基于X染色体失活分析探讨2例X连锁智力障碍Bain型患儿的临床与遗传学特征

doi:10.12372/jcp.2026.25e0552

摘要/Abstract

摘要：

目的探讨2例X连锁智力障碍Bain型（MRXSB）患儿的临床表现及遗传学特征，分析X染色体失活（XCI）分析在基因型-表型关联中的作用。方法以2023年2月和2023年11月因“全面性生长发育迟缓、智力障碍”就诊的2例女性患儿作为研究对象，收集先证者的临床资料，对先证者及其家系进行家系外显子组测序（trio-WES）及Sanger测序验证；通过XCI检测试剂盒分析甲基化敏感位点，结合毛细管电泳定量分析X染色体偏倚失活程度；应用生物信息学工具预测变异致病性。结果 2例患儿分别为11和10月龄女性，均表现为全面性生长发育迟缓、智力障碍、肌张力低下及运动里程碑缺失，其中先证者1伴有喂养困难、吞咽障碍及屏气发作。trio-WES提示2例患儿均存在HNRNPH2基因（NM_019597）c.616C>T(p.Arg206Trp)杂合变异，Sanger测序验证该变异均属新发变异。XCI分析提示先证者1与先证者2均存在X染色体偏倚失活，偏倚率分别为17.3%和14.0%。结论本研究首次确诊了2例发病年龄<1岁的MRXSB女性患儿，通过XCI分析发现患儿X染色体均发生偏倚失活，结合患儿较早、较典型的临床表型，推测患儿XCI偏倚程度可能与表型严重性相关。XCI是女性X连锁智力障碍（XLID）临床异质性的核心调控机制，XCI联合trio-WES对女性XLID早期诊断及预后评估具有重要价值。

关键词: HNRNPH2基因, X连锁智力障碍Bain型, 外显子组测序, X染色体偏倚失活

Abstract:

Objective To investigate the clinical manifestations and genetic characteristics of 2 patients with intellectual disability, X-linked, syndromic, Bain type (MRXSB). Methods Two female children who visited the hospital due to "global growth and development delay and intellectual disability" in January 2023 and November 2023 were taken as the research subjects, and the clinical data of the probands were collected. Trio-whole exome sequencing (trio-WES) and Sanger sequencing verification were performed on the proband and his family. The methylation-sensitive sites were analyzed by using the XCI detection kit (XCI Filer), and the degree of X chromosome bias inactivation was quantitatively analyzed in combination with capillary electrophoresis. Bioinformatics tools were used to predict the pathogenicity of variations. Results The two children were girls aged 11 and 10 months respectively, both presenting with global growth and development delay, intellectual disability, hypotonia and absence of motor milestones. Among them, proband 1 was accompanied by feeding difficulties, dysphagia and shortness of breath symptoms. The results of trio-WES indicated that both of the two children had heterozygous variations of c.616C>T(p.Arg206Trp) in the HNRNPH2 gene (NM_019597), and Sanger sequencing verification suggested that the variations were all spontaneous variations. XCI analysis indicated that both of the two children had X chromosome bias inactivation, with bias rates of 17.3% and 14.0% respectively. Conclusions This study diagnosed for the first time two girls with MRXSB whose age of onset was<1 year old. Through XCI analysis, it was found that the X chromosomes of all the children were inactivated due to bias. Combined with the earlier and more typical clinical phenotypes of the patients, it was speculated that the degree of XCI bias in all the children might be correlated with the severity of the phenotype. XCI is the core regulatory mechanism of clinical heterogeneity in female XLID. The combination of XCI and trio-WES is of great value for the early diagnosis and prognosis evaluation of female XLID.

Key words: HNRNPH2 gene, intellectual disability, X-linked, syndromic, Bain type, whole exome sequencing, X chromosome bias inactivation

中图分类号:

沈子涵, 张钏, 郑雷, 周秉博, 田芯瑗, 王玉佩, 惠玲. 基于X染色体失活分析探讨2例X连锁智力障碍Bain型患儿的临床与遗传学特征[J]. 临床儿科杂志, 2026, 44(3): 192-201.

SHEN Zihan, ZHANG Chuan, ZHENG Lei, ZHOU Bingbo, TIAN Xinyuan, WANG Yupei, HUI Ling. Clinical and genetic analysis of two children with Bain type of X-linked intellectual disability caused by HNRNPH2 gene variations based on XCI analysis[J]. Journal of Clinical Pediatrics, 2026, 44(3): 192-201.

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性别	文献	发育迟缓/ 智力障碍	肌肉骨骼问题/ 运动障碍	语言发育障碍	喂养困难/ 胃肠道问题	异常面容	精神行为异常	睡眠障碍	小头畸形	发育倒退	癫痫	头颅影像学异常
男性	Bain等^[16]	4/4	2/4	3/4	2/4	3/4	3/4	1/4	1/4	1/4	2/4	3/4
	Gillentine等^[17]	1/1	1/1	0/1	0/1	1/1	0/1	－	0/1	0/1	0/1	0/1
	Kreienkamp等^[18]	8/8	7/8	7/8	3/8	7/8	6/8	5/8	2/8	－	4/8	2/8
	Somashekar等^[19]	1/1	1/1	1/1	1/1	1/1	1/1	－	1/1	1/1	1/1	0/1
	Harmsen等^[20]	1/1	1/1	1/1	1/1	1/1	0/1	－	1/1	－	0/1	0/1
	Jepsen等^[21]	2/2	2/2	2/2	2/2	0/2	1/2	－	1/2	2/2	1/2	2/2
	Lin等^[22]	1/1	1/1	1/1	1/1	1/1	0/1	－	1/1	1/1	0/1	0/1
	合计	18/18	15/18	15/18	10/18	14/18	11/18	6/12	7/18	5/9	8/18	7/18
		(100%)	(83.33%)	(83.33%)	(55.56%)	(77.78%)	(61.11%)	(50.00%)	(38.89%)	(55.56%)	(44.44%)	(38.89%)
女性	Bain等^[16]	29/29	20/29	22/29	24/29	18/29	22/29	10/28	9/29	11/29	10/29	8/28
	Gillentine等^[17]	8/8	4/8	1/8	3/8	5/8	2/8	－	4/8	0/8	1/8	0/8
	Somashekar等^[19]	1/1	1/1	1/1	1/1	－	1/1	－	1/1	1/1	1/1	1/1
	White-Brown等^[23]	1/2	1/2	1/2	0/2	1/2	1/2	1/2	0/2	1/2	0/2	1/2
	Peron等^[24]	1/1	1/1	1/1	1/1	1/1	1/1	1/1	0/1	1/1	0/1	1/1
	Demos等^[25]	1/1	1/1	－	0/1	1/1	1/1	－	1/1	－	1/1	1/1
	先证者1	1/1	1/1	1/1	1/1	0/1	0/1	1/1	1/1	0/1	0/1	0/1
	先证者2	1/1	1/1	1/1	1/1	－	0/1	1/1	1/1	0/1	0/1	0/1
	合计	43/44	30/44	28/43	31/44	26/42	28/44	14/33	17/44	14/43	13/44	12/43
		(97.73%)	(68.18%)	(65.12%)	(70.45%)	(61.90%)	(63.64%)	(42.42%)	(38.64%)	(32.56%)	(29.55%)	(27.91%)
总计		61/62	45/62	43/61	41/62	40/60	39/62	20/45	24/62	19/52	21/62	19/61
		(98.39%)	(72.58%)	(70.49%)	(66.13%)	(66.67%)	(62.90%）	(44.44%)	(38.71%)	(36.54%)	(33.87%)	(31.15 %)