一对双胞胎脑瘫患儿全基因组测序分析
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摘要
目的:利用全基因组测序(WGS)技术分析一对双胞胎脑瘫患儿的遗传学病因。方法:采用WGS技术对一对双胞胎脑瘫患儿进行检测,同时对其父母进行了基因芯片的验证试验。结果:共发现30个与脑瘫有关联的基因,其中相关热点的基因有人类转录激活因子蛋白4、GAD1、ADD3等;在KANK1外显子区域发现一个共有的SNP突变;在2号染色体上发现有大约120 kb的重复,14号染色体上有大约280 kb和540 kb的缺失; 14号染色体片段异常来自母亲。结论:脑瘫遗传因素复杂,可能由多个基因诱发; WGS技术适用于脑瘫的遗传学研究。
Aim: To analyze a pair of twins with cerebral palsy by whole genome sequencing( WGS) technique. Methods: A pair of twins with cerebral palsy were subjected to WGS. The parents were tested on a microarray. Results: A total of 30 genes associated with cerebral palsy were found. The related hot genes included human transcription activator protein4,GAD1,ADD3,etc,and a common SNP mutation was found in the exon region of KANK1. The duplication of 120 kb on chromosome 2 and deletion of 280 kb and 540 kb on chromosome 14 was found,respectively. Abnormal chromosome 14 comes from mother. Conclusion: The genetic factors of cerebral palsy is complex,and cerebral palsy may be induced by multiple genes. WGS is an appropriate technique for the study of cerebral palsy.
Aim: To analyze a pair of twins with cerebral palsy by whole genome sequencing( WGS) technique. Methods: A pair of twins with cerebral palsy were subjected to WGS. The parents were tested on a microarray. Results: A total of 30 genes associated with cerebral palsy were found. The related hot genes included human transcription activator protein4,GAD1,ADD3,etc,and a common SNP mutation was found in the exon region of KANK1. The duplication of 120 kb on chromosome 2 and deletion of 280 kb and 540 kb on chromosome 14 was found,respectively. Abnormal chromosome 14 comes from mother. Conclusion: The genetic factors of cerebral palsy is complex,and cerebral palsy may be induced by multiple genes. WGS is an appropriate technique for the study of cerebral palsy.
引文
[1]冼莹,谭莉娟,樊金莲,等.高压氧综合治疗对小儿早期脑瘫患者认知言语及运动能力的改善作用[J].河北医学,2018,24(2):266
[2] OSKOUI M,GAZZELLONE MJ,THIRUVAHINDRAPURAM B,et al. Clinically relevant copy number variations detected in cerebral palsy[J]. Nat Commun,2015,8(36):7949
[3] SEGEL R,BEN-PAZI H,ZELIGSON SA,et al. Copy number variations in cryptogenic cerebral palsy[J]. Neurology,2015,84(16):1660
[4]李晓捷,唐久来,马丙祥,等.脑性瘫痪的定义、诊断标准及临床分型[J].中华实用儿科临床杂志,2014,29(19):1520
[5] INOUE K. PLPI-related inherited dysnyelinating disorders:Pelizaeus-Merzbacher disease and spastic paraplegia type2[J]. Neurogentics,2005,6(1):1
[6] KORNER G,NOAIN D,YING M,et al. brain catecholamine depletion and motor impairment in a Th knockin mouse with type B tyrosine hydroxylase deficiency[J].Brain,2015,138(10):2948
[7] ROSE SJ,YU XY,HEINZER AK,et al. A new knock-in mouse model of I-DOPA-responsive dystonua[J]. Brain,2015,138(10):2987
[8]LIU YY,BAO XH,WANG D,et al. Allelic Variations of Glut-1 deficiency syndrome:the Chinese experience[J].Pediatr Neurol,2012,47(1):30
[9]NICOLAI S,FILIPPI S,CAPUTO M. et at Identification of novel proteins Co-purifying with cockayne syndrome group B(CSB)reveals potential roles for CSB in RNA metabolism and chromatin dynamics[J]. PLo S One,2015,10(6):e0128558
[10]孟文彬,刘锋伟,董婵,等.全身振动训练对1-3岁痉挛型脑瘫患儿下肢运动功能的影响[J].郑州大学学报:医学版,2017,52(6):740
[11]MORENO-DE-LUCA A,HELMERS SL,MAO H,et al.Adaptor protein complex-4(AP-4)deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability[J]. J Med Genet,2011,48(2):141
[12]DOHARE P,ZIA MT,AHMED E,et al. AMPA-Kainate receptor inhibition promotes neurologic recovery in premature rabbits with intraventricular hemorrhage[J]. J Neurosci,2016,36(11):3363
[13]WANG HL,XU YR,CHEN MJ,et al. Genetic association study of adaptor protein complex 4 with cerebral palsy in a Han Chinese population[J]. Mol Biol Rep,2013,40(11):6459
[14]ZHUBI A,CHEN Y,GUIDOTTI A,et al. Epigenetic regulation of RELN and GAD1 in the frontal cortex(FC)of autism spectrum disorder(ASD)subjects[J]. Int J Dev Neurosci,2017,62:63
[15]PEI JH,DONG R,YANG YF,et al. Association of STAT4genetic polymorphisms with biliary atresia in Chinese patients[J]. Int J Clin Exp Pathol,2017,10(3):3451
[16]KRUER MC,JEPPERSON T,DUTTA S,et al. Mutations inγadducin are associatedwith inherited cerebral palsy[J].Ann Neurol,2013,74(6):805
[17]Varner MW,Marshall NE,Rouse DJ,et al. The association of cord serum cytokines with neurodevelopmental outcomes[J]. Am J Perinatol,2015,30(2):115
[18]BOUCHET BP,GOUGH RE,AMMON YC,et al. TalinKANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions[J].Elife,2016,5:e18124
[19]FONG CY,MUMFORD AD,LIKEMAN MJ,et al. Cerebral palsy in siblings caused by compound heterozygous mutations in the gene encoding protein C[J]. Dev Med Child Neurol,2010,52(5):489
[20]万珍艳,庄桂英,张山丹. a EEG对足月新生儿缺氧缺血性脑病患儿背景活动睡眠-清醒周期及惊厥发作的评价分析[J].河北医学,2017,23(2):309
[21]FATTAL-VALEVSKI A,KENET G,KUPFERMINC MJ,et al. Role of thrombophilic risk factors in children with nonstroke cerebral palsy[J]. Thromb Res,2005,116(2):133
[22]VERGHESE PB,CASTELLANO JM,HOLTZMAN DM.Apolipoprotein E inalzheimer's disease and other neurological disorder[J]. Lancet Neurol,2011,10(3):241
[23]XU YR,WANG HL,SUN YY,et al. The association of apolipoprotein E gene polymorphisms with cerebral palsy in Chinese infants[J]. Mol Genet Genomics,2014,289(3):411
[24]孔德荣,张小明,赵星梅,等.精神分裂症患者载脂蛋白E基因多态性[J].郑州大学学报(医学版),2012,47(5):651
[25]SHANG Q,ZHOU C,LIU D,et al. Association between osteopontin genepolymorphisms and cerebral palsy in a Chinese population[J]. Neuromolecular Med,2016,18(2):232
[26]BI D,WANG H,SHANG Q,et al. Association of COL4A1gene polymorphismswith cerebral palsy in a Chinese Han population[J]. Clin Genet,2016,90(2):149
[27]夏艳秋,王娜,阙菡雅,等. NOX1 siRNA对TNF-α诱导的A549细胞凋亡的影响[J].郑州大学学报(医学版),2016,51(5):591
[28]MCMICHAEL G,GIRIRAJAN S,MORENO-DE-LUCA A,et al. Rare copy number variation in cerebral palsy[J].Eur J Hum Genet,2014,22(1):40
[2] OSKOUI M,GAZZELLONE MJ,THIRUVAHINDRAPURAM B,et al. Clinically relevant copy number variations detected in cerebral palsy[J]. Nat Commun,2015,8(36):7949
[3] SEGEL R,BEN-PAZI H,ZELIGSON SA,et al. Copy number variations in cryptogenic cerebral palsy[J]. Neurology,2015,84(16):1660
[4]李晓捷,唐久来,马丙祥,等.脑性瘫痪的定义、诊断标准及临床分型[J].中华实用儿科临床杂志,2014,29(19):1520
[5] INOUE K. PLPI-related inherited dysnyelinating disorders:Pelizaeus-Merzbacher disease and spastic paraplegia type2[J]. Neurogentics,2005,6(1):1
[6] KORNER G,NOAIN D,YING M,et al. brain catecholamine depletion and motor impairment in a Th knockin mouse with type B tyrosine hydroxylase deficiency[J].Brain,2015,138(10):2948
[7] ROSE SJ,YU XY,HEINZER AK,et al. A new knock-in mouse model of I-DOPA-responsive dystonua[J]. Brain,2015,138(10):2987
[8]LIU YY,BAO XH,WANG D,et al. Allelic Variations of Glut-1 deficiency syndrome:the Chinese experience[J].Pediatr Neurol,2012,47(1):30
[9]NICOLAI S,FILIPPI S,CAPUTO M. et at Identification of novel proteins Co-purifying with cockayne syndrome group B(CSB)reveals potential roles for CSB in RNA metabolism and chromatin dynamics[J]. PLo S One,2015,10(6):e0128558
[10]孟文彬,刘锋伟,董婵,等.全身振动训练对1-3岁痉挛型脑瘫患儿下肢运动功能的影响[J].郑州大学学报:医学版,2017,52(6):740
[11]MORENO-DE-LUCA A,HELMERS SL,MAO H,et al.Adaptor protein complex-4(AP-4)deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability[J]. J Med Genet,2011,48(2):141
[12]DOHARE P,ZIA MT,AHMED E,et al. AMPA-Kainate receptor inhibition promotes neurologic recovery in premature rabbits with intraventricular hemorrhage[J]. J Neurosci,2016,36(11):3363
[13]WANG HL,XU YR,CHEN MJ,et al. Genetic association study of adaptor protein complex 4 with cerebral palsy in a Han Chinese population[J]. Mol Biol Rep,2013,40(11):6459
[14]ZHUBI A,CHEN Y,GUIDOTTI A,et al. Epigenetic regulation of RELN and GAD1 in the frontal cortex(FC)of autism spectrum disorder(ASD)subjects[J]. Int J Dev Neurosci,2017,62:63
[15]PEI JH,DONG R,YANG YF,et al. Association of STAT4genetic polymorphisms with biliary atresia in Chinese patients[J]. Int J Clin Exp Pathol,2017,10(3):3451
[16]KRUER MC,JEPPERSON T,DUTTA S,et al. Mutations inγadducin are associatedwith inherited cerebral palsy[J].Ann Neurol,2013,74(6):805
[17]Varner MW,Marshall NE,Rouse DJ,et al. The association of cord serum cytokines with neurodevelopmental outcomes[J]. Am J Perinatol,2015,30(2):115
[18]BOUCHET BP,GOUGH RE,AMMON YC,et al. TalinKANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions[J].Elife,2016,5:e18124
[19]FONG CY,MUMFORD AD,LIKEMAN MJ,et al. Cerebral palsy in siblings caused by compound heterozygous mutations in the gene encoding protein C[J]. Dev Med Child Neurol,2010,52(5):489
[20]万珍艳,庄桂英,张山丹. a EEG对足月新生儿缺氧缺血性脑病患儿背景活动睡眠-清醒周期及惊厥发作的评价分析[J].河北医学,2017,23(2):309
[21]FATTAL-VALEVSKI A,KENET G,KUPFERMINC MJ,et al. Role of thrombophilic risk factors in children with nonstroke cerebral palsy[J]. Thromb Res,2005,116(2):133
[22]VERGHESE PB,CASTELLANO JM,HOLTZMAN DM.Apolipoprotein E inalzheimer's disease and other neurological disorder[J]. Lancet Neurol,2011,10(3):241
[23]XU YR,WANG HL,SUN YY,et al. The association of apolipoprotein E gene polymorphisms with cerebral palsy in Chinese infants[J]. Mol Genet Genomics,2014,289(3):411
[24]孔德荣,张小明,赵星梅,等.精神分裂症患者载脂蛋白E基因多态性[J].郑州大学学报(医学版),2012,47(5):651
[25]SHANG Q,ZHOU C,LIU D,et al. Association between osteopontin genepolymorphisms and cerebral palsy in a Chinese population[J]. Neuromolecular Med,2016,18(2):232
[26]BI D,WANG H,SHANG Q,et al. Association of COL4A1gene polymorphismswith cerebral palsy in a Chinese Han population[J]. Clin Genet,2016,90(2):149
[27]夏艳秋,王娜,阙菡雅,等. NOX1 siRNA对TNF-α诱导的A549细胞凋亡的影响[J].郑州大学学报(医学版),2016,51(5):591
[28]MCMICHAEL G,GIRIRAJAN S,MORENO-DE-LUCA A,et al. Rare copy number variation in cerebral palsy[J].Eur J Hum Genet,2014,22(1):40