背景:已证明PACS基因家族与细胞内囊泡运输有关。由PACS的致病变异引起的表型表现包括癫痫,智力障碍/发育迟缓,和畸形,例如面部异常。
方法:我们使用下一代测序技术发现了7例新的致病性或可能致病性PACS变异病例。分析了从这些患者获得的详细信息以及从先前报告的患者获得的详细信息。
结果:将新诊断病例纳入本研究,报告103例PACS基因家族相关神经系统疾病,其中43例为PACS2相关病例,其余为PACS1相关病例。大多数病人都有癫痫发作,据报道,通过几种类型的抗癫痫药物(ASM)有效控制。最有效和最常用的ASM包括丙戊酸钠(43.3%,13/30),奥卡西平/卡马西平(26.7%,8/30),和左乙拉西坦(20%,6/30)。几乎所有患者都有智力障碍/发育迟缓。最常见的致病性错义变异是PACS1p。Arg203Trp和PACS2p。Glu209Lys。此外,我们报告了一名患者携带可能的致病性拷贝数变异(CNV)(chr14的从头杂合缺失:105821380-106107443,286千碱基,破坏了弗林蛋白酶结合区结构域的一部分及其后的蛋白质结构),并伴有更严重和难治性的迟发性癫痫。
结论:不同PACS杂合错义变异的临床表型相似。PACS1和PACS2的致病变异位点相当有限,但位于不同的区域。破坏部分PACS2基因的CNV也可能是致病性的。这些发现可能为进一步研究PACS基因家族相关神经系统疾病的致病机制提供重要线索。视频摘要(MP465767kb)。
The PACS gene family has been demonstrated to be related to intracellular vesicular trafficking. The phenotypic manifestations caused by the pathogenic variants of PACS include epilepsy, intellectual disability/developmental delay, and malformations, such as facial abnormalities.
We identified seven new cases with pathogenic or likely pathogenic PACS variants using next-generation sequencing. Detailed information obtained from these patients was analyzed along with that obtained from previously reported patients.
With the inclusion of the newly diagnosed cases in this study, 103 cases with PACS gene family-related neurological diseases were reported, of which 43 were
PACS2-related cases and the remaining were PACS1-related cases. Most patients had seizures, which have been reported to be effectively controlled by several types of anti-seizure medications (ASMs). The most efficacious and frequently prescribed ASMs included sodium valproate (43.3%, 13/30), oxcarbazepine/carbamazepine (26.7%, 8/30), and levetiracetam (20%, 6/30). Almost all patients had intellectual disability/developmental delay. The most common pathogenic missense variants were PACS1 p. Arg203Trp and
PACS2 p.Glu209Lys. In addition, we report a patient carrying a likely pathogenic copy number variation (CNV) (de novo heterozygous deletion of chr14:105821380-106107443, 286 kilobase, destroyed part of the furin-binding region domain and the protein structure after it) with more severe and refractory late-onset epilepsy.
The clinical phenotypes of the different PACS heterozygous missense variants were similar. The pathogenic variant sites of PACS1 and
PACS2 were quite limited but located in different regions. A CNV destroying part of the
PACS2 gene might also be pathogenic. These findings may provide an important clue for further functional studies on the pathogenic mechanism of neurological disorders related to the PACS gene family. Video Abstract (MP4 65767 kb).