Clinical Cytogenetics:Disorders of the Autosomes and the Sex ChromosomesChromosome Disease in ClinicClinical featureThe general features in autosome abnormalities are triad of growth retardation,mental retardation,and specific somatic abnormalities.Change of sex chromosome also have the abnormalities and malformations of internal or external genital organs.Autosomal Disorders(常染色体病常染色体病)Trisomy 21 Syndrome（21三体综合征三体综合征）Trisomy 18 Syndrome（18三体综合征三体综合征）Trisomy 13 Syndrome（13三体综合征三体综合征）Cri Du Chat Syndrome（猫叫综合征猫叫综合征）Microdeletion Syndrome（微小缺失综合征微小缺失综合征）Trisomy 21 Syndromel A syndrome results from complete or partial trisomy 21 chromosome,known as Down syndrome(唐氏综合症唐氏综合症)（21三体综合征）三体综合征）特殊面容：鼻梁低、眼距宽、外眼角上斜、特殊面容：鼻梁低、眼距宽、外眼角上斜、耳位低、张嘴吐舌耳位低、张嘴吐舌(伸舌样痴呆)Clinical Features The Chromosomes in Down Syndrome Trisomy 21 95%47,XX(or XY),+21 Robertsonian Translocation（罗伯逊易位）（罗伯逊易位）4%46,XX(or XY),-14,+t(14;21)(p11;q11)46,XX(or XY),-21,+t(21;21)(p11;q11)Mosaic Down Syndrome（嵌合体唐氏综合征）（嵌合体唐氏综合征）1%46,XX(or XY)/47,XX(or XY),+2147,XY,+21 Trisomy 21 Etiology of Trisomy 21 46,XX(or XY),-14,+t(14;21)(p11;q11)Or 46,XX(or XY),-14,+t(14q21q)Robertsonian Translocation Balanced Translocation Carrier 45,XX,-14,-21,+t(14;21)(p11;q11)or 45,XX,-14,-21,+t(14q21q)Etiology of Robertsonian Translocation(viable)50%Trisomy 21 50%Monosomy 21 21q21q TranslocationGerm cellGametesZygotes 2121q21qLost(abortion)(viable)Nondisjunction in mitosis Mosaic Down SyndromeThe genes on chromosome 21 Mental retardation:DSCAM、ADNP、DSCR1、ETS2 MNBH/DYRK1、SOD1 Congenital heart defects,CHD:COL6A1/2、KCNE-2Leukaemia:AML1 Risk of Trisomy 21Mother age Down syndrome incidence20 25 1:180025 29 1:150030 34 1:80035 39 1:25040 44 1:10045 1:50Trisomy 18 Syndrome The chromosomes Trisomy 18.80%47,XX(or XY),+18 Mosaic trisomy 18 syndrome.10%46,XX(or XY)/47,XX(or XY),+18（18三体综合征）三体综合征）其余为各种易位型，主要是其余为各种易位型，主要是18号染色体与号染色体与D组染组染色体的易位色体的易位Clinical Features1818三体综合征的畸形主要包括中胚层及其衍化物的异常（如骨骼、泌尿生殖系统、心脏最明显）三体综合征的畸形主要包括中胚层及其衍化物的异常（如骨骼、泌尿生殖系统、心脏最明显）此外，接近中胚层的外胚层（如皮肤皱褶、皮嵴及毛发等）及内胚层（如美克尔憩室、肺及肾）此外，接近中胚层的外胚层（如皮肤皱褶、皮嵴及毛发等）及内胚层（如美克尔憩室、肺及肾）也异常。
文献报道胚胎也异常文献报道胚胎5 5周前发育正常，在妊娠第周前发育正常，在妊娠第6-86-8周开始出现异常周开始出现异常.特殊的握拳 肌张力亢进Clinical Features弓形指纹 先天性心脏病及肾脏病Clinical FeaturesoGrowth retardationoMental retardationoCongenital heart disease（先心）（先心）oRocker-bottom feet（摇椅型足）（摇椅型足）ofixed flexion deformity of the fingers（手指弯曲畸形）手指弯曲畸形）Trisomy 18 Syndrome Etiology of Trisomy 18 Syndrome Risk of Trisomy 18 Syndromeu 1/7500 in liveborn infants,postnatal survival is poor.u About 95%of trisomy 18 conceptuses are aborted spontaneously.u About 80%of the patients are female.u The mother older,the risk of a trisomy 18 infant greater Trisomy 13 SyndromeThe chromosomes Trisomy 13.80%47,XX(or XY),+13 Robertsonian Translocation.14%46,XX(or XY),-14,+t(13q14q)46,XX(or XY),-13,+t(13q13q)Mosaic trisomy 13 syndrome.6%46,XX(or XY)/47,XX(or XY),+13Clinical Features颅面的畸形包括小头，前额、前脑发育缺陷，23患儿有上唇裂，并常有腭裂，耳位低，耳廓畸形，颌小，其它常见多指（趾），手指相盖叠，足跟向后突出及足掌中凸，形成所谓摇椅底足。
男性常有阴囊畸形和隐睾，女性则有阴蒂肥大，双阴道，双角子宫等智力发育障碍见于所有的患者，而且程度严重，存活较久的患儿还有癫痫样发作，肌张功力低下等.oVarying degrees of mental retardationoCleft lip&Cleft palate（唇裂腭裂）（唇裂腭裂）oPolydactyly(postaxial)（多指）（多指）oEquinovarus（马蹄内翻足）（马蹄内翻足）耳位低，耳廓畸形，耳位低，耳廓畸形，眼球小，常有虹膜缺损，鼻宽眼球小，常有虹膜缺损，鼻宽而扁平，而扁平，Trisomy 13 Syndrome Etiology of Trisomy 13 Syndromeusually arises from nondisjunction in maternal meiosis I14%of the cases are caused by an unbalanced translocation Risk of Trisomy 13 syndromen 1/22,700 in liveborn infantsn About 50%of trisomy 13 die within the first month.nA subsequent liveborn child of one balanced translocation carrier will have the syndrome is less than 2%.Cri Du Chat Syndrome The karyotype 46,XX(or XY),del(5)(p15)常染色体结构畸变的一种1 in 50000 newborns满月脸）满月脸）Clinical feature:Clinical FeaturesRisk of Cri Du Chat Syndromel 1/50,000 in liveborn infants.l The syndrome accounts for about 1%of all institutionalized mentally retarded patients.Etiology of Cri Du Chat Syndromel Several dysmorphic syndromes（畸形综合征）（畸形综合征）are associated with small,but sometimes cytogenetically visible,deletions,leading to a form of genetic imbalance referred to as segmental aneusomy(部分异倍体部分异倍体).l That can result in contiguous（邻近的）（邻近的）gene syndrome.Microdeletion Syndrome22q11.2微小缺失微小缺失：DiGeorge综合征综合征腭帆腭帆-心心-面综合征面综合征(velocardiofacial)面部畸形及心室流出道缺陷综合征面部畸形及心室流出道缺陷综合征 (conotruncal anomaly face syndrome)Microdeletion or Contiguous gene Syndrome RearrangementDisorder Location Type Size(kb)Repeat Length(kb)Smith-Magenis syndrome 17p11.2 Deletion 5000 200 dup(17)(p11.2)DuplicationPrader-Willi/Angelman syndromes 15q11-q13 Deletion 4000 50400DiGeorge syndrome/22q11 DeletionVelocardiofacial 3000 200syndromeCat-eye syndrome DuplicationUnequal Crossing OverGene AGene BGene CGene AGene BGene CGene AGene BGene CGene AGene BGene CUnequal crossing overdeletionduplicationRepeated sequencesThe Sex Chromosomes and Their AbnormalitiesThe Chromosomal Basis of Sex Determinationn Karyotype Phenotype 47,XXY male (Klinefelter syndrome)46,XX normal female 45,X female (Turner syndrome)46,XY normal malen The Y chromosome makes a crucial role in normal male development.The Y ChromosomeSRY:sex-determining region of Y chromosomeTDF：testis-determining factorSex-reversal Disordersl XX males(46，XX)1/20,000 births l XY females(46,XY)1/20,000 births Etiology of Sex-reversal DisordersXThe X Chromatin (the Barr body)46,XX 46,XY 47,XXXThe Lyon hypothesis1.In the somatic cells of female mammals,only one X chromosome is transcriptionally active.The second X is heterochromatic and inactive and appears in interphase cells as sex chromatin,the Barr body.2.Inactivation occurs early in embryonic life.3.In any one female somatic cell,the inactive X may be either the paternal or the maternal X,namely the inactivation is randomly.Mary F.Lyon （1961）occurs early in embryonic lifeThe X Inactivation Center(XIC)and the XIST Genel The X inactivation center has been mapped to proximal Xq,in the band Xq13.2(长约长约800kb).l The XIST gene is expressed only from the allele on the inactive X;It is transcriptionally silent on the active X in both male and female cells.XIST:inactive X(Xi)-specific transcriptThe X Inactivation Center(XIC)and the XIST GeneXq13.245，X46，XX47，XXXKaryotypes and PhenotypesEscape From InactivationNonrandom X InactivationIncidence of Sex Chromosome AbnormalitiesSex Disorder Karyotype Approximate IncidenceMale Klinefelter syndrome 47,XXY 1/1000 males 48,XXXY 1/25,000 males Others(48,XXYY;1/10,000 males 49,XXXYY,mosaics)47,XYY syndrome 47,XYY 1/1000 males XX males 46,XX 1/20,000 malesFemales Trisomy X 47,XXX 1/1000 females Turner syndrome 45,X 1/5000 females 46,X,Xi(Xq)1/50,000 females Others(deletions,mosaics)1/15,000 females XY females 46,XY 1/20,000 females Karyotype 47,XXY 1/1000 male live births 80%48,XXXY 1/25,000 males 48,XXYY 49,XXXYY 1/1000 males mosaics 15%46,XY/47,XXY 或或 46,XY/48,XXXY Klinefelter Syndrome（先天性睾丸发育不全或原发性小睾丸症）Clinical Features 身材较高，四肢细长，身材较高，四肢细长，生殖器官发育不全，睾丸生殖器官发育不全，睾丸不发育或隐睾，曲细精管不发育或隐睾，曲细精管萎缩，呈玻璃样变性，无萎缩，呈玻璃样变性，无精子生成，不育，第二性精子生成，不育，第二性征发育不良，女性化性状，征发育不良，女性化性状，有男子女性型乳房，因雌有男子女性型乳房，因雌激素增高。
激素增高Karyotype from a male with Klinefelter syndrome(47,XXY)Etiology of Klinefelter SyndromePaternal meiosis I 1/2Maternal meiosis I 1/3Maternal meiosis II/postzygotic mitosis remainderNondisjunction of the X and the Y1 in 1000 malesoTall statureoPredisposition to violent,180 cm:1/200190 cm:1/30200 cm:1/10XYY syndrome(47,XYY)Karyotype 45,X 1/5000 female live births 50%46,X,i(Xq)1/50,000 females 15%and deletions Mosaics 1/15,000 females 45,X/46,XX 15%Turner SyndromeClinical Features(45,X)1 in 5000 liveborn femalesoShort stature&Webbed neck（身（身材矮，有蹼颈）材矮，有蹼颈）oOvarian dysgenesis,primary amenorrhea,infertility（卵巢发育（卵巢发育不良，原发性闭经，不孕）不良，原发性闭经，不孕）oAbsence of secondary sex characteristics（第二性征不发育）（第二性征不发育）oUnderdeveloped breasts;wide nipples（乳房发育不良，乳距宽）（乳房发育不良，乳距宽）Clinical FeaturesClinical FeaturesClinical Features淋巴样肿大spontaneous abortions 99%Karyotype from a female with Turner syndrome(45,X)Fragile X Syndromel Fragile sitel Fragile XWhat is Fragile X Syndrome不凝缩，呈细丝状Fragile X syndrome Karyotype Incidence 46,fra(X)Y 1/4000 males 1/4000-8000 females Clinical FeatureslMental retardation（精神发育迟缓）（精神发育迟缓）lLanguage handicap(语言障碍）语言障碍）lVery active and restless(多动）多动）lImpaired concentration（凝视回避）（凝视回避）lSelf-mutilation（自残）（自残）lSpecific feature（长脸、大下颌）（长脸、大下颌）lHuge testis（大睾丸）（大睾丸）Clinical FeaturesyoungyoungoldoldClinical FeaturesXq27.3Etiology of Fragile X SyndromeFragile X mental retardation gene 1,FMR-1l FMR-1 gene mutation is caused by an unusual expansion of a repeat of CGG(triplet repeat).l The repeat size will expand from generation to generation,So this mutation is also called instable mutation.Premutation and Full Mutationl Normal CGG 200l“Grey zone”CGG 45-59Clinical CytogeneticsKey Points Etiology of trisomy syndrome The Basis of Sex Determination The Lyon hypothesis Nonrandom X inactivation Escape From InactivationThank you for your attendence。