DDX3X基因变异致X连锁智力障碍3例临床分析及康复随访

Clinical analysis and follow-up of rehabilitation training of X-linked intellectual disability caused by DDX3X gene variation:a report of three cases

目的总结DDX3X基因变异导致X连锁智力障碍(XLID)患儿的临床特征及基因变异特点。方法回顾性分析2018年1月至2021年4月在康复科就诊的3例因DDX3X基因变异致XLID患儿的基因检测结果及临床表型,长期随访其康复训练效果。结果例1为8个月23天男孩,例2为6个月女孩,例3为1岁6个月女孩。3例患儿首次就诊均表现为全面发育迟缓,特殊面容及肌张力障碍。全外显子测序发现例1为DDX3X基因c.1025+3A>C(p?)剪切突变,其母亲该位点为杂合子状态,父亲为野生型,根据美国医学遗传学与基因组学学会(ACMG)指南,该变异为临床意义未明性变异。经RT-PCR及Sanger验证后,该变异可引起内含子10部分保留及外显子10部分跳跃,提示该变异可能是导致基因功能异常的候选位点,该位点未经报道。例2为c.1535-1536 delAT(p.H 512 Rfs*5)缺失突变,其父母该位点均为野生型,根据ACMG指南,该变异为新发致病性变异。例3为在DDX3X基因7号内含子区域发现一处c.679+2T>G剪切突变,其父母该位点均为野生型,该变异为新发致病性变异。结论本研究发现3个新的国内首次报道的DDX3X基因变异位点,其中1例剪切突变经验证为候选位点;丰富了DDX3X基因变异谱,为患儿的临床诊断和遗传咨询提供了依据。

Objective To summarize the clinical and genetic characteristics of X-linked intellectual disability(XLID)caused by DDX3X gene variation.Methods The clinical data of 3 children with XLID caused by DDX3X gene variation who were treated in the rehabilitation department from January 2018 to April 2021 were retrospectively analyzed.Results Case 1 was a boy aged 8 months and 23 days,case 2 was a girl aged 6 months,and case 3 was a girl aged 1 year and 6 months.All the three patients presented with total growth retardation,special facial features and muscle dystonia at the first visit.The whole exome sequencing showed that case 1 had a splicing mutation of C.1025+3A>C(p?)in the DDX3X gene.The site was heterozygous in the mother and wild-type in the father.According to the American College of Medical Genetics and Genomics(ACMG)guidelines,this variant was of unknown clinical significance.After RT-PCR and Sanger verification,it was found that this mutation could cause partial retention of intron 10 and partial skipping of exon 10,suggesting that the mutation might be a candidate site for abnormal gene function,and this site has not been reported.Patient 2 had a deletion mutation of c.1535-1536 delAT(p.H 512 Rfs*5),which was wild-type in both of her parents.According to ACMG guidelines,this mutation was a de novo pathogenic mutation.In child 3,a splicing mutation of c.679+2T>G was found in the intron 7 region of DDX3 X gene.Both of her parents had wild type at this site,and this mutation was a de novo pathogenic mutation.Conclusions In this study,three new DDX3X gene mutation sites were reported for the first time in China and one of them was verified as a candidate site for splicing mutation.Above findings have enriched the mutation spectrum of DDX3X gene and provided a basis for clinical diagnosis and genetic counseling.