PPP2R1A基因变异致智力障碍、小头畸形和胼胝体缺如1例并文献复习

Case report and literature review on PPP2R1A gene mutation-associated intellectual disability, microcephalus and corpus callosum agenesis

目的 总结PPP2R1A基因变异的临床特征,探讨基因表型关系。方法 回顾性分析1例2021年7月确诊的PPP2R1A基因变异患儿临床资料,并复习相关文献。结果 2岁男性患儿,临床特征为智力障碍、发育迟缓、小头畸形、长脸、四肢肌张力低下和胼胝体缺如。全外显子测序发现PPP2R1A基因R258H新生错义变异。目前无中文文献报道,全球检索到4篇英文文献37例病例。所有变异均为新生错义变异(共17个单核苷酸变异),其中以p.R182W和p.M180T为热点变异。具有至少两个临床表型,共同临床特征为中重度智力障碍(91.2%),发育迟缓(78.9%),肌张力低下(86.8%),轻症为p.F141I、p.T178N/S和p.M180T/V/K/R变异伴巨头畸形,没有痫性发作;重症为p.P179L、p.R182W、p.R183W/Q、p.S219L、p.V220M和p.R258S/H变异伴小头畸形、长脸、痫性发作和胼胝体发育不全。结论 PPP2R1A基因变异以不同程度智力障碍/发育迟缓合并肌张力低下为主要特征,巨头或小头畸形伴胼胝体发育不全、面部畸形等。基因型与表型存在一定相关性。

Objective To summarize the clinical features and genotypic-phenotypic correlation of PPP2 R1 A gene variation, so as to provide reference for clinical diagnosis. Methods The medical record of the child with PPP2R1 A gene variation diagnosed in July 2021 was retrospectively analyzed. The relevant studies of PPP2 R1 A gene variation were retrieved. Results The case was a 2-year-old boy manifested with intellectual disability, developmental delay, microcephalus, long face, hypotonia, and corpus callosum agenesis. The whole exome-sequencing test identified a de novo heterozygous variation p.R258 H in the PPP2 R1 A gene. So far, there has been no report of PPP2 R1 A variation on Chinese journals, but a total of 37 cases have been reported worldwide. All variations of cases were de novo missense mutations(a total of 17 single nucleotide variants), of which p.R182 W and p.M180 T were the most common sites. The PPP2 R1 A-related disorder had at least two distinguishable phenotypic subgroups. Common features included moderate to severe intellectual disability(91.2%), developmental delay(78.9%) and hypotonia(86.8%). The least severely affected subgroup encompassed variants in p.F141 I, p.T178 N/S, and p.M180 T/V/K/R, characterized with macrocephaly, absence of seizures. The severely affected subgroup consisted of variants in p.P179 L, p.R182 W, p.R183 W/Q, p.S219 L, p.V220 M, and p.R258 S, characterized with microcephaly, a long face, seizures and corpus callosum hypoplasia. Conclusions The clinical feature of patients with PPP2 R1 A gene variations is mainly moderate to severe intellectual disability/developmental delay, most co-morbid with hypotonia, macrocephaly or microcephaly, corpus callosum hypoplasia, and abnormal facial shape. There is a certain correlation between genotype and phenotype.