5例环状染色体综合征的产前诊断和表型分析
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摘要
目的通过对5例环状染色体综合征患者进行细胞遗传学分析,探讨高分辨率G显带核型分析和微阵列比较基因组杂交两种方法对环状染色体的诊断优势,并探讨5例环状染色体综合染色体缺失片段和定位于其中的基因与临床表型的关系。方法 2017年就诊于深圳市妇幼保健院的5例环状染色体综合征病例纳入研究。用染色体G带高分辨显带和微阵列比较基因组杂交技术对5例环状染色体进行识别与定位。结果病例1羊水染色体核型结果:45,XN,-18[13]/46,XN,r(18)(p11.2q22.3)[47],羊水微阵列比较基因组杂交结果:arr[GRCH37]18q22.3q23(70,063,358-78,013,728)x1;18p11.32p11.23(136,227-8,002,810)x1;18p11.23p11.22(8,013,797-8,877,061)x3。病例2脐血染色体核型结果:46,XN,rec(21)r(21q)dup(21q)(q11.2-q22.2)?,脐血微阵列比较基因组杂交结果:arr[GRCH37]21q11.2q22.3(15,016,486-47,044,951)x2～4;32MB.21q22.3(47,052,734-48,093,361)x1。病例3脐血染色体核型结果:45,XY,-21[14]/46,XN,r(21)[86],脐血微阵列比较基因组杂交结果:arr[GRCh37]21q11.2q22.3(15016486_47632178)x3[0.47];21q22.3(47632178_48093361)x1。病例4羊水染色体核型结果:46,XX,r(4)(p16q35),羊水微阵列比较基因组杂交结果:arr[GRCH37]4p16.3p16.1(68,345-8,721,580)x1;4q35.2(190,602,426-190,957,460)x1。病例5羊水染色体核型结果:mos45,X[46]/46,x,r(x)(p22.3q21.1)[34],羊水微阵列比较基因组杂交结果:Xq21.1q28(82119329_155233098)x1;Xp22.33p22.32(168551_5677733)x1;Xp22.32q21.1(5677733-82119329)x1[0.4]。结论 (1)环状染色体综合征患儿的临床特征与染色体区带缺失重复部位和大小相关。(2)G显带核型分析和微阵列比较基因组杂交诊断环状染色体各有优势:第一传统的G显带核型分析首先可判断是否存在嵌合的染色体核型;第二即使微阵列比较基因组结果提示染色体仅有长臂或短臂的缺失,也不能排除环状染色体的可能,亦需要传统的G显带染色体核型共同分析;第三微阵列比较基因组杂交能够精确基因组微小缺失和重复,利于基因组拷贝数变异与临床表型分析。因此联合G显带核型分析和微阵列比较基因组杂交对于环状染色体的诊断和遗传咨询具有指导意义。
Objective:To assess 5 prenatal cases with ring chromosome using both G-banding karyotype analysis and microarray comparative genomic hybridization;To explore diagnostic advantages of the two methods;To search the correlation between the genotype and the clinical phenotype on the 5 ring chromosome cases. Methods:Five fetuses were enrolled in this study. Identification and location of ring chromosome were performed with G-banding karyotype and microarray comparative genomic hybridization. Results:The karyotype of case 1 was 45,XN,-18[13]/46,XN,r(18)(p11.2 q22.3)[47],the aCGH revealed arr[GRCH37] 18 q22.3 q23(70,063,358-78,013,728)×1;18 p11.32 p11.23(136,227-8,002,810)×1;The karyotype of case 2 was46,XN,rec(21)r(21 q)dup(21 q)(q11.2-q22.2)?,the aCGH revealed arr[GRCH37]21 q11.2 q22.3(15,016,486-47,044,951)×2～4;32 MB.21 q22.3(47,052,734-48,093,361)x1;The karyotype of case 3 was45,XY,-21[14]/46,XN,r(21)[86],the aCGH revealed arr[GRCh37] 21 q11.2 q22.3(15016486 _476 32178)×3[0.47];21 q22.3(47632178_48093361)×1;The karyotype of case 4 was46,XX,r(4)(p16 q35),the aCGH revealed arr[GRCH37]4 p16.3 p16.1(68,345-8,721,580)×1;4 q35.2(190,602,426-190,957,460)×1;The karyotype of case 5 was mos45,X[46]/46,X,r(x)(p22.3 q21.1)[34],the aCGH revealed Xq21.1 q28(82119329_155233098)×1;Xp22.33 p22.32(168551_5677733)×1;Xp22.32 q21.1(5677733-82119329)x1[0.4].Conclusions:Phenotype associated with ring chromosomes were extreme variable by multiple factors,including the highly variable extent and location,and the presence of duplications. And our data confirm the importance of G-banding karyotype and microarray comparative genomic hybridization to determine the ring chromosome morphology and content.
Objective:To assess 5 prenatal cases with ring chromosome using both G-banding karyotype analysis and microarray comparative genomic hybridization;To explore diagnostic advantages of the two methods;To search the correlation between the genotype and the clinical phenotype on the 5 ring chromosome cases. Methods:Five fetuses were enrolled in this study. Identification and location of ring chromosome were performed with G-banding karyotype and microarray comparative genomic hybridization. Results:The karyotype of case 1 was 45,XN,-18[13]/46,XN,r(18)(p11.2 q22.3)[47],the aCGH revealed arr[GRCH37] 18 q22.3 q23(70,063,358-78,013,728)×1;18 p11.32 p11.23(136,227-8,002,810)×1;The karyotype of case 2 was46,XN,rec(21)r(21 q)dup(21 q)(q11.2-q22.2)?,the aCGH revealed arr[GRCH37]21 q11.2 q22.3(15,016,486-47,044,951)×2～4;32 MB.21 q22.3(47,052,734-48,093,361)x1;The karyotype of case 3 was45,XY,-21[14]/46,XN,r(21)[86],the aCGH revealed arr[GRCh37] 21 q11.2 q22.3(15016486 _476 32178)×3[0.47];21 q22.3(47632178_48093361)×1;The karyotype of case 4 was46,XX,r(4)(p16 q35),the aCGH revealed arr[GRCH37]4 p16.3 p16.1(68,345-8,721,580)×1;4 q35.2(190,602,426-190,957,460)×1;The karyotype of case 5 was mos45,X[46]/46,X,r(x)(p22.3 q21.1)[34],the aCGH revealed Xq21.1 q28(82119329_155233098)×1;Xp22.33 p22.32(168551_5677733)×1;Xp22.32 q21.1(5677733-82119329)x1[0.4].Conclusions:Phenotype associated with ring chromosomes were extreme variable by multiple factors,including the highly variable extent and location,and the presence of duplications. And our data confirm the importance of G-banding karyotype and microarray comparative genomic hybridization to determine the ring chromosome morphology and content.
引文
[1]Guilherme R KE,Hamid A,Bhatt S,Volleth M,Polityko A,Kulpanovich A,Dufke A,Albrecht B,Morlot S,Brecevic L,Petersen M,Manolakos E,Kosyakova N,Liehr T.Human Ring Chromosomes-New Insights for their Clinical Significance[J].Balkan J Med Genet,2013 Jun,16(1):13-20.
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[6]Rossi E,Riegel M,Messa J,Gimelli S,Maraschio P,Ciccone R,et al.Duplications in addition to terminal deletions are present in a proportion of ring chromosomes:clues to the mechanisms of formation[J].Journal of Medical Genetics,2007,45(3):147-54.
[7]Blewitt ME,Gendrel AV,Pang Z,Sparrow DB,Whitelaw N,Craig JM,et al.SmcHD1,containing a structural-maintenanceof-chromosomes hinge domain,has a critical role in Xinactivation[J].Nature genetics,2008,40(5):663-9.
[8]Ferguson PJ.Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia(Majeed syndrome)[J].Journal of Medical Genetics,2005,42(7):551-7.
[9]Poretti A,H?usler M,von Moers A,Baumgartner B,Zerres K,Klein A,et al.Ataxia,Intellectual Disability,and Ocular Apraxia with Cerebellar Cysts[J]:A New Disease?The Cerebellum,2013,13(1):79-88.
[10]Idkowiak J RT,Dhir V,Patel P,Shackleton CH,Taylor NF,Krone N,Arlt W.A Missense Mutation in the Human Cytochrome b5 Gene causes 46,XY Disorder of Sex Development due to True Isolated 17,20 Lyase Deficiency.Send to[J]J Clin Endocrinol Metab,2012 Mar,97(3):E465-75.
[11]Feenstra I,Vissers Lisenka ELM,Pennings Ronald JE,Nillessen W,Pfundt R,Kunst Henricus P,et al.Disruption of Teashirt Zinc Finger Homeobox 1 Is Associated with Congenital Aural Atresia in Humans[J].The American Journal of Human Genetics,2011,89(6):813-9.
[12]Opitz JM,Burn J.RE:Correspondence from Wieczorek&Gillessen-Kaesbach and Hing&Parisi[J].American Journal of Medical Genetics Part A,2006,140A(21):2385.
[13]Ioannis Papoulidis EM,Elisavet Siomou,Kostantinos Kefalas,Loretta Thomaidis,Thomas Liehr AV,Apostolos Athanasiadis,Orsetta Zuffardi and Michael B.Petersen1.A fetus with ring chromosome 21 characterized by aCGH shows no clinical findings after birth[J].PRENATAL DIAGNOSIS,2010,30:586-588.
[14]Muroya K,Yamamoto K,Fukushima Y,Ogata T.Ring chromosome 21 in a boy and a derivative chromosome 21 in the mother:Implication for ring chromosome formation[J].American Journal of Medical Genetics,2002,110(4):332-7.
[15]Samarth RM,Gandhi P,Pandey H,Maudar KK.Mosaicism for trisomy 21 and ring(21)in a male born to normal parents:A case report[J].Gene,2012,511(1):109-12.
[16]Cetin Z,Altiok-Clark O,Sevuk M,Berker Karauzum S.Ring chromosome 21 and monosomy 21 mosaicism in a patient with azoospermia[J].Andrologia,2015,47(1):112-5.
[17]Chen CP,Lin YH,Chou SY,Su YN,Chern SR,Chen YT,et al.Mosaic ring chromosome 21,monosomy 21,and isodicentric ring chromosome 21:prenatal diagnosis,molecular cytogenetic characterization,and association with 2-Mb deletion of21q21.1-q21.2 and 5-Mb deletion of 21q22.3[J].Taiwanese journal of obstetrics&gynecology,2012,51(1):71-6.
[18]Akbas H,Cine N,Erdemoglu M,Atay AE,Simsek S,Turkyilmaz A,et al.Prenatal diagnosis of 4p and 4q subtelomeric microdeletion in de novo ring chromosome 4[J].Case reports in Obstetrics and Gynecology,2013,2013:248050.
[19]Paththinige CS,Sirisena ND,Kariyawasam UGIU,Saman Kumara LPC,Dissanayake VHW.Ring Chromosome 4 in a Child with Multiple Congenital Abnormalities:A Case Report and Review of the Literature[J].Case Reports in Genetics,2016,2016:1-7.
[20]Zollino M,Murdolo M,Marangi G,Pecile V,Galasso C,Mazzanti L,et al.On the nosology and pathogenesis of WolfHirschhorn syndrome:Genotype-phenotype correlation analysis of80 patients and literature review[J].American Journal of Medical Genetics Part C:Seminars in Medical Genetics,2008,148C(4):257-69.
[21]Chauhan P,Jaiswal SK,Lakhotia AR,Rai AK.Molecular cytogenetic characterization of two Turner syndrome patients with mosaic ring X chromosome[J].Journal of Assisted Reproduction and Genetics,2016,33(9):1161-8.
[22]钟燕,叶赵祝.一例环状X染色体嵌合体Turner综合征的双色荧光原位杂交[J].中华医学遗传学杂志,2006,23(6):700-1.
[23]Lachlan KL,Youings S,Costa T,Jacobs PA,Thomas NS.Aclinical and molecular study of 26 females with Xp deletions with special emphasis on inherited deletions[J].Human Genetics,2005,118(5):640-51.
[24]Darrell J Tomkins HLM,Sandra A Farrell and Carolyn J Brown.Lack of expression of XIST from a small ring Xchromosome containing the XIST locus in a girl with short stature,facial dysmorphism and developmental delay[J].Eur J Hum Genet,2002Jan,10(1):44-51.
[25]Matsuo M MK,Adachi M,Tachibana K,Asakura Y,Nakagomi Y,Hanaki K,Yokoya S,Yoshizawa A,Igarashi Y,Hanew K,Matsuo N,Ogata T.[J].Hum Genet,2000 Nov,107(5):433-9.
[2]MY Y.Autosomal ring chromosomes in human genetic disorders[J].Transl Pediatr,2015 Apr,4(2):164-74.
[3]Carter E HP,Hasi M,Soileau B,Sebold C,Hale DE,Cody JD.Ring 18 Molecular Assessment and Clinical Consequences[J].Am J Med Genet A,2015 Jan,167A(1):54-63.
[4]Zollino M,Ponzi E,Gobbi G,Neri G.The ring 14 syndrome[J].European Journal of Medical Genetics,2012,55(5):374-80.
[5]Conlin LK,Kramer W,Hutchinson AL,Li X,Riethman H,Hakonarson H,et al.Molecular analysis of ring chromosome 20syndrome reveals two distinct groups of patients[J].Journal of Medical Genetics,2010,48(1):1-9.
[6]Rossi E,Riegel M,Messa J,Gimelli S,Maraschio P,Ciccone R,et al.Duplications in addition to terminal deletions are present in a proportion of ring chromosomes:clues to the mechanisms of formation[J].Journal of Medical Genetics,2007,45(3):147-54.
[7]Blewitt ME,Gendrel AV,Pang Z,Sparrow DB,Whitelaw N,Craig JM,et al.SmcHD1,containing a structural-maintenanceof-chromosomes hinge domain,has a critical role in Xinactivation[J].Nature genetics,2008,40(5):663-9.
[8]Ferguson PJ.Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia(Majeed syndrome)[J].Journal of Medical Genetics,2005,42(7):551-7.
[9]Poretti A,H?usler M,von Moers A,Baumgartner B,Zerres K,Klein A,et al.Ataxia,Intellectual Disability,and Ocular Apraxia with Cerebellar Cysts[J]:A New Disease?The Cerebellum,2013,13(1):79-88.
[10]Idkowiak J RT,Dhir V,Patel P,Shackleton CH,Taylor NF,Krone N,Arlt W.A Missense Mutation in the Human Cytochrome b5 Gene causes 46,XY Disorder of Sex Development due to True Isolated 17,20 Lyase Deficiency.Send to[J]J Clin Endocrinol Metab,2012 Mar,97(3):E465-75.
[11]Feenstra I,Vissers Lisenka ELM,Pennings Ronald JE,Nillessen W,Pfundt R,Kunst Henricus P,et al.Disruption of Teashirt Zinc Finger Homeobox 1 Is Associated with Congenital Aural Atresia in Humans[J].The American Journal of Human Genetics,2011,89(6):813-9.
[12]Opitz JM,Burn J.RE:Correspondence from Wieczorek&Gillessen-Kaesbach and Hing&Parisi[J].American Journal of Medical Genetics Part A,2006,140A(21):2385.
[13]Ioannis Papoulidis EM,Elisavet Siomou,Kostantinos Kefalas,Loretta Thomaidis,Thomas Liehr AV,Apostolos Athanasiadis,Orsetta Zuffardi and Michael B.Petersen1.A fetus with ring chromosome 21 characterized by aCGH shows no clinical findings after birth[J].PRENATAL DIAGNOSIS,2010,30:586-588.
[14]Muroya K,Yamamoto K,Fukushima Y,Ogata T.Ring chromosome 21 in a boy and a derivative chromosome 21 in the mother:Implication for ring chromosome formation[J].American Journal of Medical Genetics,2002,110(4):332-7.
[15]Samarth RM,Gandhi P,Pandey H,Maudar KK.Mosaicism for trisomy 21 and ring(21)in a male born to normal parents:A case report[J].Gene,2012,511(1):109-12.
[16]Cetin Z,Altiok-Clark O,Sevuk M,Berker Karauzum S.Ring chromosome 21 and monosomy 21 mosaicism in a patient with azoospermia[J].Andrologia,2015,47(1):112-5.
[17]Chen CP,Lin YH,Chou SY,Su YN,Chern SR,Chen YT,et al.Mosaic ring chromosome 21,monosomy 21,and isodicentric ring chromosome 21:prenatal diagnosis,molecular cytogenetic characterization,and association with 2-Mb deletion of21q21.1-q21.2 and 5-Mb deletion of 21q22.3[J].Taiwanese journal of obstetrics&gynecology,2012,51(1):71-6.
[18]Akbas H,Cine N,Erdemoglu M,Atay AE,Simsek S,Turkyilmaz A,et al.Prenatal diagnosis of 4p and 4q subtelomeric microdeletion in de novo ring chromosome 4[J].Case reports in Obstetrics and Gynecology,2013,2013:248050.
[19]Paththinige CS,Sirisena ND,Kariyawasam UGIU,Saman Kumara LPC,Dissanayake VHW.Ring Chromosome 4 in a Child with Multiple Congenital Abnormalities:A Case Report and Review of the Literature[J].Case Reports in Genetics,2016,2016:1-7.
[20]Zollino M,Murdolo M,Marangi G,Pecile V,Galasso C,Mazzanti L,et al.On the nosology and pathogenesis of WolfHirschhorn syndrome:Genotype-phenotype correlation analysis of80 patients and literature review[J].American Journal of Medical Genetics Part C:Seminars in Medical Genetics,2008,148C(4):257-69.
[21]Chauhan P,Jaiswal SK,Lakhotia AR,Rai AK.Molecular cytogenetic characterization of two Turner syndrome patients with mosaic ring X chromosome[J].Journal of Assisted Reproduction and Genetics,2016,33(9):1161-8.
[22]钟燕,叶赵祝.一例环状X染色体嵌合体Turner综合征的双色荧光原位杂交[J].中华医学遗传学杂志,2006,23(6):700-1.
[23]Lachlan KL,Youings S,Costa T,Jacobs PA,Thomas NS.Aclinical and molecular study of 26 females with Xp deletions with special emphasis on inherited deletions[J].Human Genetics,2005,118(5):640-51.
[24]Darrell J Tomkins HLM,Sandra A Farrell and Carolyn J Brown.Lack of expression of XIST from a small ring Xchromosome containing the XIST locus in a girl with short stature,facial dysmorphism and developmental delay[J].Eur J Hum Genet,2002Jan,10(1):44-51.
[25]Matsuo M MK,Adachi M,Tachibana K,Asakura Y,Nakagomi Y,Hanaki K,Yokoya S,Yoshizawa A,Igarashi Y,Hanew K,Matsuo N,Ogata T.