Cytogenetics I Numerical chromosomal abnormalities RNDr Z.Polívková Lecture No 430 – course :...
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Transcript of Cytogenetics I Numerical chromosomal abnormalities RNDr Z.Polívková Lecture No 430 – course :...
![Page 1: Cytogenetics I Numerical chromosomal abnormalities RNDr Z.Polívková Lecture No 430 – course : Heredity.](https://reader033.fdocuments.net/reader033/viewer/2022042717/56649d355503460f94a0c816/html5/thumbnails/1.jpg)
Cytogenetics I
Numerical chromosomal abnormalitiesRNDr Z.Polívková
Lecture No 430 – course: Heredity
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Frequencies of chromosomal abnormalities (CHA)
30 % of all spontaneous abortion (SA) > 50% of early abortions 0.6% liveborn babies 5% of all recognised pregnancies
Estimate: > 50% of all human zygotes with CHA
Most of them are lost before recognition of pregnancy
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Occurence of CHA in:
stillbirth, neonathal death mentally retarded congenital malformations with/without
mental retardation disorders of sexual development dysfertile couples (with spontaneous abortions,
sterility…)
infertile males
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Review of chromosomal abnormalities
congenital
acquired
numerical
aneuploidy
polyploidy
trisomy 2n+1
monosomy 2n-1
triploidy 3n
tetraploidy 4n
structuralbalanced
unbalanced
Robertsonian translocationreciprocal translocation inversioninsertion
deletionduplicationring chromosomedicentric chromosomeisochromosome
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mosaic = 2 or more cell lines
origin from 1 zygote
chimaera = karyotype 46,XX/46,XY
2 cell lines - origin from 2 zygotes
Acquired CHA : chromatid and chromosome breaks, chromatid exchanges, chromosome exchanges: dicetrics, rings, translocations
caused by mutagens – clastogens
- mutagenesis - genotoxicology
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23
23
23
69
46 23
69
23 46
69
+
+
+
Dispermy
Diploid ovum + haploid sperm
Haploid ovum + diploid sperm
Partial mole (hyperplasia of trophoblast, reduced embryonal tissues)
Partial mole
Origin of triploidy
nonmolar product (small placenta)
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Triploidy – lethal genetic constitution
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46
92
Origin of tetraploidy
endoreduplication in mitotic division of zygote
Tetraploidy = lethal genetic constitution
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23,X
23,X
46,XX 46,XY
23,Y
23,X
Origin of chimaera
+
ovum
polar body
Fertilization of egg and polar body each by sperm with different gonosome
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Human partenogenesis
ovarial teratoma = duplication of chromosomes and division of unfertilized ovum (diploid)
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Hydatiforme mole (complete = without embryonal tissues) = dispermy or duplication of sperm in enucleated ovum
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Nondisjunction in meiosis
= failure of homologs (in M I) or sister chromatids (in M II) to disjoin to daughter cells
Consequence: disomic, nullisomic gametes -trisomy, monosomy after fertilization
Nondisjunction in mitosis= failure of chromatids to disjoin to daughter cells
Consequence: mosaics
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Meiotic nondisjunction
+ +
trisomic zygote 47,XXorXY,+21
MI
MII
in II.meiotic division in I.meiotic division
nullisomic gamete disomic gamete
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23,X 23,Y
46,XY
46,XY46,XY
47,XY,+21
45,XY -21
46,XY46,XY
47,XY,+21
46,XY46,XY46,XY46,XY 47,XY,+21
Mitotic nondisjunction – origin of mosaic
mosaic - 2 or more cell lines with different karyotypes– origin from 1 zygote
normal zygote
trisomic cell line
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47
47 47
2324
47 47 47
46 46 47 47 47 47 47 47
46
Origin of mosaic from trisomic zygote – by chromosomal loss during mitotic division
loss of chromosomeby anaphase lag
47,XXorXY,+21/46XXorXY
normal cell
trisomic zygote
normal cell line
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46,XX
46,XX 45,X
46,XX 45,X 45,X46,XX
loss of X chromosome during mitotic division of normal zygote
Origin of monosomy X - postzygotic
45,X/46,XX
monosomic cell line
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Numerical CHA – origin
Triploidy 3n – dispermy = fertilization of ovum by 2 sperms
- fusion of haploid and diploid gametes (nondisjunction of all chromosome in M I or MII)
Tetraploidy 4n – endoreduplication in mitotic division of zygote (= division of chromosomes without division of cell)
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Trisomy 2n+1 – nondisjunction of homologs in M I or chromatids in M II
and fertilization of disomic gamete
Mosaic trisomy – nondisjunction in mitotic division of normal zygote or loss of chromosome from trisomic zygote
mosaic – 2 (or more)cell lines with different karyotypes – origin from one cell during mitotic division of zygote
Monosomy – nondisjunction and fertilization of nullisomic gamete
- loss of one chromosome (lagging in anaphase)
– in meiosis,in mitosis
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Chimaera – 2 cell lines with different karyotypes – origin from 2 zygotes
fertilization of egg and polar body each by sperm with different gonosome
46,XX/46,XY
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monosomy X = only X monosomy is compatible with life but 99% of X monosomies are aborted autosomal monosomies –lethal – very early abortion or
failure of implantation
autosomal trisomies = only some are compatible with life (+21, +18, +13, mos +8)
other autosomal trisomies are only in abortions (+16….)
Consequences of chromosomal abnormalities
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nondisjunction: in oogenesis > in spermatogenesis
liveborn +21 - 80% mat : 20 pat
in M I > in M II
+21 mat - 80% in M I : 20 in M II
Parental origin of nondisjunction –detected by tracing of variants on acrocentrics or by molecular genetics methods
Nondisjunction - most frequently maternal
and in the 1st meiOtic division
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Causes of nondisjunction
Internal – individual risk of chromosomes to nondisjunction
main factor = age of mother > 35 let - age of father > 50 let
External – environmental factors –chemicals, radiation
are not main factors of nondisjunction
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Maternal age :
Error in M I : agging of ovum
failure in function of mitotic spindle
changes in intracellular condition caused
by hormonal insufficiency
accumulation of mutagenic events during life
Error in M II: delayed fertilization –
overripness of ovulated egg
agging of sperms
(low frequent sexual intercourses in older couples)
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M.Down (DS)- trisomy 21Frequeny in liveborn: 1/800
3/4 of DS are aborted
95% of DS = 47,XX or XY, +21= free trisomy
5% of DS = translocation form of trisomy
t(14/21, 13/21, 21/22, 21/21)
in 1/2 of cases with translocation form of trisomy -1 parent = carrier of balanced Robertsonian translocation !!!
empiric risk for carriers of balanced nonhomologous Robertsonian translocation = 15% for women carriers
< 2% for men carriers
Risk for carriers of balanced homologous Robertsonian translocation
21/21 = 100%
1% of DS – mosaic form of trisomy
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Risk of trisomy 21 and maternal age
Mother´s age risk +21 35 1/350 37 1/225 40 1/100 45 1/25
Reccurence risk (after previous pregnancy with free trisomy 21) 1% ??
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47,XX,+21 – free trisomy 21
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46,XX,der(14;21)(q10;q10),+21 translocation form of trisomy
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45,XX,der(14;21)(q10;q10) - balanced Robertsonian translocation
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Phenotype of DS
dysmorphic features of the face:
round face
flat nasal bridge
mongoloid slant of palpebral fissures big tongue short fingers, clinodactyly simian creases on hands short stature organ malformations mental retardation
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Down syndrome
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Simian crease in DS
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Downův syndrome
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Edwards syndrome (ES) - trisomy 18
frequency: 1/5000 of liveborn
karyotype: 47,XX or XY,+18
Clinical signs:• dysmorphic features of face• low set malformed ears• prominent occiput• short sternum• abnormal overlapping of fingers• severe malformations of heart or other organs• severe retardation of development
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47,XX +18
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Edwards syndrome
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Overlapping of fingers in ES
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Patau syndrome
frequency: 1/10000 of liveborn karyotype: 47,XX or XY,+13 20% translocation form - t 13/13, t 13/14
Clinical signs: - dysmorfic features (hypertelorismus, microphthalmia)
- microcephaly
- polydactyly- cleft lip and palate- severe organ malformations (heart defect, malf.CNS)- severe retardation of development
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47,XX +13
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Patau syndrome (PS)
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Polydactyly in PS
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Turner syndrome
Frequency: 1/5000 liveborn girls
99% of monosomy X - abortions karyotypes: 45,X 53% 45,X/46,XX 15% 46,X,i(Xq) 10% 45,X/46,X,i(Xq) 8% 46,XXq- nebo p- 6% others (with Y chrom., dic X...) 8%
45,X - in 77% of monosomies X - paternal gonosome is lost (X or Y)
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45,X
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Clinical signs of TS small stature sterility (degeneration of gonads) - except i(Xq), Xp- underdevelopment of secondary sexual characteristics amenorrhea neck webbing, low hair line (posterior) mostly normal inteligency
in newborns often edema on foot dorsum !!!
(lymphedema in fetal life – cystic hygroma) Xp- phenotype of TS, but fertility
Xq- gonadal dysgenesis
Karyotype with Y chromosome = risk of malignity of gonade
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Turner syndrome (TS)
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Klinefelter syndrome
frequency: 1/1000 liveborn boys
karyotypes: 47,XXY 46,XY/47,XXY 48,XXYYor 48,XXXY 49,XXXXY – phenotype similar to DS
but patients are tall 1/3 of cases-nondisjunction in paternal M I 47% nondisjunction in maternal M I –
efect of mother´s age 22% nondisjunction in maternal M II
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Clinical signs in KS
sterility hypogonadism – atrophy of testes gynecomastia – secondary sexual characteristics of female
type (is not constant feature) tall stature inteligence may be slightly reduced or normal
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47,XXY
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Klinefelter syndrome
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Syndrome 47,XXX frequency: 1/1000 of women
phenotype normal, only in some patients psychiatric problems
fertile – mostly chromosomally normal progeny
Syndrome 47,XYYfrequency : 1/1000 of men
phenotype normal, tall stature
supposed connection with agresivity was not proved
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47,XXX
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47,XYY
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http://dl1.cuni.cz/course/view.php?id=324 presentation
http://dl1.cuni.cz/course/view.php?id=324 supplementary text to cytogenetics
Thompson &Thompson: Genetics in medicine, 7th ed. Chapter 5: Principles of clinical cytogeneticsChapter 6: Clinical cytogenetics: Disorders of the autosomes and the sex chromosomes