EBF3基因杂合突变导致1例神经发育障碍综合征

doi:10.6040/j.issn.1671-7554.0.2019.1529

摘要/Abstract

摘要： 目的对一例体格发育迟缓、智力低下、共济失调及肌张力低下等神经发育障碍患儿的临床特点及致病基因进行分析。方法详细分析患儿的临床表型,分别采集患儿及父母的抗凝外周血,对患儿样本进行外周血淋巴细胞G显带核型分析和SNP-array检测,对患儿及父母的外周血DNA进行全外显子组测序,生物信息学分析突变位点的致病性。结果患儿外周血染色体核型分析及SNP-array未发现致病突变,全外显子组测序结果表明患儿存在EBF3基因杂合突变 c.626G>A(p.Arg209Gln),利用Sanger测序进行突变位点验证,结果证实患儿存在该位点突变,而父母没有该位点突变。结论该患儿的发病原因为EBF3基因新发杂合突变 c.626G>A(p.Arg209Gln),该突变位点国内尚无报道。

关键词: 肌张力减退、共济失调和发育迟缓综合征, 全外显子组测序, EBF3基因, 基因突变

Abstract: Objective To explore the genetic basis of an infant with global developmenfal delay, mental retardation,hypotonia and ataxia. Methods The clinical phenotypes of the infant were analyzed. Peripheral blood samples were collected from the infant and his parents. The infant blood sample underwent G-banding chromosome analysis and SNP-array. The infant and his parents’ blood samples underwent whole exome sequencing. The pathogenicity of mutation sites was analyzed with bioinformatics. Results The G-band chromosome analysis and SNP-array of the infant showed no pathogenic mutation. The whole exome sequencing revealed that there was a heterozygous mutation of EBF3 c.626G>A(p.Arg209Gln)in the infant, which was validated by Sanger sequencing, but the parents had no such mutation. Conclusion The heterozygous mutation of EBF3 c.626G>A(p.Arg209Gln)probably underlies the disorder in the infant, which has not been reported in China.

Key words: Hypotonia, ataxia and delayed development syndrome, Whole exome sequencing, EBF3 gene, Gene mutation

中图分类号:

R596.2

刘娜,刘奇迹,牟凯,程翠云. EBF3基因杂合突变导致1例神经发育障碍综合征[J]. 山东大学学报 (医学版), 2020, 58(4): 105-109.

LIU Na, LIU Qiji, MOU Kai, CHENG Cuiyun. A case of syndromic neurodevelopmental disorder caused by heterozygous mutation in EBF3[J]. Journal of Shandong University (Health Sciences), 2020, 58(4): 105-109.

参考文献

[1] Sleven H, Welsh SJ, Yu J, et al. De novo mutations in EBF3 cause a neurodevelopmental syndrome [J]. Am J Hum Genet, 2017, 100(1): 138-150.
[2] Zardo G, Tiirikainen MI, Hong C, et al. Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors [J]. Nat Genet, 2002, 32(3): 453-458.
[3] Lopes F, Soares G, Goncalves-Rocha M, et al. Whole gene deletion of EBF3 supporting haploinsufficiency of this gene as a mechanism of neurodevelopmental disease[J]. Front Genet, 2017, 8: 143. doi: 10.3389/fgene.2017.00143. eCollection 2017.
[4] Chao HT, Davids M, Burke E, et al. A syndromic neurodevelopmental disorder caused by de novo variants in EBF3[J]. Am J Hum Genet, 2017, 100(1): 128-137.
[5] Blackburn PR, Barnett SS, Zimmermann MT, et al.Novel de novo variant in EBF3 is likely to impact DNA binding in a patient with a neurodevelopmental disorder and expanded phenotypes: patient report, in silico functional assessment, and review of published cases [J]. Cold Spring Harb Mol Case Stud, 2017, 3(3): a001743. doi:10.1101/mcs.a001743.
[6] Tanaka AJ, Cho MT, Willaert R, et al. De novo variants in EBF3 are associated with hypotonia, developmental delay, intellectual disability, and autism[J]. Cold Spring Harb Mol Case Stud, 2017, 3(6). pii: a002097. doi: 10.1101/mcs.a002097.
[7] Harms FL, Girisha KM, Hardigan AA, et al. Mutations in EBF3 disturb transcriptional profiles and cause intellectual disability, ataxia, and facial dysmorphism [J]. Am J Hum Genet, 2017, 100(1): 117-127.
[8] Friocourt G, Parnavelas JG. Identification of Arx targets unveils new candidates for controlling cortical interneuron migration and differentiation [J]. Front Cell Neurosci, 2011, 27, 5: 28. doi: 10.3389/fnbeh.2011.00028.
[9] Prasad BC, Ye B, Zackhary R, et al.unc-3, a gene required for axonal guidance in Caenorhabditis elegans, encodes a member of the O/E family of transcription factors[J]. Development, 1998, 125(8): 1561-1568.
[10] Hattori Y, Usui T, Satoh D, et al. Sensory-neuron subtype-specific transcriptional programs controlling dendrite morphogenesis: genome-wide analysis of abrupt and Knot/Collier [J]. Dev Cell, 2013, 27(5): 530-544.
[11] Wang SS, Lewcock JW, Feinstein P, et al. Genetic disruptions of O/E2 and O/E3 genes reveal involvement in olfactory receptor neuron projection[J]. Development, 2004, 131(6): 1377-1388.
[12] Jin S, Kim J, Willert T, et al. Ebf factors and MyoD cooperate to regulate muscle relaxation via Atp2a1 [J]. Nat Commun, 2014, 5: 3793. doi: 10.1038/ncomms4793.
[13] Faria AC, Rabbi-Bortolini E, Reboucas M, et al. Craniosynostosis in 10q26 deletion patients: A consequence of brain underdevelopment or altered suture biology [J] Am J Med Genet A, 2016, 170A(2): 403-409.
[14] Liberg D, Sigvardsson M, Akerblad P. The EBF/Olf/Collier family of transcription factors: regulators of differentiation in cells originating from all three embryonal germ layers [J]. Mol Cell Biol, 2002, 22(24): 8389-8397.
[15] Siponen MI, Wisniewska M, Lehtio L, et al. Structural determination of functional domains in early B-cell factor(EBF)family of transcription factors reveals similarities to Rel DNA-binding proteins and a novel dimerization motif[J]. J Biol Chem, 2010, 285(34): 25875-25879.
[16] Fulp CT, Cho G, Marsh ED, et al. Identification of Arx transcriptional targets in the developing basal forebrain[J]. Hum Mol Genet, 2008, 17(23): 3740-3760.
[17] Alwan A, Modell B. Recommendations for introducing genetics services in developing countries[J]. Nat Rev Genet, 2003, 4(1): 61-68.
[18] de Ligt J, Willemsen MH, van Bon BW, et al. Diagnostic exome sequencing in persons with severe intellectual disability[J]. N Engl J Med, 2012, 367(20): 1921-1929.
[19] Zhu X, Petrovski S, Xie P, et al. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios[J]. Genet Med, 2015, 17(10): 774-781.

相关文章 15

[1]	薛美娟,石艳,邵琳琳,王琳,张昀,张阿敏. 遗传性血栓性血小板减少性紫癜1例并文献复习[J]. 山东大学学报 (医学版), 2022, 60(3): 121-124.
[2]	亓梦雨,周敏然,孙洺山,李世洁,陈春燕. T大颗粒淋巴细胞白血病合并原发性骨髓纤维化1例[J]. 山东大学学报 (医学版), 2022, 60(2): 118-120.
[3]	潘鹏飞,徐立升,纪坤乾,王得翔,李玉. 以呼吸衰竭起病的线粒体肌病1例及文献回顾[J]. 山东大学学报 (医学版), 2022, 60(2): 54-59.
[4]	史本康,陈守臻,曲思凤,王勇,刘磊. 临床常见快速进展前列腺癌临床特点及研究进展[J]. 山东大学学报 (医学版), 2021, 59(9): 110-116.
[5]	孙宇,陈娜,马爱华. SLC35A2基因突变致先天性糖基化障碍1例[J]. 山东大学学报 (医学版), 2021, 59(4): 113-116.
[6]	黄秀丽,刘丙菊,孙立锋. PIK3CD基因突变致PI3Kδ过度活化综合征1例并文献复习[J]. 山东大学学报 (医学版), 2021, 59(3): 107-112.
[7]	王正阳,夏艳,师凯旋,陶琨,王小杰. 曲美替尼在卵巢癌中对PAX8的表达作用[J]. 山东大学学报 (医学版), 2021, 59(10): 23-29.
[8]	丁婷婷,邹东,刘浩辰. 一个非综合征型先天缺牙家系的MSX1基因突变分析[J]. 山东大学学报 (医学版), 2019, 57(4): 97-100.
[9]	窦春慧,邵建华,董学斌,张凌,陈萍,赵红玉,顾琳萍,孙琳,解杰,王敏,王娟,李娜,李凡,李大启. 骨髓增生异常综合征患者基因突变对地西他滨临床疗效的影响[J]. 山东大学学报 (医学版), 2019, 57(3): 42-48.
[10]	张文慧,陈昀,常亚丽,周亚伟,房云海,张心声,郭农建. 山东省55例血友病A患者基因检测及分析[J]. 山东大学学报 (医学版), 2019, 57(12): 57-61.
[11]	胡丽萍,王乐,金亮,刘燕霞,崔东清,曹丽丽. SYNE1基因复合杂合突变导致常染色体隐性小脑共济失调1型病例报告并文献复习[J]. 山东大学学报 (医学版), 2019, 57(11): 78-82.
[12]	肖红梅. 卵母细胞成熟障碍研究进展[J]. 山东大学学报 (医学版), 2018, 56(4): 18-22.
[13]	卢敏, 陈昀, 丁卜同, 常亚丽, 周亚伟, 赵爱平, 郭农建. 山东省乙型血友病患者的基因检测及分析[J]. 山东大学学报（医学版）, 2015, 53(3): 87-92.
[14]	朱发梅, 郑家法, 谢鼎华, 胡鹏. 5个大前庭水管综合征家系SLC26A4基因的检测分析[J]. 山东大学学报（医学版）, 2014, 52(10): 90-95.
[15]	孙瑾，韩波，魏美丽，杨文巍，王介忠，刘永蛟. 动脉导管未闭患儿TFAP2B基因变异筛查[J]. 山东大学学报(医学版), 2013, 51(3): 72-75.

多维度评价

Viewed

Full text

619

HTML			PDF

Just accepted	Online first	Issue	Just accepted	Online first	Issue
0	0	0	0	0	619

From	Others	local

Times	131	488
Rate	21%	79%

Abstract

2036

Just accepted	Online first	Issue

0	0	2036

	From	Others

	Times	2036
	Rate	100%

Cited

Web of Science	Crossref	ScienceDirect	Search for Citations in Google Scholar >>


This page requires you have already subscribed to WoS.

Shared

Discussed