DDX3X基因变异致X连锁智力障碍3例临床分析及康复随访

doi:10.12372/jcp.2024.23e1018

临床儿科杂志 ›› 2024, Vol. 42 ›› Issue (11): 948-954.doi: 10.12372/jcp.2024.23e1018

DDX3X基因变异致X连锁智力障碍3例临床分析及康复随访

夏秦¹, 顾琴¹, 陈婷², 张何威¹, 霍洪亮¹, 曹徐君¹, 王巍巍¹, 吉永春¹()

1.苏州大学附属儿童医院康复科，（江苏苏州 215000）
2.苏州大学附属儿童医院内分泌科（江苏苏州 215000）

收稿日期:2023-10-24 出版日期:2024-11-15 发布日期:2024-11-08
通讯作者: 吉永春 E-mail:277965661@qq.com
基金资助:
苏州市科教兴卫青年科技项目(KJXW2021027)

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

XIA Qin¹, GU Qin¹, CHEN Ting², ZHANG Hewei¹, HUO Hongliang¹, CAO Xujun¹, WANG Weiwei¹, JI Yongchun¹()

1. Department of Rehabilitation, Children's Hospital of Soochow University, Suzhou 215000, Jiangsu, China
2. Department of Endocrinology, Children's Hospital of Soochow University, Suzhou 215000, Jiangsu, China

Received:2023-10-24 Published:2024-11-15 Online:2024-11-08
Contact: JI Yongchun E-mail:277965661@qq.com

摘要/Abstract

摘要：

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.1535-1536delAT（p.H512Rfs*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。

关键词: DDX3X基因, X连锁智力障碍, 遗传学分析

Abstract:

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.1535-1536delAT (p.H512Rfs*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 DDX3X 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.

Key words: DDX3X gene, X-linked intellectual disability, genetic analysis

夏秦, 顾琴, 陈婷, 张何威, 霍洪亮, 曹徐君, 王巍巍, 吉永春. DDX3X基因变异致X连锁智力障碍3例临床分析及康复随访[J]. 临床儿科杂志, 2024, 42(11): 948-954.

XIA Qin, GU Qin, CHEN Ting, ZHANG Hewei, HUO Hongliang, CAO Xujun, WANG Weiwei, JI Yongchun. Clinical analysis and follow-up of rehabilitation training of X-linked intellectual disability caused by DDX3X gene variation: a report of three cases[J]. Journal of Clinical Pediatrics, 2024, 42(11): 948-954.

图/表 3

图1

图2

表1

参考文献 21

[1]	Snijders Blok L, Madsen E, Juusola J, et al. Mutations in DDX3X are a common cause of unexplained intellectual disability with gender-specific effects on Wnt signaling[J]. Am J Hum Genet, 2015, 97(2): 343-352. doi: 10.1016/j.ajhg.2015.07.004 pmid: 26235985
[2]	Cruciat CM, Dolde C, de Groot RE, et al. RNA helicase DDX3 is a regulatory subunit of casein kinase 1 in Wnt-β-catenin signaling[J]. Science, 2013, 339(6126): 1436-1441.
[3]	Riggs ER, Andersen EF, Cherry AM, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)[J]. Genet Med, 2020, 22(2): 245-257. doi: 10.1038/s41436-019-0686-8 pmid: 31690835
[4]	Dikow N, Granzow M, Graul-Neumann LM, et al. DDX3X mutations in two girls with a phenotype overlapping Toriello-Carey syndrome[J]. Am J Med Genet A, 2017, 173(5): 1369-1373.
[5]	Fieremans N, Van Esch H, Holvoet M, et al. Identification of intellectual disability genes in female patients with a skewed X-inactivation pattern[J]. Hum Mutat, 2016, 37(8): 804-811. doi: 10.1002/humu.23012 pmid: 27159028
[6]	Kellaris G, Khan K, Baig SM, et al. A hypomorphic inherited pathogenic variant in DDX3X causes male intellectual disability with additional neurodevelopmental and neurodegenerative features[J]. Hum Genomics, 2018, 12(1): 11.
[7]	Nicola P, Blackburn PR, Rasmussen KJ, et al. De novo DDX3X missense variants in males appear viable and contribute to syndromic intellectual disability[J]. Am J Med Genet A, 2019, 179(4): 570-578.
[8]	Wang X, Posey JE, Rosenfeld JA, et al. Phenotypic expansion in DDX3X - a common cause of intellectual disability in females[J]. Ann Clin Transl Neurol, 2018, 5(10): 1277-1285.
[9]	Carneiro TN, Krepischi AC, Costa SS, et al. Utility of trio-based exome sequencing in the elucidation of the genetic basis of isolated syndromic intellectual disability: illustrative cases[J]. Appl Clin Genet, 2018, 11: 93-98.
[10]	Beal B, Hayes I, McGaughran J, et al. Expansion of phenotype of DDX3X syndrome: six new cases[J]. Clin Dysmorphol, 2019, 28(4): 169-174.
[11]	Scala M, Torella A, Severino M, et al. Three de novo DDX3X variants associated with distinctive brain developmental abnormalities and brain tumor in intellectually disabled females[J]. Eur J Hum Genet, 2019, 27(8): 1254-1259.
[12]	Chanes NM, Wong J, Lacassie Y. Further delineation of DDX3X syndrome[J]. Clin Dysmorphol, 2019, 28(3): 151-153.
[13]	Chen Y, Liu KY, Yang ZL, et al. A de novo DDX3X variant is associated with syndromic intellectual disability: case report and literature review[J]. Front Pediatr, 2020, 8: 303. doi: 10.3389/fped.2020.00303 pmid: 32714884
[14]	Hu L, Xin X, Lin S, et al. A child with a novel DDX3X variant mimicking cerebral palsy: a case report[J]. Ital J Pediatr, 2020, 46(1): 88.
[15]	Okano S, Miyamoto A, Makita Y, et al. Severe gastrointestinal symptoms caused by a novel DDX3X variant[J]. Eur J Med Genet, 2020, 63(12): 104058.
[16]	Lennox AL, Hoye ML, Jiang R, et al. Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis during fetal cortical development[J]. Neuron, 2020, 106(3): 404-420.
[17]	Moresco G, Costanza J, Santaniello C, et al. A novel de novo DDX3X missense variant in a female with brachycephaly and intellectual disability: a case report[J]. Ital J Pediatr, 2021, 47(1): 81.
[18]	Tang L, Levy T, Guillory S, et al. Prospective and detailed behavioral phenotyping in DDX3X syndrome[J]. Mol Autism, 2021, 12(1): 36.
[19]	高延, 洪琦, 吴慧旦, 等. 基因型-表型关联分析在孤独症谱系障碍早期诊断的研究[J]. 中国儿童保健杂志, 2018, 26(7): 733-736. doi: 10.11852/zgetbjzz2018-26-07-10
[20]	刘念, 王越, 史丹丹, 等. DDX3X基因突变致X连锁精神发育迟滞1例并文献复习[J]. 中华实用儿科临床杂志, 2020, 35(15): 1188-1190.
[21]	王琼, 杨颖, 刘黎礼, 等. 一例DDX3X基因新发变异所致X连锁精神发育迟滞患儿的分析[J]. 中华医学遗传学杂志, 2022, 39(10): 1111-1115.

参考文献	性别及例数	发育迟缓	面部畸形	小头畸形	肌张力低	癫痫或脑电图异常	运动障碍	行为问题	头颅MRI异常	视力问题	听力问题
[1]	女38例、男5例	43	30/38	12/38	29/38	6/38	18	23	13/37	13/38	3/38
[4]	女2例	2	2	2	2	2	0	0	2	2	2
[5]	女2例	2	2	0	1	0	1	0	0	1	0
[6]	男2例	2	0	0	0	0	2	1	2	0	0
[7]	男3例	3	3	0	2	1	3	0	2	2	2
[8]	女28例	28	19	7	19	1/13	17	6	18/20	9	0
[9]	女1例	1	1	0	0	0	0	0	1	0	1
[10]	女6例	6	6	1	0	1	2	3	1/4	3	0
[11]	女3例	3	3	0	2	2	3	1/1	3	2/2	1/1
[12]	女1例	1	1	0	0	0	0	1	1	1	0
[13]	女1例	1	1	1	0	1	1	1	1	0	0
[14]	女1例	1	1	0	1	0	1	1	1	0	0
[15]	女1例	1	1	0	1	0	0	1	1	0	0
[16]	女104例、男3例	106/106	NA	34/90	54/93	17/93	NA	48/48	82/89	37/92	7/95
[17]	女1例	1	1	0	1	1	0	0	1	1	0
[18]	女14例、男1例	12	14	NA	14	2	15	9	12/14	11	3
[19?-21]	女3例	3	3	2	3	0/1	3	3	2	0	0
本研究	女2例、男1例	3	3	2	3	0	3	1	1	1	0

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

RichHTML

PDF (PC)

赞

可视化

摘要/Abstract

引用本文

使用本文

图/表 3

参考文献 21

相关文章 1

Metrics

本文评价

推荐阅读 0