Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Ophthalmology, Beijing Jishuitan Hospital, Beijing, China.
Pediatr Res. 2023 Aug;94(2):683-690. doi: 10.1038/s41390-023-02515-3. Epub 2023 Feb 9.
Sengers syndrome characterized by hypertrophic cardiomyopathy is an extremely rare genetic disorder. Sengers syndrome associated with left ventricular non-compaction (LVNC) has not been described.
Genetic testing was used to identify candidate AGK variants in the proband. The predicted molecular structures were constructed by protein modeling. Exon skipping caused by the identified splicing mutations was verified by in silico analyses and in vitro assays. The genotypic and phenotypic features of patients with AGK splicing mutations were extracted by a systematic review.
The proband was characterized by Sengers syndrome and LVNC and caused by a novel compound heterozygous AGK splicing mutation. This compound mutation simultaneously perturbed the protein sequences and spatial conformation of the acylglycerol kinase protein. In silico and in vitro analyses demonstrated skipping of exons 7 and 8 and premature truncation as a result of exon 8 skipping. The systematic review indicated that patients with an AGK splicing mutation may have milder phenotypes of Sengers syndrome.
The genotypic and phenotypic spectrums of Sengers syndrome have been expanded, which will provide essential information for genetic counseling. The molecular mechanism in AGK mutations can offer insights into the potential targets for treatment.
First description of a child with Sengers syndrome and left ventricular non-compaction cardiomyopathy. A novel pathogenic compound heterozygous splicing mutation in AGK for Sengers syndrome was identified. The identified mutations led to exons skipping by in silico analyses and in vitro assays.
Sengers 综合征的特征是肥厚型心肌病，是一种极其罕见的遗传疾病。与左心室致密化不全（LVNC）相关的 Sengers 综合征尚未被描述。
使用基因测试来鉴定先证者中的候选 AGK 变体。通过蛋白质建模构建预测的分子结构。通过计算机分析和体外检测验证鉴定出的剪接突变引起的外显子跳跃。通过系统评价提取 AGK 剪接突变患者的基因型和表型特征。
先证者的特征是 Sengers 综合征和 LVNC，由一种新的复合杂合 AGK 剪接突变引起。这种复合突变同时干扰了酰基甘油激酶蛋白的序列和空间构象。计算机分析和体外检测表明，外显子 7 和 8 跳跃以及外显子 8 跳跃导致的提前截断。系统评价表明，AGK 剪接突变的患者可能具有更轻微的 Sengers 综合征表型。
Sengers 综合征的基因型和表型谱已经扩大，这将为遗传咨询提供重要信息。AGK 突变的分子机制为治疗提供了潜在的靶点。
首次描述了一名患有 Sengers 综合征和左心室致密化不全心肌病的儿童。鉴定了一种新的 AGK 致病复合杂合剪接突变，用于 Sengers 综合征。鉴定出的突变通过计算机分析和体外检测导致外显子跳跃。
