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

Abstract

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

CLC Number:

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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References 30

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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 %)

Clinical and genetic analysis of two children with Bain type of X-linked intellectual disability caused by HNRNPH2 gene variations based on XCI analysis

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