into the functional consequences of RREB1 mutations.

中文翻译：

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Noonan 样 Ras 病中首例 RREB1 基因点致病性变异

RREB1 是一种锌指转录因子，在调节基因表达和失活 MAPK 信号传导成分中发挥作用。迄今为止，尚无RREB1基因的致病性变异与任何疾病相关，但已报道了几起影响RREB1基因的 6p 末端缺失病例。在这项研究中，我们报告了首例由该基因内的致病性变异引起的RREB1相关努南样 RAS 病。基因检测包括先证者的全基因组测序（WGS）以及先证者、其父母和兄弟姐妹的桑格测序。先证者有一个新的 c.2677del, p.(Ala893Argfs*20) 变异，可能导致RREB1单倍体不足。对具有微缺失（包括RREB1基因）的患者进行的比较分析，证实了共同的临床特征，同时突出了独特的特征，例如蓝色巩膜和不存在心脏异常。这项研究强化了之前的数据，即RREB1单倍体不足是一种新的 Noonan 样 RAS 病变异的驱动因素，其中包括智力障碍、运动技能迟缓、身材矮小、短颈和独特的面部畸形等关键临床指标。这些发现揭示了这种RREB1相关综合征，并强调了进一步研究RREB1突变的功能后果的必要性。