Guo Yufan, Wu Xintao, Jin Yuting, Gu Yu, Lou Yuting, Miao Pu, Wang Ye, Zhang Bijun, Lin Xueting, Zhang Chudi, Feng Jianhua
Department of Pediatrics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Zhejiang University School of Medicine, Hangzhou, China.
Mol Genet Genomic Med. 2025 Jul;13(7):e70109. doi: 10.1002/mgg3.70109.
SOST encodes a secreted glycoprotein that is similar in sequence to the differential screening-selected gene aberrative in neuroblastoma (DAN) family of bone morphogenetic protein (BMP) antagonists. Pathogenic variants in the SOST gene result in sclerosteosis, van Buchem disease (VBD), or craniodiaphyseal dysplasia. SOST-related genetic disorders are very rare, and limited studies have reported variants associated with sclerosteosis.
Clinical tests such as magnetic resonance imaging (MRI), computed tomography (CT), emission computed tomography (ECT), electromyogram (EMG), routine blood tests, and physical examinations were conducted for the proband. Trio-whole exome sequencing (Trio-WES) was performed, and the rare variants (allele frequency < 0.01) in the exon and splicing regions were selected for further pathogenic evaluation. Candidate pathogenic variants were validated through Sanger sequencing. The wild and mutant SOST sequences were cloned into the pcDNA3.1 expression vector, and the RNA and protein expression levels were investigated in the HEK293T cell line.
In this study, we present a case study of a proband who displays abnormal facial expressions accompanied by numbness. The results of the brain MRI show thickening of the skull and disappearance of the diplopia signal. The temporal bone CT scan indicates diffuse osteosclerosis affecting the bilateral ossicular chains and internal auditory meatus, as well as stenosis of the bilateral internal auditory meatus. Trio-WES sequencing detected a novel homozygous variant in the proband: NM_025237.3(SOST): c.327C>A (p.Cys109*), which was also validated in his sister from the same family. According to the ACMG guidelines, the variant is classified as "likely pathogenic." The in vitro experiments demonstrated that the variant caused a decrease in SOST expression at RNA and protein level and produced a truncated protein.
The report presents new evidence for the clinical diagnosis of SOST-related facial numbness and expands the variant spectrum of SOST.
SOST编码一种分泌型糖蛋白，其序列与骨形态发生蛋白（BMP）拮抗剂的神经母细胞瘤差异筛选选择基因异常（DAN）家族相似。SOST基因的致病变异会导致骨硬化症、范布赫姆病（VBD）或颅骨骨干发育异常。与SOST相关的遗传疾病非常罕见，仅有有限的研究报道了与骨硬化症相关的变异。
对先证者进行了磁共振成像（MRI）、计算机断层扫描（CT）、发射计算机断层扫描（ECT）、肌电图（EMG）、血常规检查和体格检查等临床检测。进行了三人全外显子测序（Trio-WES），并选择外显子和剪接区域中的罕见变异（等位基因频率<0.01）进行进一步的致病性评估。候选致病变异通过桑格测序进行验证。将野生型和突变型SOST序列克隆到pcDNA3.1表达载体中，并在HEK293T细胞系中研究RNA和蛋白质表达水平。
在本研究中，我们报告了一例先证者病例，其表现为面部表情异常并伴有麻木感。脑部MRI结果显示颅骨增厚且复视信号消失。颞骨CT扫描表明双侧听骨链和内耳道出现弥漫性骨硬化，以及双侧内耳道狭窄。Trio-WES测序在先证者中检测到一个新的纯合变异：NM_025237.3(SOST): c.327C>A（p.Cys109*），其在同一家族的妹妹中也得到验证。根据美国医学遗传学与基因组学学会（ACMG）指南，该变异被分类为“可能致病”。体外实验表明，该变异导致SOST在RNA和蛋白质水平表达降低，并产生截短蛋白。
本报告为SOST相关面部麻木的临床诊断提供了新证据，并扩展了SOST的变异谱。
