第五章-染色体病15-9-17.ppt

单击此处编辑母版标题样式,*,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Human chromosome,&chromosome disorders,人类染色体,和染色体病,概 述,历史,：,1956,年明确人类染色体为,2n=46,条,1959年发现第一例染色体异常患者,70年代显带技术应用于临床诊断,80年代以来与分子遗传学技术结合，出现了FISH,等新方法用于基因定位等,特点：,直观性强，染色体病检出率高,Human chromosome&chromosome disorders,人类染色体的研究方法,人类细胞遗传学国际命名体制,人类染色体畸变,染色体病,染色体微缺失综合征,两性畸形,人类染色体的研究方法,标本制备,染色体标本的获取,染色体标本的制备步骤,染色体的形态和分类,研究方法,非显带染色体分类依据及分组,显带技术及其应用,常用的染色体分析方法,标本制备,取材的基本条件：有核的活细胞,外周血淋巴细胞,（,Peripheral blood lymphocytes(PBL),）,骨髓细胞,(,Bone-marrow cells),羊水细胞,(,Amniotic fluid cells,),绒毛细胞,(,Chorinic villus cells,),皮肤成纤维细胞,(,Skin fibroblasts),癌肿细胞,(,Cancer cells),(,divided,cells,),进入母体循环的胎儿淋巴细胞,(1/5 000-1/20 000),(,un,divided,cells,),Preparation of human chromosome,Staining methods:,1)Solid staining(non-banding method),2)Differential stained(banding method),:,(,Phytohemagglutinin,),(,Colchicine or colcemid,),(Hypotonic treatment),Staining methods,(,染色法,),Solid staining(non-banding method):,The air-dried slide is directly stained with Giemsa stain.Each chromosome appears to be homogeneously stained X-shaped solid structure.,Differential stained(banding method):,The air-dried slide is stained directly with Giemsa stain after various pretreatments,Criteria of chromosome groups,染色体分组指标,：,相对长度,(,Relative length,)=,臂比率,(,arm ratio,)=,着丝粒指数,(,centromere index,)=,有无随体,(,with or without satellite,),Definition of human chromosome groups,ABCDEFG,各组染色体对数为,:,3273322+,性染色体,Karyotype and karyotyping,Karyotype,(,核型,):,The particular chromosome complement of an individual arranged according to standard classification as defined both the number and morphology of the chromosome in mitotic metaphase.,Karyotyping,(,核型分析,):,Chromosome from a single spread are arranged according to standard classification to see if the karyotype is normal and abnormal.,Chromosome banding techniques,显带技术代号,Abbreviation of Chromosome band,带型,Band,处理方法,Treatment method,染色方法,Staining method,QFQ,Q,荧光,F,luorescence,氮介喹丫因,染液,(,Q,uinacrine),GTG,G,胰酶,T,rypsin,G,iemsa,染液,RHG,R,高温加热,H,eat,G,iemsa,染液,CBG,C,氢氧化钡,B,arium hydroxide,G,iemsa,染液,QFQ,GTGCBG,RHG,High resolution banding,400 550 850,ISCN 2009,Fluorescence in situ hybridization,FISH,（,荧光原位杂交,）,显带技术的命名和书写,Chromosome landmarks:,Centromere,Telomeres,Pronounced bands.,Description of chromosome:,Chromosome number(122),Chromosome arm(p or q),Region(5q,1,6q,1,),Band(5q,14,6q,14,),sub-band(5p15.2,6q,22.3,),Chromosome aberration,(,染色体畸变,),In the broadest sense,all types of changes in chromosome number and chromosome structure.,Numerical aberrations,（,数目畸变）,Structure aberrations,（结构畸变,）,Numerical aberrations,(,数目畸变,),整倍体,(euploid),非整倍体,(aneuploid),嵌合体,(mosaic),染色体数目畸变的原因,(Causes of chromosome aberration),An,I,nternational,S,ystem for Human,C,ytogenetic,N,omenclature,ISCN 2009),符号,字源,意义,+,符号前表示整条额外增加或丢失，符号后表示部分增长或缺失,/,嵌合体,从,到,:,或,:,断裂,或,断裂后从接,;,区分涉及结构重排的染色体,cen,centromere,着丝粒,del,deletion,缺失,dup,duplicaton,重复,end,endoreduplication,内复制,i,isochromosome,等臂染色体,inv,inversion,倒位,r,ring chromosome,环形染色体,rep,reciprocal translocation,相互易位,rob,Robertsonian translocation,罗伯逊易位,t,translocation,易位,ter,terminal,染色体末端,完整表格,见,p93,表,5-4,整倍体,(euploid),正常人体细胞染色体数目为,46,条（,2n,）称为二倍体,(diploid),配子细胞染色体数目为,23,条（,n,）称为单倍体,(haploid),若细胞的染色体数目以,n,为基数成倍的增加，则称为整倍体,(euploid),。,Euploid,(,整倍体畸变,),整倍体细胞表现为多倍体polyploid,）,染色体数目,3n,如：三倍体（,triploid,）,69,XXY,四倍体（,tetraploid),92,XXYY,多倍体细胞多见于肿瘤细胞或流产儿细胞，一般不能存活。,69,XXY,Aneuploid,(,非整倍体畸变,),超二倍体,(hyperdiploid),（,2n+A,）,指一个细胞中的染色体数目增加了一个或数个。如,47,XX,+21,（,21,三体）,Cells or individuals with one or more extra chromosome in addition to a diploid set of chromosomes.,For example:,47,XYY,or,47,XXX,Aneuploid,(,非整倍体畸变,),亚二倍体,(hypodiploid)(2n-B),指一个细胞中的染色体数目减少了一个或数个。如,45,，,XY,，,-21,（,21,单体）,45,，,X0,Cells or individuals with one or more chromosome absent from a diploid set of chromosomes,For example:,45,XY,-21,(21monosomy)or,45,X0,Aneuploid,(,非整倍体畸变,),假二倍体,(pseudodiploid)(2n+A-B,A=B),指某对染色体减少一个，同时另一对染色体又增加 一个，染色体的总数不变，这种情况称为假二倍体。如46，,XY,，,-18,，,+21,Cells or individuals with apparently diploid number of chromosomes having one or more chromosomes absent from and one or more chromosomes in addition to a diploid set of chromosome,For example:,46,XY,-18,+21,Mosaic,(,嵌合体,),一个个体内同时有两种或两种以上不同核型的细胞系称为嵌合体。,在受精卵的卵裂过程中及胚胎发育早期的细胞分裂过程中发生染色体不分离现象，使一个胚胎的部分细胞发生染色体的数目畸变，形成一个个体具有几种不同核型的细胞系。,Cell populations or individuals whose component cells differ with respect to their chromosome structure or chromosome number,irrespective of whether these members are euploid or aneuploide.g.,45,X0/46,XX/47,XXX,Numerical aberration,(,数目畸变,),（,P100,表,5-5,）,Type,Example,Triploid,69,XXY,Trisomic,47,XY,+21;47,XXY,Monosomic,45,XO;45,XX,-C,Pseudodiploid,46,XY,+18,-21,Mosaic,45,XO/46,XX/47,XXX,染色体不分离,(,Nondisjunction is the most commonly cause of numerical aberration,),染色体数目畸变的原因,染色体发生断裂和再接合,异常,。,Chromosome breaks and then reunion,染色体结构畸变的原因,Structural aberration,常见的染色体结构畸变的类型：,缺失,(deletion,del),重复,(duplication,dup),倒位,(inversion,inv),易位,(translocation,t),环形染色体,(ring chromosome,r),等臂染色体,(isochromosome,i),Deletion,del,(,缺失,),指染色体臂的部分缺失,(,A chromosomal structure resulting in the loss of a section of the genetic material and the genetic information contained therein from a chromosome,),。,末端缺失,(terminal deletion):,染色体的长臂或短臂发生一次断裂，缺失了末端节段。,46,XX,del(1)(q21),46,XX,del(1)(pter q21:),中间缺失,(interstitial deletion):,染色体的长臂或短臂内发生了两次断裂，两断裂面之间的断片脱离后两断裂面又重新结合。,46,XX,del(1)(q21q31),46,XX,del(1)(pter q21:q31qter),Duplication,dup,(,重复,),系指同源染色体中一条断裂后，其断片连接到另一条同源染色体上的相应部位，或是由同源染色体间的不等交换，结果一条同源染色体上部分基因重复了，而另一条同源染色体则相应缺失,。,46,XX,dup(1)(q22q25)or,46,XX,dup(1)(pterq25:q22qter),(direct),46,XX,dup(1)(pterq22:q25qter),or(pter q25:q25 q22:q25 qter),(inverted),Inversion,inv,(,倒位,),染色体发生两处断裂后，中间断片倒转,180,度后又重新连接。,(,A chromosome structural change resulting in the reversal of a chromosome segment,and the gene sequence contained therein,relative to the standard arrangement of the chromosome in question.),臂内倒位：,(paracentric inversion),系指倒位部分不包括着丝粒而仅限于一臂之内。,臂间倒位：,(pericentric inversion),系指倒位部分包括着丝粒。,Translocation,t,（易位）,广义的易位,:,一条染色体断裂后其片段接到同一条染色体的另一处或接到另一条染色体上去。,狭义的易位,:,两条染色体都发生断裂，相互交换断片后又重新接合，形成两条新的易位染色体,。,Robertsonian translocation,rob,(Centri fusion),罗伯逊易位：断裂发生在着丝粒部位或着丝粒附近，整个染色体臂发生了相互易位，形成两个中着丝粒染色体。其中由染色体短臂形成的小染色体往往丢失。,The fusion by reciprocal translocation of two acrocentrics to give a metacentric and a small fragment which is usually lost.,Ring chromosome,r,环形染色体：断裂发生在染色体两个臂的远端，随后这两臂的断裂端彼此粘着形成环形结构。,A physically circular chromosome formed by the loss of both telomere segments from a chromosome and rejoining of the broken ends.,46,XX,r(2)(p21q31),46,XX,r(2)(:p21q31:),I,sochromosomei,等臂染色体：系指染色体的两臂带有相等的遗传信息。,A chromosome with homologous(equal and genetically identical)arms which are mirror images of one another.,46,X,i(Xq),46,X,i(X)(qterq10:q10qter),Chromosomal changes,Terminal,Deletion,Ring,Chromosome,Robertsonian,Translocation,Deletion,Reciprocal,translocation,Isochromosomes,Insertion,Inversion,Duplication,Structural aberration,(p106,表,5-6,；,5-7),Type,Example,Partial lengthening,46,XY,1q+,Translocation,45,XX,-D,-G,+t(DqGq),Terminal deletion,46,XX,del(1)(q21)or(pterq21),Paracentric inversion,46,XY,inv(2)(p13p24),Reciprocal translocation,46,XY,t(2;5)(q21;q31)or(2pter q21:5q315qter;5pter5q31:2q21 2qter),Ring chromosome,46,XY,r(2)(p21q31)or(:p21q31:),Isochromosome,46,X,i(Xq)or i(qter,q10:q10,qter),Chromosome disorders,Common clinical manifestation,：,Growth retardation,(,生长障碍,),Mental retardation,(,智力障碍,),Congenital malformation,(,先天畸形,),Usually sporadic,(,多为散发,),Dermatoglyphic change,(,肤纹改变,),Prenatal diagnosis,(,产前诊断,),Autosome Disorders,(,常染色体病,),Down syndrome(,先天愚型,21-,三体综合征，,trisomy 21 syndrome),Edward syndrome(18-,三体综合征,，,trisomy 18 syndrome),Cats cry syndrome(,猫叫综合征,，,5p-syndrome),Down syndrome,(,先天愚型,软白痴,),主要症状（,Major clinic features,）：,特殊面容：鼻梁低，眼斜视，外眼角上翘，内眦赘皮，耳小，低位，口常开，流口水。,智力发育落后，智商一般在,25-50,。,Mongoloid facial:,Inner eye angles masked by epicanthal folds,Nose short with nasal bridge,Mouth small with thick and protruding tongue,Ears round and small,Mental retardation,IQ of 50 at the age of 5 years,IQ of 38 at around of 15 years,“妈妈，我知道我不是个聪明的孩子，这个世界上只有你最欣赏我,”,这句话，是,“唐宝宝”，,也称先天愚型患儿内心的呼唤。图为来自全国,23,个城市的,56,个“唐宝宝”家庭汇聚山东烟台，开展唐宝宝夏令营活动。,“唐宝宝”在幼儿园进行融合活动,“唐宝宝”在幼儿园进行融合活动,Down syndrome,主要症状：,50%,有先天性心脏畸形，通关手（猿线），草鞋脚。,Visceral malformations frequent with 50%,Sandle gap,Transverse palmar crease in about 40%of the cases.,Down syndrome,Karyotype,：,Free 21 trisomy,47,XX(XY),+21,Mosaic,46,XY/47,XY,+21,Down syndrome,Karyotype:,Translocation,46,XY,-15,+t(15q21q),14/21,易位染色体的传递,如母亲的核型为：,45,XX,-14,-21,+t(14q21q),其生殖细胞可有,6,种类型：,23,X,；,22,X,-14,-21,+t(14q21q),22,X,-21,；,23,X,-14,+t(14q21q),22,X,-14,；,23,X,-21,+t(14q21q),14/21,易位染色体的传递,如与正常的男性生殖细胞,(23,X),受精后可出现下列情况：,46,XX,正常,45,XX,-14,-21,+t(14q21q),携带者,46,XX,-21,+t(14q21q),很少成活,45,XX,-14,致死,45,XX,-21,致死,46,XX,-14,+t(14q21q),易位型,21,三体,Down syndrome,预后：男性患者不育,.,发病率与母亲年龄有关。,Edwards syndrome,1960,年,Edwards,首报。,主要症状：手呈特殊握拳状，摇篮足,Clenched fists with the 2ed finger overlapping the 2ed one and the 5th finger overlapping the 4th one.,Rocker-bottom feet,Karyotype:,47,XX,+18,46,XX/47,XX,+18,48,XXX,+18,Edwards syndrome,Cat,s cry syndrome,1963,年，,Lejeune,首次报导。,哭声如猫叫，智力落后，生长阻滞，小头，满月脸，斜视，心脏畸形。,Cats cry,Microcephaly,Moon like face,Mental retardation severe,核型：,46,XY,5p-,46,XY,del(5)(p15),46,XY,del(5)(:5p15 qter),Gonosome disorders,Sex chromatin,(,性染色质,),Klinefelter syndrome,(,先天性睾丸发育不全综合征,),Turner syndrome,(,先天性卵巢发育不全综合征,),Martin-Bell syndrome,(,脆性,X,染色体智力障碍综合征,),Sex chromatin,X chromatin,（,X body,，,Barr body,）,Y chromatin,Lyon hypothesis,Lyon hypothesis,(Lyonization,1961),在哺乳动物（包括人类）的正常雌性间期细胞，两条,X,染色体中的一条是遗传上失活的，形成,X,性染色质。,最初的失活发生在胚胎发育的早期。,最初的失活是随机的，不同的细胞中，其失活的染色体可能源自父方或母方，但一旦发生，就在其子细胞中保持恒定。,In the somatic cells of female mammals,all but one of the X chromosomes are inactivated and condensed and appear in interphase cells as the sex chromatin(Barr body).,The inactivation occurs early in embryonic life.,The inactive X chromosome can be either paternal or maternal X in different cells of the same individual;but after the“decision”has been made in a particular cell,all the clonal descendants of that cell will“abide by the decision”;i.e.,they will have the same inactive X.In other words,inactivation is RANDOM but FIXED.,X-chromatin=X chromosome-1,Y-chromatin=Y chromosome,The Y chromosome in sex determination and in disorders of sexual differentiation.Individual genes and regions implicated in sex determination,sex reversal,and defects of spermatogenesis are indicated.,Klinefelter syndrome,Major clinical features,：,外表男性，睾丸小，不育，男性乳房发育,(gynecomastia),。其性情体态女性化。,身材瘦长，体力较弱。,Major clinical features,：,Male appearance,，,Gynecomastia,Testicular atrophy,Sterility,。,Klinefelter syndrome,Karyotype,：,47,XXY,48,XXXY,49,XXXXY,46,XY/47,XXY,Turner syndrome,(,先天性卵巢发育不全综合征,),外表女性，原发闭经，卵巢萎缩，外生殖器发育不良，身材矮小身高一般不超过,1.50M,）肘外翻，盾状胸，乳房不发育，,色素痣，一般不育。,Female appearance,Short stature,Lack of pubertal development,Ovarian dysgenesis,Characteristic somatic malformation,Neck web(,蹼颈,),Hairline very low(,低发际,),Turner syndrome,(,先天性卵巢发育不全综合征,),核型：,45,X0,45,X0/46,XX,46,X,i(Xq),46,X,r(X),46,X,del(X),Turner syndrome先天性卵巢发育不全综合征,),Poly X syndrome,(,超雌综合征,),1959,年,Jacobs,首报,Major clinical features,：大多数无外形、性功能与生育异常。仅少数患者有月经减少、继发闭经或过早绝经等现象。约,60%,的患者智力稍低下，并伴有精神病倾向。,Karyotype,：,47,，,XXX,；,48,，,XXXX,；,49,，,XXXXX,；,46,，,XX/47,，,XXX,等,。,Poly Y syndrome,(,超雄综合征,),Major clinical features,身材高大，常在,180cm,以上。多数患者有生育能力，少数患者有阴睾、睾丸发育不全并有生精过程障碍和生育力下降等。患者智力正常，但性格暴躁粗鲁，厌学，自我克制能力差，行为过火，常发生攻击性犯罪行为。,Karyotype,：,47,，,XYY,；,48,，,XXYY,Martin-Bell syndrome,(,脆性,X,染色体智力障碍综合,征,),Major clinical features,：,三大一低,Macroorchidism(,大睾丸,),Macrognathia,(,大下巴,),Macrotia(,大耳朵,),Mental,retardation(,低智商,),Karyotype,：,fra(X)(q27.3),(CGG),n,n 200Martin-Bell syndrome,(,脆性,X,染色体智力障碍综合,征,),Microdeletion syndrome,Prader-Willi syndrome,(,阴睾,-,侏儒,-,肥胖,-,低能,),出生时吸吮困难，外生殖器发育不良。2-3岁时转为饮食过量，肥胖。轻度或中度智力 障碍。父传子,.,染色体微缺失部位：,15q11-13,(paternal origin),Microdeletion syndrome,Angelman syndrome,严重运动和智力发育障碍，共济失调，肌张力减退，患儿有急冲式动作，阵发不恰当的大笑，故有“快乐木偶”综合征,(Happy puppet syndrome),之称。,染色体微缺失部位：,15q11-13,(,maternal origin,),表观遗传学,(epigenetics),是研究不涉及,DNA,序列改变的基因表达和调控的可遗传变化，或者说是研究从基因演绎为表型的过程和机制的一门新兴的遗传学分支。详见第,13,章。,Hermaphroditism,真两性畸形：指内外生殖器都具有两性特征的个体，其外表可为男性或女性。,True hermaphroditism has both testicular and ovarian tissues,either as two separate organs or a single ovotestis,not necessarily functional but histologically identifiable.,假两性畸形：生殖腺只有一种，但其第二性征及外生殖器均有不同程度的畸形。,Pseudo hermaphroditism has gonadal tissue of only one sex,either testicular or ovarian tissue.,True hermaphroditism,生殖腺组成（,Gonadal tissue,）,：,一侧卵巢,一侧睾丸：,约占40%,。,Alternate hermaphroditism with an ovary on one side and a testicle on the other:40%,一侧卵巢或睾丸，一侧为卵睾丸,：约占,40%,Unilateral hermaphroditism,with an ovary or testicle on one side and an ovotestis on the other,两侧均为卵睾丸，约占,20%,。,Bilater hermaphroditism with an ovotestis on both sides:20%,True hermaphroditism,Karyotype,：,46,，,XX 50%,46,XY 20%,46,XX/46,XY,30%,男孩问题：阴睾，周期性血尿等。,Boys problems:,Cryptorchidism,Hypospadias,Gynecomastia,Periodic hematuria,女孩问题：青春期不来月经，生殖器异常。,Girls problems:Amenorrhea;Hypertrophy of the clitoris,Pseudohermaphroditism,男性假两性畸形,(,Male pseudohermaphroditism),Karyotype,：,46,XY,X,小体,(-),Y,小体,(+),女性假两性畸形,(,Female pseudohermaphroditism),Karyotype,：,46,XX,X,小体,(+),Y,小体,(-),Male Pseudohermaphroditism,睾丸女性化综合征,(,testicular feminization),XR,。,主要表现：外形女性，子宫、卵巢缺如，腹股沟或腹腔可触及睾丸。,发病原因：靶细胞缺少雄激素受体。,Female phenotype,Feminization at puberty,sexual rather than beautiful and nice;Bilater testes usually normal in size and located either in abdomen,inguinal canal,or labia;Primary amenorrhea,infertility,and“hernia”lead the affected to see a doctor.,Female Pseudohermaphroditism,先天性肾上腺皮质增生症,(,congenital adrenocortical hyperlasia,),AR,发病原因：缺少,21,羟化酶氢化皮质酮不足,ACTH,肾上腺皮质增生雄激素,主要症状,:,女孩男性化,声音低沉,乳房不发育,原发闭经。,Ambiguous external genitalia at birth in 46,XX females,Clitoral enlargement,Labioscrotal fusion,Occasionally phallic urethra,南非新秀塞门娅,男,/,女,?,简述非显带染色体制备的过程及关键步骤。,秋水仙素中期染色体有哪些形态结构？,染色体的分组依据是什么？每组有哪些特征？,人类染色体和染色体病思考题,常用的显带染色体技术有哪些？它们各有什么特点？,名词解释：整倍体畸变，超二倍体，亚二倍体，嵌合体，缺失，倒位，易位（罗伯逊易位），环形染色体，等臂染色体。,简述染色体核型的书写规则。表,5-5,、,5-6,、,5-7,核型的意义是什么？,21,三体综合征、猫叫综合征、先天性睾丸发育不全综合征、先天性卵巢发育不全综合征和脆性,X,染色体智力障碍综合征的主要临床症状和核型是什么？,一个表型正常的女孩，其体细胞染色体总数为45，她有一个正常的哥哥和一个先天愚型的弟弟，两兄弟的染色体总数均为46，试问三兄妹各自的核型是什么？他们是怎样形成的,？,