TRIO基因相关儿童智力发育障碍的临床特点和基因分析

Clinical characteristics and genetic analysis of mental retardation disorder with TRIO gene variant

目的总结TRIO基因相关儿童智力发育障碍(MRD)的临床表现和基因特点。方法病例系列研究,回顾性收集首都医科大学附属北京儿童医院神经内科及郑州大学第三附属医院儿科2019年8月至2024年3月就诊的9例TRIO基因相关MRD患儿病例资料,包括性别、年龄、智力及运动发育、外观、癫痫发作、头颅影像学和基因结果,总结其临床特点及基因型表型特点。结果9例患儿中男6例、女3例,4例患儿符合MRD63型表型,表现为中重度发育落后伴大头畸形;5例患儿符合MRD44型表型,表现为轻中度发育落后伴小头畸形。伴有明显特殊面容(枕部扁平、眉毛粗重、连眉、耳朵大、手指短小、肤白发黄和斜视等)5例,伴有癫痫发作2例(肌阵挛发作和失神发作各1例),伴有喂养困难4例,伴有先天性白内障、先天性心脏病、反复感染、眼底改变(漆裂纹样改变)各1例。9例患儿携带的TRIO基因变异均为新生变异,包括8个变异位点,其中错义变异7个、移码变异1个,分别为c.3232C>T/p.R1078W(2例)、c.3920A>G/p.Y1307C、c.4112A>T/p.H1371L、c.4283G>T/p.R1428L、c.4394A>G/p.N1465S、c.6041T>C/p.I2014T、c.6821G>A/p.R2274H、c.7027delC/p.Q2343Sfs*70。2例变异位点位于Spectrin结构域,4例位于鸟嘌呤核苷酸交换因子(GEF)D1结构域,2例位于GEFD2结构域,1例(移码变异)位于PH2-SH3结构域。移码变异者表现为失神发作和轻度发育落后,表型最轻。肌阵挛发作癫痫患儿加用丙戊酸联合左乙拉西坦发作控制,失神癫痫患儿加用丙戊酸联合拉莫三嗪发作控制。9例患儿均进行积极康复训练,发育缓慢进步。结论TRIO基因相关儿童MRD表现为不同程度的发育落后,多伴有大头或小头畸形,特殊面容,伴或不伴癫痫发作;变异类型以错义变异为主,错义变异大多集中于Spectrin结构域和GEFD结构域,p.R1078W可能为相对热点变异,移码变异者表型相对较轻。

ObjectiveTo summarize the clinical and genetic characteristics of mental retardation disorder(MRD)with TRIO gene variant in children.MethodsCase series study.The data of 9 children with TRIO gene variants were collected retrospectively from August 2019 to March 2024 in Department of Neurology,Beijing Children′s Hospital,Capital Medical University and Department of Pediatrics,the Third Affiliated Hospital of Zhengzhou University.The data included gender,age,intellectual and motor development,appearance,seizures,neuroimaging and genetic results.The clinical features and genotype-phenotype correlations were summarized.ResultsOf the 9 children,6 boys and 3 girls,4 MRD63 children presented with moderate to severe developmental delays accompanied by macrocephaly;5 MRD44 children had mild to moderate developmental delays with microcephaly.A total of 5 children had dysmorphic facial features(flat occiput,thick eyebrows,unibrow,large ears,short fingers,pale skin,yellow hair,and strabismus),2 children experienced seizures(1 child with myoclonic seizure and 1 with absence seizure),4 children had feeding difficulties,1 child had congenital cataracts,1 child had congenital heart disease,1 child had recurrent infections,and 1 child had tiger-striped changes in the fundus examination.TRIO gene variants carried by the 9 children were all de novo,involving 8 variant sites,including 7 missense variants and 1 frameshift variant,c.3232C>T/p.R1078W(2 cases),c.3920A>G/p.Y1307C,c.4112A>T/p.H1371L,c.4283G>T/p.R1428L,c.4394A>G/p.N1465S,c.6041T>C/p.I2014T,c.6821G>A/p.R2274H,c.7027delC/p.Q2343Sfs*70.Among them,2 sites are located in the Spectrin domain,4 sites are in the GEFD1 domain,2 sites are in the GEFD2 domain,and 1 site(frameshift variant)is in the PH2-SH3 domain.The individual with frameshift variant exhibit absence seizures,mild developmental delay,and the mildest phenotype.The child with myoclonic seizures was treated with valproic acid and levetiracetam for seizure control,while the child with absence epilepsy was treated with valproic acid and lamotrigine for seizure control.All 9 children underwent regular rehabilitation exercises,making slow progress.ConclusionsTRIO gene related MRD is characterized by varying degrees of developmental delay,and often accompanied by macrocephaly or microcephaly,dysmorphic facial features,and with or without seizures.The main variant types are missense variants,which are mostly concentrated in the Spectran domain and GEFD domain.p.R1078W may be a relative hotspot variant.The phenotype caused by the frameshift variant is relatively milder.