Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka, Japan.
Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan.
Mol Genet Genomic Med. 2024 Feb;12(2):e2396. doi: 10.1002/mgg3.2396.
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.
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.
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).
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.
Rauch-Steindl 综合征（RAUST）是一种非常罕见的遗传综合征，由 4p16.3 染色体上 NSD2 的致病性变异引起。虽然 NSD2 以前被认为是 Wolf-Hirschhorn 综合征（WHS）的主要基因，WHS 是 4p16.3 缺失的连续基因综合征，但 RAUST 已被发现与 WHS 的面部和临床特征不同。在这项研究中，我们报告了两个新诊断的 RAUST 个体的详细信息，以便更好地了解 RAUST 的分子和临床特征。
对两个有精神运动发育迟缓及生长不良的个体进行全基因组测序。对生长参数、头面部特征、脑电图（EEG）、脑部磁共振成像和发育评估进行详细的临床评估。
两个个体均存在 NSD2 的新生截断变异。一个有新的变异（c.2470C>T，p.Arg824*），另一个有重复变异（c.4028del，p.Pro1343Glnfs*49）。两者均表现出 RAUST 的特征性面部特征、生长不良和轻度精神运动发育迟缓。RAUST 的一个新发现见于个体 2，即 Chiari 畸形 1 型，两者均显示骨龄延迟。他们缺乏 WHS 的常见特征，如先天性心脏病、唇腭裂和癫痫发作（脑电图有异常发现）。
我们提出了 RAUST 的一个新变异和临床表现，扩展了 RAUST 的分子和临床多样性，并提高了我们对这种不同于 WHS 的罕见综合征的认识。需要对更多的 RAUST 病例进行进一步研究，并对 NSD2 进行功能分析。
