背景:Rauch-Steindl综合征(RAUST)是一种非常罕见的遗传综合征,由染色体4p16.3上NSD2的致病变异引起。尽管NSD2以前被认为是Wolf-Hirschhorn综合征(WHS)的主要基因,染色体4p16.3缺失的连续基因综合征,已发现RAUST具有与WHS不同的面部和临床特征。在这项研究中,为了更好地了解RAUST的分子和临床特征,我们报告了两名新诊断的RAUST患者的细节.
方法:对两个患有精神运动延迟和生长障碍的个体进行全基因组测序。生长参数的详细临床评估,颅面特征,脑电图(EEG),大脑的磁共振成像,并进行发育评估。
结果:两个个体在NSD2中具有从头截短变体。一个有一个新的变体(c.2470C>T,p.Arg824*),另一个有一个复发性变异(c.4028del,p.Pro1343Glnfs*49)。两者都表现出特征性的RAUST面部特征,生长失败,和轻微的精神运动延迟。在Chiari畸形1型个体2中发现了RAUST的新发现,两者均显示骨龄延迟。他们缺乏常见的WHS特征,如先天性心脏缺陷,唇裂/腭裂,和癫痫(脑电图异常发现)。
结论:我们提出了一种新的RAUST变体和临床表现,扩大RAUST的分子和临床多样性,提高我们对这种罕见综合征的认识,这与WHS不同。需要进一步研究更多的RAUST病例和NSD2的功能分析。
BACKGROUND: Rauch-Steindl syndrome (RAUST) is a very rare genetic syndrome caused by a pathogenic variant in NSD2 on chromosome 4p16.3. Although NSD2 was previously thought to be the major gene in Wolf-Hirschhorn syndrome (WHS), a contiguous gene syndrome of chromosome 4p16.3 deletion, RAUST has been found to present different facial and clinical features from WHS. In this study, we report the details of two newly diagnosed individuals with RAUST in order to better understand the molecular and clinical features of RAUST.
METHODS: Whole-genome sequencing was performed on two individuals with psychomotor delay and growth failure. Detailed clinical evaluation of growth parameters, craniofacial features, electroencephalogram (EEG), magnetic resonance imaging of the brain, and developmental assessment were performed.
RESULTS: Both individuals had de novo truncating variants in NSD2. One had a novel variant (c.2470C>T, p.Arg824*), and the other had a recurrent variant (c.4028del, p.Pro1343Glnfs*49). Both exhibited characteristic RAUST facial features, growth failure, and mild psychomotor delay. A novel finding of RAUST was seen in individual 2, a Chiari malformation type 1, and both showed delayed bone age. They lacked common WHS features such as congenital heart defects, cleft lip/palate, and seizures (EEG with abnormal findings).
CONCLUSIONS: We present a novel variant and clinical presentations of RAUST, expand the molecular and clinical diversity of RAUST, and improve our understanding of this rare syndrome, which is distinct from WHS. Further researches are needed on more RAUST cases and on functional analysis of NSD2.