12q24.31缺失所致智力发育障碍伴癫痫发作和语言迟缓患儿临床表型及遗传学分析

Clinical phenotype and genetic analysis of intellectual developmental disorder with seizures and language delay due to 12q24.31 deletion

目的:总结12q24.31缺失及SETD1B基因点变异所致智力发育障碍伴癫痫发作和语言迟缓(IDDSELD)患儿的临床特征及遗传学特点。方法:回顾性分析2022年9月于郑州大学第三附属医院儿童神经内科确诊的1例12q24.31缺失所致IDDSELD患儿的临床资料,利用染色体拷贝数变异测序(CNV-seq)及家系全外显子组测序(trio-WES)进行遗传学分析,并复习文献总结该病的临床特征。结果:先证者女性,7岁9个月,临床表现为全面发育落后、癫痫发作、多动、肌张力高、步态障碍,伴有特殊面容(眉弓高、大耳、上唇前突)、漏斗胸、腰椎前凸。CNV-seq结果示12q24.31区域(chr12:121895654-122449092)存在约553.44 kb片段致病性缺失,包含SETD1B基因,trio-WES结果示SETD1B基因1~16号外显子全部杂合缺失。患儿父母染色体该区段未见异常,SETD1B基因为野生型,国内未见该类型报道。检索到关于12q24.31缺失(含SETD1B基因)所致IDDSELD患儿4例,加上本例共5例,男女比例1∶4,均为新发变异,均存在智力发育障碍、头面部及骨骼畸形,3例存在癫痫发作,2例经治疗均仍有发育落后,1例发作得到控制。SETD1B基因点变异所致IDDSELD患儿47例,男女比例31∶16,以错义突变为主(38/47),多为新发突变(36/47),少数遗传自其父亲/母亲(6/47)或来源不明(5/47),临床表现为语言迟缓(43/47)、生长发育落后(43/47)、智力障碍(37/41)、行为问题(37/47)、面部畸形(34/47)、骨骼畸形(23/47)、肥胖(16/47)、皮肤异常(11/47)等,39例合并癫痫发作,经治疗23例发作得到控制,8例治疗后均仍存在发育落后。结论:IDDSELD患者国内外少见,临床表型多样,诊断较为困难,以对症治疗为主,可遗留癫痫发作及不同程度的发育落后。其中12q24.31缺失型患者相对罕见,国内未见报道,此类型女性多见,均为新发变异,基因检测有助于IDDSELD的早期诊断。

Objective:To summarize the clinical and genetic features of children with intellectual developmental disorder with seizures and language delay(IDDSELD)due to 12q24.31 deletion and SETD1B locus variants.Methods:The clinical data of a child with 12q24.31 deletion diagnosed in the Department of Pediatric Neurology of the Third Affiliated Hospital of Zhengzhou University in September 2022 were retrospectively analyzed.Trio-whole exome sequencing(trio-WES)and copy number variations sequencing(CNV-seq)were used for genetic analysis.The relevant literatures were reviewed to summarize the clinical features of the disease.Results:The proband was a 7 years and 9 month old girl who had clinical features of global developmental delay,epilepsy,hyperactivity,hypertonia,gait disorder,special facial features(high eyebrow arch,big ears,upper lip protrusion),funnel chest,lumbar lordosis.Karyotypic analysis showed 46XX in the proband.CNV-seq showed 12q24.31(chr12:121895654-122449092)position had a deletion of about 553.44 kb which contained the SETD1B gene.Trio-WES showed deletion of all exons 1-16 of the SETD1B gene.CNV-seq results of her parents were normal:the SETD1B gene was wild-type.This type has not been reported in China.Four children with IDDSELD caused by 12q24.31 deletion(including the SETD1B gene)were retrieved(totally 5 cases including this case),with male to female ratio of 1∶4,all with de novo mutations,and all with mental retardation,cephalo-facial and skeletal malformations.Three cases had seizures,2 cases still had developmental backwardness after treatment,and 1 case was seizure controlled.Forty-seven cases of IDDSELD due to point mutation in the SETD1B gene were retrieved:male to female ratio was 31∶16,missense mutations(38/47)were predominant,most were de novo mutations(36/47),and a few were inherited from their fathers/mothers(6/47)or of unknown origin(5/47),with clinical manifestations of speech delay(43/47),growth retardation(43/47),intellectual disability(37/41),behavioral problems(37/47),facial malformations(34/47),skeletal malformations(23/47),obesity(16/47),skin abnormalities(11/47),etc.Thirty-nine cases were combined with seizures,23 of whom were under control after treatment,and 8 cases were recorded as still having developmental backwardness after treatment.Conclusions:IDDSELD patients are rare at home and abroad,with diverse clinical phenotypes and difficult diagnosis.Symptomatic treatment is the main approach.And the patients can leave behind seizures and varying degrees of developmental backwardness.Among them,patients with 12q24.31 deletion are relatively rare and have not been reported in China,and this type is more common in females,all of whom have de novo mutations,and genetic testing is helpful for the early diagnosis of IDDSELD.