医学遗传学英文教学课件：Chromosome-b

1、Trisomy 21 Downs syndromenMost common Most common trisomy 1:800 in trisomy 1:800 in new bornnew bornnMost common Most common sever mental sever mental retardationretardationnEyes with brushfield spot Eyes with brushfield spot nFlat nosal bridgeFlat nosal bridgenLow set earLow set earnOpen mouth with

2、 Open mouth with protruding tongueprotruding tonguenShort and broad hand with Short and broad hand with a single transverse palmar a single transverse palmar creasecreaseTrisomy 21 Downs syndrome20-291;150030-341:100035-401:10040-451:40Age of WomenBirth RateRelated with advanced maternal ageRelated

3、with advanced maternal ageTrisomy 21 Downs syndromeTrisomy 18 Edwards syndromen1:7500 in liveborn 1:7500 in liveborn and more common and more common in abortion and in abortion and stillbirthstillbirthnSever mental Sever mental retardation and retardation and multiple structural multiple structural

4、anomaliesanomalies18-green, X-aquaTrisomy 18 Edwards syndrome47, XY, +18Trisomy 13Pataus syndromen1:20,000 in liveborn 1:20,000 in liveborn and more common in and more common in abortion and stillbirthabortion and stillbirthnSever structural Sever structural anomalies lead to anomalies lead to death

5、 in one monthdeath in one monthTrisomy 13Pataus syndrome13-green, 21-orange47, XY, +13XXY, Klinefelters syndromen1:1,000 in male 1:1,000 in male livebornlivebornnHypogonadism Hypogonadism and Infertility:and Infertility:1. 1.Tall statureTall stature2.2.Long limbsLong limbs3.3.Small genitaliaSmall ge

6、nitalia4.4.GynecomastiaGynecomastiaXXY, Klinefelters syndromeX-green, Y-red47, XXY47, XYY syndromen1:1,000 in male live birth1:1,000 in male live birthnNormal intelligence and normal appearance Normal intelligence and normal appearance but:but:1. 1.Educational problem: language delays and Educationa

7、l problem: language delays and spelling difficultiesspelling difficulties2.2.Behavioral problems: attention deficits, Behavioral problems: attention deficits, hyperactivity and impulsivenesshyperactivity and impulsiveness3.3.Fertility problem: increase risk of chromosomal Fertility problem: increase

8、 risk of chromosomal abnormal childabnormal child47, XYY syndrome47, XYY47, XXX syndromen1:1,000 in Female live birth1:1,000 in Female live birthnNormal intelligence and normal Normal intelligence and normal appearanceappearancenA significant deficit in performance on IQ A significant deficit in per

9、formance on IQ teststestsn70 % with some learning problems70 % with some learning problemsnInfertility: 50%Infertility: 50%47, XXX syndrome47, XXXXXXXX SyndromeWhy? Autosome: only Autosome: only trisomy 21, 18 and trisomy 21, 18 and 13 found in live-13 found in live-birth, no monsomybirth, no monsom

10、ySex chromosome in Sex chromosome in livebirth: XO, XXX, livebirth: XO, XXX, XXY, XYY, XXXX, XXY, XYY, XXXX, XXXXXXXXXX50, XXXXXX chromosome inactivation and XISTnGene dosage compensation is achieved in all Gene dosage compensation is achieved in all persons with two or more X chromosomes in their p

11、ersons with two or more X chromosomes in their genetic constitution by partial inactivation of all X genetic constitution by partial inactivation of all X chromosomes except one. chromosomes except one. nThe process is controlled by XIST (X inactive The process is controlled by XIST (X inactive spec

12、ific transcripts) gene in Xq13.2, which encodes specific transcripts) gene in Xq13.2, which encodes a large RNA that appears to coat the X a large RNA that appears to coat the X chromosome and facilitate inactivation of genes on chromosome and facilitate inactivation of genes on the X chromosome.the

13、 X chromosome.nDuring the late blastocyst stage, all X chromosomes During the late blastocyst stage, all X chromosomes except one undergo heterochromatinization and except one undergo heterochromatinization and form X chromatin bodies in each cell.form X chromatin bodies in each cell.nThe balance of

14、 gene dosage on X chromosome is The balance of gene dosage on X chromosome is achieved. achieved. The explanation of The explanation of various kinds of X polysomies in live-birth. various kinds of X polysomies in live-birth. Barr body(3) Mosaic and chimeraMosaicChimeraAberrationAberrationMosaic and

15、 chimera45,X/47,XXXnResulted from chromosome breakage and Resulted from chromosome breakage and reunion.reunion.nBalanced structural abnormality Balanced structural abnormality With normal complement of chromosomal With normal complement of chromosomal materialmaterialnUnbalanced structural abnormal

16、ityUnbalanced structural abnormality With loss or gain of chromosomal material With loss or gain of chromosomal material(2). Abnormalities of chromosome structurea. Unbalanced structure abnormalitynDeletion: Loss of a chromosome Loss of a chromosome segment segment Resulted from breakage or Resulted

17、 from breakage or unequal cross-over or unequal cross-over or segregation of balanced segregation of balanced abnormalityabnormalityCri Du Chat (5p-) syndrome nDeletion: 5p15Deletion: 5p15nCrying sounds like a Crying sounds like a newing catnewing catnTypical features: Typical features: hyperteloris

18、m, hypertelorism, epicanthus and epicanthus and retrognathiaretrognathiaCri Du Chat (5p-) syndrome 5-p-telomere -green 46,XY,5p-; 46, XY, del(5p15:)46, XY, del(5)(p15:)46, XY, del(5)(qter-cen-p15:)4p- syndrome46, XX, del(4)(p16:)Deletion of 22q-, Mosaic 46, XY (40) / 46, XY, del(22)(q13:) (10) Dupli

19、cationnGain of a extract Gain of a extract chromosome segment in the chromosome segment in the same chromosomesame chromosomenResulted from unequal cross-Resulted from unequal cross-over or segregation of over or segregation of balanced abnormalitybalanced abnormality18q2318 Dup (18)46,XY,dup (18)(q

20、23) 46, XY, dup(18)(pter -cen-q23:q23:qter)46,X, dup(X)(q13q26)46, X, dup(X)(pter-q26:q13q26:q26-qter)InsertionnGain of a extract chromosome segment from the Gain of a extract chromosome segment from the different chromosomedifferent chromosomenResulted from segregation of balanced Resulted from seg

21、regation of balanced abnormalityabnormalityFather46, XY, t(3;11)(q27;q13), ins(11;3)(q13;p26p13)Son46, XY, der(11) ins(11;3)(q13;p26p13)Isochromosomes One arm is deleted and One arm is deleted and the other duplicatedthe other duplicated One arm is monosomy One arm is monosomy and other is trisomyan

22、d other is trisomy The most common The most common isochromosome is i(Xq)isochromosome is i(Xq)46, X, i(Xq)Ring chromosomesFormed when a chromosome undergoes two Formed when a chromosome undergoes two breaks and broken ends of the chromosome breaks and broken ends of the chromosome reunite in a ring

23、 structurereunite in a ring structure46, X, r(X)Ring chromosome, unstableSummary of chromosome number abnormalitynDeletionDeletionnDuplicationDuplicationnInsertionInsertionnRing chromosomeRing chromosomenIsochromosomeIsochromosomenWith normal complement of chromosomal With normal complement of chrom

24、osomal materialmaterialnUsually have no phenotypic effectsUsually have no phenotypic effectsnRepeated abortion, intrauterus fetal death, Repeated abortion, intrauterus fetal death, stillbirth and birth defects due to the stillbirth and birth defects due to the abnormal segregation of involved abnorm

25、al segregation of involved chromosomes in meiosischromosomes in meiosisb. Balanced structure abnormality (a) InversionsnA single chromosome undergoes two breaks A single chromosome undergoes two breaks and is reconstituted with the segment and is reconstituted with the segment between the breaks inv

26、erted.between the breaks inverted.Inversion of Chromosome 146, XX, inv(1) 46, XY, inv(1)46, XX, inv(1)(q24q32)nPericentric: involving centromerePericentric: involving centromerenParacentric: not involving centromereParacentric: not involving centromerenUsually no abnormal phenotype Usually no abnorm

27、al phenotype nA inversion loop is formed between the pair A inversion loop is formed between the pair of chromosomes and may lead to produce of chromosomes and may lead to produce unbalanced gametes or offspring:unbalanced gametes or offspring:InversionsPericentric inversionThe products of meiosis1/

28、4：Normal1/4：Inversion1/2：Partial trisomy and partial monosomyA inversion loopParacentric inversionThe products of meiosis1/4：Normal1/4： Bicentric ch.1/4： Acentris frag.1/4：InversionA inversion loopnReciprocal Resulted from breakage of nonhomologous Resulted from breakage of nonhomologous chromosomes

29、, with reciprocal exchange of chromosomes, with reciprocal exchange of the broke-off segmentsthe broke-off segmentsTranslocationReciprocal Translocation (9;22)t(9;22)(q34;q12)t(9;22)(9pter-cen-9q34:22q21-22qter; 22pter-cen-22q21:9q34-9qter)Reciprocal translocation in meiosis2:2 separationHigh Risk t

30、o produce High Risk to produce unbalanced offspringunbalanced offspring2:2Abortion, Fetal death, Birth defects 1/18 Normal, 1/18 carrier，8/9 various kinds of unbalancedPossible offsprings of Reciprocal translocation Abortion, Fetal death, Birth defects Mother: 46, XX, t(11;22)(q24;q12)Normal phenoty

31、peSon: 47, XX, +der(22) t(11;22)(q24;q12)matMental retardation Multiple structural abnormalitiesUnbalanced derivated from reciprocal translocation of the parents45,XY,-22,der(6)t(6;22)(p25.3;q11.2)45,XY,-22,der(6)t(6;22)(6qter-cen-6p25.3:22q11.2-22qter)Robertsonian TranslocationnTwo acrocentric Two

32、acrocentric chromosomes fuse near chromosomes fuse near the centromere region the centromere region with loss of the short with loss of the short arms, which carry arms, which carry multiple copies of genes multiple copies of genes for rRNA.for rRNA.n Only 45 chromosomes with balanced karyotype Only

33、 45 chromosomes with balanced karyotype and phenotypeand phenotype 45, XX, rob t ( 13q14q)t(14q21q) 14 21Offspring of Rob. translocation Normal, Carrier, Tri 14, Mono14, Tri 21, Mono 21 Fertilized by normal gameteGametesZygotesMeoisisnLimitation of resolution of microscopy: Limitation of resolution

34、of microscopy: 4 Mb DNA 4 Mb DNAnDuplication or deletion 4 Mb DNA:Duplication or deletion 4 Mb DNA: Microdeletion Microdeletion Microduplication Microduplication nDiagnosis with Fluorescent in-situ Diagnosis with Fluorescent in-situ hybridization (FISH) with specific DNA hybridization (FISH) with sp

35、ecific DNA probe or cprobe or comparative genomic omparative genomic hybridization (CGH)hybridization (CGH)(3) Chromosomal micro-abnormality Parader-Willi Syndromes(PWS)nExcessive eating and Excessive eating and ObesityObesitynSmall hands, feet and Small hands, feet and short statureshort staturenHy

36、pogonadismHypogonadismnMental retardationMental retardationnUnusual facial Unusual facial appearance,appearance,nShort statureShort staturenSpasticity,SeizureSpasticity,SeizurenS mental retardationS mental retardationPWSAS46, XX or XY, del(15)(q11-q13)70% paternal70% maternalSimilar deletion, Differ

37、ent origin, Similar deletion, Different origin, Associated with gene imprintingAssociated with gene imprintingDiGeorge (velo-cardio-facial, 22q11.2 deletion) syndromeCongenital heart disease (particularly Congenital heart disease (particularly conotruncal malformations) conotruncal malformations) Pa

38、latal abnormalities especially Palatal abnormalities especially velopharyngeal insufficiency (VPI) velopharyngeal insufficiency (VPI) Hypocalcemia Hypocalcemia Immune deficiency Immune deficiency Learning difficultiesLearning difficulties46, XX, del( 22q11.2)Williams syndromenCharacteristic dysmorph

39、ic facies, Characteristic dysmorphic facies, frequently referred to as elfin facies frequently referred to as elfin facies (100%)(100%)nSupravalvular aortic stenosis (80%)Supravalvular aortic stenosis (80%)nVariable mental retardation (75%)Variable mental retardation (75%)nCharacteristic cognitive/b

40、ehavioral Characteristic cognitive/behavioral profile (90%)profile (90%)Williams syndromeDeletion of 7q11.23 or elastin gene 46, XY, del(7q11.23)Steroid Sulfatase Deficiency and X-Linked IchthyosisDeletion of Xp22.3 STS46, X, del(Xp22.3)nX-linked ichthyosis showing X-linked ichthyosis showing thick,

41、 large, polygonal, dark-thick, large, polygonal, dark-brown scales involving the brown scales involving the extensor.extensor.nSteroid sulfatase deficiency Steroid sulfatase deficiency during pregnancy in carrier during pregnancy in carrier females: Leads to an overall females: Leads to an overall d

42、ecrease in the levels of decrease in the levels of estrogenestrogenSteroid Sulfatase Deficiency and X-Linked IchthyosisKallmanns syndromeDeletion of Xp22.3 KALnCongenital reduced pituitary gonadotropic Congenital reduced pituitary gonadotropic activity with resulting association of activity with res

43、ulting association of hypogonadism, eunuchoidism and anosmia.hypogonadism, eunuchoidism and anosmia.46, Y, del(Xp22.3) Summary of Chromosome disorders Duplication or deletion of the certain Duplication or deletion of the certain chromosomes or the certain chromosomal chromosomes or the certain chrom

44、osomal segmentssegments Number or structure abnormality Number or structure abnormality 0.6 % in live birth and 50% in spontaneous 0.6 % in live birth and 50% in spontaneous abortions in first-trimester in microscopic abortions in first-trimester in microscopic observation observation Summary of Chr

45、omosome disordersnInvolving the changes of a groups of Involving the changes of a groups of genes: complicated symptom genes: complicated symptom nSyndrome: Featured by serious mental Syndrome: Featured by serious mental retardation, structural abnormality of retardation, structural abnormality of f

46、ace, body and multiple organsface, body and multiple organsHermaphroditismSex Differentiation nGenes, Chromosome nOvary and TesitisnHormone: female hormones, Male hormonesnMallerian duct: uterus, fallopian tubenWolffian duct: epididymis. glandula seminalis nExterior genitalianSocial, BrainSex Differ

47、entiation nTwo intact and normally functioning X chromosomes, in the absence of a Y chromosome lead to the formation of an ovarynFemale sex differentiation will occur in the presence of an ovary or streak gonads or if no gonad is present n8w: exterior genitalia in all fetus remains like femalesFemal

48、e sex differentiationnA Y chromosome or the presence of the testis-testis-determining factordetermining factor (SRY) will lead to testicular organogenesisnDifferentiation of the external genitalia along male lines depends on the action of testosterone and particularly dihydrotestosteroneMale sex dif

49、ferentiationSRY F m m 1. True Hermaphroditism nBoth ovarian and testicular tissue are present in one (ovotestis) or both gonads. nDifferentiation of the internal and external genitalia is highly variable, and most often they are ambiguous. nA testis and ovary or ovotestis is located in the A testis

50、and ovary or ovotestis is located in the the labioscrotal folds, inguinal canal or the the labioscrotal folds, inguinal canal or the abdomen in the remainder. abdomen in the remainder. nA uterus is usually present, hypoplastic or A uterus is usually present, hypoplastic or unicornuate. unicornuate.

51、nThe ovotestis is the most common gonad found The ovotestis is the most common gonad found in true hermaphrodites (60%), followed by the in true hermaphrodites (60%), followed by the ovary and, least commonly, ovary and, least commonly, 1.1 Phenotype: True hermaphrodites n20%: 46, XX/46, XY 20%: 46,

52、 XX/46, XY n20%: 46, XY : 20%: 46, XY : Y-to-X and Y-to-autosome translocations, hidden sex chromosome mosaicism, or chimerism can explain the pathogenesis in these patients. n60%: 46, XX60%: 46, XX1.2 Karyotype: True hermaphrodites Diagnosis depending on pathology !2. Female Pseudohermaphroditism n

53、Affected individuals have normal ovaries and mllerian derivatives associated with ambiguous external genitalia. nIn the absence of testes, a female fetus will be masculinized if subjected to increased circulating levels of androgens derived from a fetal or maternal source. nThe degree of masculiniza

54、tion depends upon the stage of differentiation at the time of exposure 2.1 Congenital Adrenal Hyperplasia nMost cases of female pseudohermaphroditism and around 50% of all cases of ambiguous genitalianDefect in the synthesis of cortisol that results in an increase in ACTH and consequently in adrenal

55、 hyperplasia nFive major types: AR single gene disorder. 2.2Maternal androgens & progestogens nMasculinization of the external genitalia of a female infant can occur if the mother is given testosterone, other androgenic steroids, or certain synthetic progestational agents during pregnancy. 3. Male PseudohermaphroditismnGonads are testes, but the genital ducts or external Gonads are testes, but the genital ducts or external genitalia, or both, are not completely masculinized.genitalia, or